1 Biochemistry

HIGH-YIELD PRINCIPLES IN
Biochemistry
“Biochemistry is the study of carbon compounds that crawl.” ``Molecular 34

—Mike Adams
``Cellular 46
“We think we have found the basic mechanism by which life comes from
life.” ``Laboratory Techniques 52
—Francis H. C. Crick
``Genetics 56
“The biochemistry and biophysics are the notes required for life; they
conspire, collectively, to generate the real unit of life, the organism.” ``Nutrition 65
—Ursula Goodenough
``Metabolism 72
This high-yield material includes molecular biology, genetics, cell

biology, and principles of metabolism (especially vitamins, cofactors,
minerals, and single-enzyme-deficiency diseases). When studying
metabolic pathways, emphasize important regulatory steps and enzyme
deficiencies that result in disease, as well as reactions targeted by
pharmacologic interventions. For example, understanding the defect
in Lesch-Nyhan syndrome and its clinical consequences is higher yield
than memorizing every intermediate in the purine salvage pathway.
Do not spend time on hard-core organic chemistry, mechanisms, or
physical chemistry. Detailed chemical structures are infrequently tested;
however, many structures have been included here to help students
learn reactions and the important enzymes involved. Familiarity with
the biochemical techniques that have medical relevance—such as
ELISA, immunoelectrophoresis, Southern blotting, and PCR—is
useful. Review the related biochemistry when studying pharmacology or
genetic diseases as a way to reinforce and integrate the material.
33
FAS1_2018_01-Biochem_27-92_Indexed.indd 33 10/10/17 10:38 AM

34 SEC TION II Biochemistry 
B IOCHEMISTRY—Molecular
BIOCHEMISTRY—MOLECULAR
``
Chromatin structure DNA exists in the condensed, chromatin form to

fit into the nucleus. DNA loops twice around a
histone octamer to form a nucleosome (“beads
DNA double-helix on a string”). H1 binds to the nucleosome
and to “linker DNA,” thereby stabilizing the
chromatin fiber.
H1 histone Phosphate groups give DNA a ⊝ charge. Lysine
(linker)
DNA and arginine give histones a ⊕ charge.
In mitosis, DNA condenses to form
chromosomes. DNA and histone synthesis
Nucleosome Euchromatin Supercoiled occurs during S phase.
(H2A, H2B, structure Mitochondria have their own DNA, which is
H3, H4) 2 Heterochromatin circular and does not utilize histones.
Metaphase
chromosome
Heterochromatin Condensed, appears darker on EM (labeled HeteroChromatin = Highly Condensed.

A
H in A ; Nu, nucleolus). Transcriptionally Barr bodies (inactive X chromosomes) may be
E inactive, sterically inaccessible. methylation, visible on the periphery of nucleus.
H acetylation.
Nu
Euchromatin Less condensed, appears lighter on EM (labeled Eu = true, “truly transcribed.”

E in A ). Transcriptionally active, sterically Euchromatin is Expressed.
accessible.
DNA methylation Changes the expression of a DNA segment DNA is methylated in imprinting.
without changing the sequence. Involved Methylation within gene promoter (CpG islands)
with genomic imprinting, X-chromosome typically represses gene transcription.
inactivation, repression of transposable CpG Methylation Makes DNA Mute.
elements, aging, and carcinogenesis.
Histone methylation Usually causes reversible transcriptional Histone Methylation Mostly Makes DNA Mute.
suppression, but can also cause activation
depending on location of methyl groups.
Histone acetylation Relaxes DNA coiling, allowing for transcription. Histone Acetylation makes DNA Active.

Biochemistry 
B IOCHEMISTRY—Molecular SEC TION II 35
Nucleotides NucleoSide = base + (deoxy)ribose (Sugar).

NucleoTide = base + (deoxy)ribose + phosphaTe; 5′ end of incoming nucleotide bears the
linked by 3′-5′ phosphodiester bond. triphosphate (energy source for the bond).
Triphosphate bond is target of 3′ hydroxyl
attack.
PURines (A,G)—2 rings. PURe As Gold.
PYrimidines (C,U,T)—1 ring. CUT the PY (pie).
Thymine has a methyl.
Deamination of cytosine forms uracil. G-C bond (3 H bonds) stronger than A-T bond
Deamination of adenine forms hypoxanthine. (2 H bonds). G-C content melting
Deamination of guanine forms xanthine. temperature of DNA. “C-G bonds are like
Deamination of 5-methylcytosine forms Crazy Glue.”
thymine.
Uracil found in RNA; thymine in DNA. Amino acids necessary for purine synthesis (Cats
Methylation of uracil makes thymine. purr until they GAG):
Glycine
Purine (A, G) Pyrimidine (C, U, T)
Aspartate
CO2
Carbamoyl Aspartate Glutamine
Aspartate Glycine phosphate
C N C
N C N C
C N10–Formyl-
C C tetrahydrofolate C C
N N N
N10–Formyl-
Glutamine
tetrahydrofolate

De novo pyrimidine Various immunosuppressive, antineoplastic, and antibiotic drugs function by interfering with
and purine synthesis nucleotide synthesis:
Pyrimidine base production Purine base production or Pyrimidine synthesis:
(requires aspartate) Ribose 5-P reuse from salvage pathway Leflunomide: inhibits dihydroorotate
(de novo requires aspartate, dehydrogenase
Glutamine + CO2 glycine, glutamine, and THF)
2 ATP
Methotrexate (MTX), trimethoprim (TMP),
CPS2 (carbamoyl
phosphate and pyrimethamine: inhibit dihydrofolate
2 ADP + Pi + synthetase II) PRPP (phosphoribosyl
Glutamate pyrophosphate) synthetase reductase ( deoxythymidine monophosphate
[dTMP]) in humans, bacteria, and protozoa,
Carbamoyl respectively
phosphate
Aspartate 5-fluorouracil (5-FU) and its prodrug
Leflunomide
6-MP capecitabine: form 5-F-dUMP, which inhibits
PRPP
Orotic thymidylate synthase ( dTMP)
acid
Purine synthesis:
Impaired in UMP Mycophenolate, 6-mercaptopurine (6-MP) and its prodrug
orotic aciduria IMP ribavirin
UDP azathioprine: inhibit de novo purine synthesis
ctas ide
reduucleot
Hydroxyurea AMP GMP Mycophenolate and ribavirin: inhibit inosine

e
n
monophosphate dehydrogenase
Ribo
dUDP CTP
Purine and pyrimidine synthesis:
Hydroxyurea: inhibits ribonucleotide
N5N10- dUMP
reductase
Thymidylate
methylene THF
synthase
5-FU
THF
Dihydrofolate
DHF CPS1 = m1tochondria (urea cycle)
reductase dTMP CPS2 = cyTWOsol
MTX, TMP,
pyrimethamine

Biochemistry 
Purine salvage deficiencies
Nucleic acids Ribose-5-phosphate Nucleic acids

PRPP synthetase De novo synthesis
Nucleotides GMP IMP AMP
ADA APRT
Nucleosides Guanosine HGPRT Inosine Adenosine
PRPP
Free bases Guanine PRPP Hypoxanthine Adenine
XO
– Allopurinol
Xanthine Febuxostat
– Degradation and salvage
XO
Uric acid
Probenecid
Aspirin – Rasburicase
Urine Excretion
ADA, adenosine deaminase; APRT, adenine phosphoribosyltransferase;

HGPRT, hypoxanthine guanine phosphoribosyltransferase; XO, xanthine oxidase.
Adenosine deaminase ADA is required for degradation of adenosine One of the major causes of autosomal recessive
deficiency and deoxyadenosine. In ADA deficiency, SCID.
dATP lymphotoxicity.
Lesch-Nyhan Defective purine salvage due to absent HGPRT, HGPRT:
syndrome which converts hypoxanthine to IMP and Hyperuricemia
guanine to GMP. Results in excess uric acid Gout
production and de novo purine synthesis. Pissed off (aggression, self-mutilation)
X-linked recessive. Retardation (intellectual disability)
Findings: intellectual disability, self-mutilation, DysTonia
aggression, hyperuricemia (orange “sand”
[sodium urate crystals] in diaper), gout,
dystonia.
Treatment: allopurinol or febuxostat (2nd line).
Genetic code features

Unambiguous Each codon specifies only 1 amino acid.
Degenerate/ Most amino acids are coded by multiple codons. Exceptions: methionine (AUG) and tryptophan
redundant Wobble—codons that differ in 3rd, “wobble” (UGG) encoded by only 1 codon.
position may code for the same tRNA/amino
acid. Specific base pairing is usually required
only in the first 2 nucleotide positions of
mRNA codon.
Commaless, Read from a fixed starting point as a continuous Exceptions: some viruses.
nonoverlapping sequence of bases.
Universal Genetic code is conserved throughout Exception in humans: mitochondria.
evolution.

DNA replication Eukaryotic DNA replication is more complex than the prokaryotic process but uses many
enzymes analogous to those listed below. In both prokaryotes and eukaryotes, DNA replication is
semiconservative, involves both continuous and discontinuous (Okazaki fragment) synthesis, and
occurs in the 5′ 3′ direction.
Origin of Particular consensus sequence of base pairs AT-rich sequences (such as TATA box regions)
replication A in genome where DNA replication begins. are found in promoters and origins of
May be single (prokaryotes) or multiple replication.
(eukaryotes).
Replication fork B Y-shaped region along DNA template where
leading and lagging strands are synthesized.
Helicase C Unwinds DNA template at replication fork. Helicase Halves DNA.
Single-stranded Prevent strands from reannealing.
binding proteins D
DNA Create a single- or double-stranded break in the In eukaryotes: irinotecan/topotecan inhibit
topoisomerases E helix to add or remove supercoils. topoisomerase (TOP) I, etoposide/teniposide
inhibit TOP II.
In prokaryotes: fluoroquinolones inhibit TOP II
(DNA gyrase) and TOP IV.
Primase F Makes an RNA primer on which DNA
polymerase III can initiate replication.
DNA polymerase III G Prokaryotes only. Elongates leading strand DNA polymerase III has 5′ 3′ synthesis and
by adding deoxynucleotides to the 3′ end. proofreads with 3′ 5′ exonuclease.
Elongates lagging strand until it reaches Drugs blocking DNA replication often have a
primer of preceding fragment. 3′ 5′ modified 3′ OH, thereby preventing addition of
exonuclease activity “proofreads” each added the next nucleotide (“chain termination”).
nucleotide.
DNA polymerase I H Prokaryotic only. Degrades RNA primer; Same functions as DNA polymerase III, also
replaces it with DNA. excises RNA primer with 5′ 3′ exonuclease.
DNA ligase I Catalyzes the formation of a phosphodiester Joins Okazaki fragments.
bond within a strand of double-stranded DNA. Ligase Links DNA.
Telomerase Eukaryotes only. A reverse transcriptase (RNA- Often dysregulated in cancer cells, allowing
dependent DNA polymerase) that adds DNA unlimited replication.
(TTAGGG) to 3′ ends of chromosomes to avoid Telomerase TAGs for Greatness and Glory.
loss of genetic material with every duplication.
G 3'
E
DNA polymerase III 5'
Topoisomerase
C A
Helicase Origin of replication
Leading strand
B
Replication fork Lagging strand 3'
Okazaki fragment 5'
D
A
Area of interest Single-stranded RNA primer
Origin of replication binding protein
Leading strand Lagging strand I
F DNA ligase
Fork Fork Primase
movement movement
G
DNA polymerase III H
Lagging strand Leading strand
DNA polymerase I

Biochemistry 
Mutations in DNA Severity of damage: silent << missense < nonsense < frameshift.
For point (silent, missense, and nonsense) mutations:
Transition—purine to purine (eg, A to G) or pyrimidine to pyrimidine (eg, C to T).
Transversion—purine to pyrimidine (eg, A to T) or pyrimidine to purine (eg, C to G).
Silent Nucleotide substitution but codes for same
(synonymous) amino acid; often base change
in 3rd position of codon (tRNA wobble).
Missense Nucleotide substitution resulting in changed Sickle cell disease (substitution of glutamic acid
amino acid (called conservative if new amino with valine).
acid is similar in chemical structure).
Nonsense Nucleotide substitution resulting in early stop Stop the nonsense!
codon (UAG, UAA, UGA). Usually results in
nonfunctional protein.
Frameshift Deletion or insertion of a number of nucleotides Duchenne muscular dystrophy, Tay-Sachs
not divisible by 3, resulting in misreading of disease.
all nucleotides downstream. Protein may be
shorter or longer, and its function may be
disrupted or altered.
Splice site Mutation at a splice site retained intron in Rare cause of cancers, dementia, epilepsy, some
the mRNA protein with impaired or altered types of β-thalassemia.
function.
Lac operon Classic example of a genetic response to an environmental change. Glucose is the preferred
metabolic substrate in E coli, but when glucose is absent and lactose is available, the lac operon is
activated to switch to lactose metabolism. Mechanism of shift:
Low glucose adenylate cyclase activity generation of cAMP from ATP activation of
catabolite activator protein (CAP) transcription.
High lactose unbinds repressor protein from repressor/operator site transcription.
Genes
CAP
Adenylate Lacl site P O LacZ LacY LacA
CAP cAMP cyclase Glucose DNA 5′ 3′
AUG AUG AUG

Messenger RNA
Binds CAP site, ATP
induces transcription
RNA
Lac operon STATE CAP polymerase
Low glucose
Lactose available
Lac genes strongly expressed
Lacl CAP site Promoter Operator LacZ LacY LacA Repressor protein
High glucose
o r, Lactose unavailable
e ra t o n Lac genes not expressed
Binds opnscripti
blocks tra
Low glucose
Repressor Lactose unavailable Lac genes not expressed
protein CAP
High glucose
site P O
Lactose available Very low (basal) expression
Allolactose Inactivated
(inducer) repressor

DNA repair
Single strand
Nucleotide excision Specific endonucleases release the Defective in xeroderma pigmentosum (inability
repair oligonucleotides containing damaged bases; to repair DNA pyrimidine dimers caused by
DNA polymerase and ligase fill and reseal the UV exposure).
gap, respectively. Repairs bulky helix-distorting Findings: dry skin, extreme light sensitivity, skin
lesions. Occurs in G1 phase of cell cycle. cancer.
Base excision repair Base-specific Glycosylase removes altered base Important in repair of spontaneous/toxic
and creates AP site (apurinic/apyrimidinic). deamination.
One or more nucleotides are removed by “GEL PLease”
AP-Endonuclease, which cleaves the 5′ end.
Lyase cleaves the 3′ end. DNA Polymerase-β
fills the gap and DNA Ligase seals it. Occurs
throughout cell cycle.
Mismatch repair Newly synthesized strand is recognized, Defective in Lynch syndrome (hereditary
mismatched nucleotides are removed, nonpolyposis colorectal cancer [HNPCC]).
and the gap is filled and resealed. Occurs
predominantly in S phase of cell cycle.
Double strand
Nonhomologous end Brings together 2 ends of DNA fragments to Defective in ataxia telangiectasia and Fanconi
joining repair double-stranded breaks. No requirement anemia.
for homology. Some DNA may be lost.
Homologous Requires two homologous DNA duplexes. A Defective in breast/ovarian cancers with BRCA1
recombination strand from the damaged dsDNA is repaired mutation.
using a complementary strand from the intact
homologous dsDNA as a template. Restores
duplexes accurately without loss of nucleotides.
Start and stop codons

mRNA start codons AUG (or rarely GUG). AUG inAUGurates protein synthesis.
Eukaryotes Codes for methionine, which may be removed
before translation is completed.
Prokaryotes Codes for N-formylmethionine (fMet). fMet stimulates neutrophil chemotaxis.
mRNA stop codons UGA, UAA, UAG. UGA = U Go Away.
UAA = U Are Away.
UAG = U Are Gone.

Biochemistry 
Functional Transcription start

(mRNA synthesized 5′ 3′)
organization of a
Polyadenylation
eukaryotic gene ATG = Start codon
CAAT box TATA box signal
DNA coding strand 5′ CAAT TATAAT Exon 1 GT AG Exon 2 GT AG Exon 3 AATAAA 3′
Promoter 5′ UTR Intron 1 Intron 2 3′ UTR
Regulation of gene expression

Promoter Site where RNA polymerase II and multiple Promoter mutation commonly results in
other transcription factors bind to DNA dramatic in level of gene transcription.
upstream from gene locus (AT-rich upstream
sequence with TATA and CAAT boxes).
Enhancer DNA locus where regulatory proteins Enhancers and silencers may be located close to,
(“activators”) bind increasing expression of far from, or even within (in an intron) the gene
a gene on the same chromosome. whose expression it regulates.
Silencer DNA locus where regulatory proteins
(“repressors”) bind decreasing expression of
a gene on the same chromosome.
RNA polymerases
Eukaryotes RNA polymerase I makes rRNA, the most I, II, and III are numbered in the same order
common (rampant) type; present only in that their products are used in protein
nucleolus. synthesis: rRNA, mRNA, then tRNA.
RNA polymerase II makes mRNA (largest RNA, α-amanitin, found in Amanita phalloides (death
massive). mRNA is read 5′ to 3′. cap mushrooms), inhibits RNA polymerase II.
RNA polymerase III makes 5S rRNA, tRNA Causes severe hepatotoxicity if ingested.
(smallest RNA, tiny). Actinomycin D inhibits RNA polymerase in
No proofreading function, but can initiate both prokaryotes and eukaryotes.
chains. RNA polymerase II opens DNA at
promoter site.
Prokaryotes 1 RNA polymerase (multisubunit complex) Rifampin inhibits DNA-dependent RNA
makes all 3 kinds of RNA. polymerase in prokaryotes.
RNA processing Initial transcript is called heterogeneous nuclear mRNA is transported out of the nucleus into the
(eukaryotes) RNA (hnRNA). hnRNA is then modified and cytosol, where it is translated.
becomes mRNA. mRNA quality control occurs at cytoplasmic
The following processes occur in the nucleus: processing bodies (P-bodies), which contain
Cap Coding
5'
Capping of 5′ end (addition of exonucleases, decapping enzymes, and
Gppp 7-methylguanosine cap) microRNAs; mRNAs may be degraded or
3' Polyadenylation of 3′ end (≈ 200 A’s) stored in P-bodies for future translation.
HO-AAAAA
Tail
Splicing out of introns Poly-A polymerase does not require a template.
Capped, tailed, and spliced transcript is called AAUAAA = polyadenylation signal.
mRNA.

Splicing of pre-mRNA
Primary transcript combines with 5′ splice site U1 snRNP Branch point U2 snRNP 3′ splice site
small nuclear ribonucleoproteins
(snRNPs) and other proteins to
form spliceosome. 5′ O P GU A AG P O 3′
Exon 1 Intron Exon 2
Spliceosome
Cleavage at 5′ splice site; lariat-

shaped (loop) intermediate is
generated. UG
P A
OH 3′ AG P O
Exon 1 Exon 2
Cleavage at 3′ splice site; lariat

is released to precisely remove
intron and join 2 exons.
P +
Exon 1 Exon 2 UG
P A
AG OH 3′

Biochemistry 
Introns vs exons Exons contain the actual genetic information Introns are intervening sequences and stay
coding for protein. in the nucleus, whereas exons exit and are
Introns are intervening noncoding segments of expressed.
DNA. Variants in which splicing occurs abnormally are
Different exons are frequently combined by implicated in oncogenesis and many genetic
alternative splicing to produce a larger number disorders (eg, β-thalassemia, Gaucher disease,
of unique proteins. Tay-Sachs disease, Marfan syndrome).
Alternative splicing can produce a variety
of protein products from a single hnRNA
sequence (eg, transmembrane vs secreted Ig,
tropomyosin variants in muscle, dopamine
receptors in the brain).
Exon 1 Exon 2 Exon 3 Exon 4 Exon 5 Exon 6
5′ 3′
DNA 3′ 5′
Transcription
hnRNA 5′ 3′
1 2 3 4 5 6
Splicing Alternative splicing
mRNA 5′ 3′ 5′ 3′ 5′ 3′
1 2 4 5 6 1 3 5 6 1 3 4 5 6
Translation
1 5 1 5 1 5
Proteins 6 6 6
4 4
2 3 3
microRNAs MicroRNAs (miRNAs ) are small, conserved, noncoding RNA molecules that posttranscriptionally
regulate gene expression by targeting the 3′ untranslated region of specific mRNAs for
degradation or translational repression. Abnormal expression of miRNAs contributes to certain
malignancies (eg, by silencing an mRNA from a tumor suppressor gene).

tRNA
Structure 75–90 nucleotides, 2º structure, cloverleaf form, anticodon end is opposite 3′ aminoacyl end. All
tRNAs, both eukaryotic and prokaryotic, have CCA at 3′ end along with a high percentage of
chemically modified bases. The amino acid is covalently bound to the 3′ end of the tRNA. CCA
Can Carry Amino acids.
T-arm: contains the TΨC (ribothymidine, pseudouridine, cytidine) sequence necessary for tRNA-
ribosome binding. T-arm Tethers tRNA molecule to ribosome.
D-arm: contains dihydrouridine residues necessary for tRNA recognition by the correct aminoacyl-
tRNA synthetase. D-arm Detects the tRNA by aminoacyl-tRNA synthetase.
Acceptor stem: the 5′-CCA-3′ is the amino acid acceptor site.
Charging Aminoacyl-tRNA synthetase (1 per amino acid; “matchmaker”; uses ATP) scrutinizes amino acid
before and after it binds to tRNA. If incorrect, bond is hydrolyzed. The amino acid-tRNA bond
has energy for formation of peptide bond. A mischarged tRNA reads usual codon but inserts
wrong amino acid.
Aminoacyl-tRNA synthetase and binding of charged tRNA to the codon are responsible for
accuracy of amino acid selection.
Structure Charging Pairing
(aminoacylation) (codon-anticodon)
Amino acid Amino acid
O O
Acceptor stem OH 3´ 3´ 3´
A A A
C C C
C C C
5´ 5´ 5´
IF2
T-arm
D-arm ATP AMP + PPi (initiation factor)
D D D
C Ψ T
Aminoacyl-tRNA C Ψ T C Ψ T
D D D
synthetase
Variable arm
Anticodon
loop U A C U A C Anticodon (5´ CAU 3´) U A C
Wobble
position C C C A U G A U A C
mRNA
Codon
(5´ AUG 3´)

Biochemistry 
Protein synthesis
Initiation Eukaryotic initiation factors (eIFs) identify Eukaryotes: 40S + 60S 80S (Even).
either the 5′ cap or an internal ribosome entry PrOkaryotes: 30S + 50S 70S (Odd).
site (IRES). IRES can be located at many Synthesis occurs from N-terminus to
places in an mRNA (most often 5′ UTR). The C-terminus.
eIFs then help assemble the 40S ribosomal
ATP—tRNA Activation (charging).
subunit with the initiator tRNA and are
GTP—tRNA Gripping and Going places
released when the mRNA and the ribosomal
(translocation).
60S subunit assemble with the complex.
Requires GTP. Think of “going APE”:
Elongation 1. Aminoacyl-tRNA binds to A site (except for A site = incoming Aminoacyl-tRNA.
initiator methionine), requires an elongation P site = accommodates growing Peptide.
factor and GTP E site = holds Empty tRNA as it Exits.
2. rRNA (“ribozyme”) catalyzes peptide bond
Eukaryotic
formation, transfers growing polypeptide to ribosome 60S
amino acid in A site 3´
AC G U
3. Ribosome advances 3 nucleotides toward 3′ A G
G
P
end of mRNA, moving peptidyl tRNA to P 5´
A
E
G
A
site (translocation) U
C G
A
G U
G C
Termination Release factor recognizes stop codon and U G
U U U
halts translation completed polypeptide is 40S

released from ribosome. Requires GTP.
Posttranslational modifications
Trimming Removal of N- or C-terminal propeptides from zymogen to generate mature protein (eg,
trypsinogen to trypsin).
Covalent alterations Phosphorylation, glycosylation, hydroxylation, methylation, acetylation, and ubiquitination.
Chaperone protein Intracellular protein involved in facilitating and/or maintaining protein folding. For example,
in yeast, heat shock proteins (eg, HSP60) are expressed at high temperatures to prevent protein
denaturing/misfolding.

B IOCHEMISTRY—Cellular
BIOCHEMISTRY—CELLULAR
``
Cell cycle phases Checkpoints control transitions between phases of cell cycle. This process is regulated by cyclins,
cyclin-dependent kinases (CDKs), and tumor suppressors. M phase (shortest phase of cell cycle)
includes mitosis (prophase, prometaphase, metaphase, anaphase, telophase) and cytokinesis
(cytoplasm splits in two). G1 and G0 are of variable duration.
REGULATION OF CELL CYCLE
Cyclin-dependent Constitutive and inactive.
kinases
Cyclins Regulatory proteins that control cell cycle G2 M
Mit
osi
events; phase specific; activate CDKs. s
s
esi
Cyclin-CDK complexes Phosphorylate other proteins to coordinate o kin
Cy t
cell cycle progression; must be activated and
inactivated at appropriate times for cell cycle
to progress. GO
DNA
IN
ER
th
T
Tumor suppressors p53 induces p21, which inhibits CDKs PH
Sy
w
he ASE G1
ro
nt
sis G
hypophosphorylation (activation) of Rb
inhibition of G1-S progression. Mutations S
in tumor suppressor genes can result in

Rb, p53 modulate
unrestrained cell division (eg, Li-Fraumeni G1 restriction point
syndrome).
Growth factors (eg, insulin, PDGF, EPO, EGF)
bind tyrosine kinase receptors to transition the
cell from G1 to S phase.
CELL TYPES
Permanent Remain in G0, regenerate from stem cells. Neurons, skeletal and cardiac muscle, RBCs.
Stable (quiescent) Enter G1 from G0 when stimulated. Hepatocytes, lymphocytes, PCT, periosteal cells.
Labile Never go to G0, divide rapidly with a short G1. Bone marrow, gut epithelium, skin, hair follicles,
Most affected by chemotherapy. germ cells.
Rough endoplasmic Site of synthesis of secretory (exported) proteins Mucus-secreting goblet cells of the small
reticulum and of N-linked oligosaccharide addition to intestine and antibody-secreting plasma cells
many proteins. are rich in RER.
Nissl bodies (RER in neurons)—synthesize
peptide neurotransmitters for secretion.
Free ribosomes—unattached to any membrane;
site of synthesis of cytosolic and organellar
proteins.
Smooth endoplasmic Site of steroid synthesis and detoxification of Liver hepatocytes and steroid hormone–
reticulum drugs and poisons. Lacks surface ribosomes. producing cells of the adrenal cortex and
gonads are rich in SER.

Biochemistry 
B IOCHEMISTRY—Cellular SEC TION II 47
Cell trafficking Golgi is the distribution center for proteins and lipids from the ER to the vesicles and plasma
membrane. Modifies N-oligosaccharides on asparagine. Adds O-oligosaccharides on serine and
threonine. Adds mannose-6-phosphate to proteins for trafficking to lysosomes.
Endosomes are sorting centers for material from outside the cell or from the Golgi, sending it to
lysosomes for destruction or back to the membrane/Golgi for further use.
I-cell disease (inclusion cell disease/mucolipidosis type II)—inherited lysosomal storage disorder;
defect in N-acetylglucosaminyl-1-phosphotransferase failure of the Golgi to phosphorylate
mannose residues ( mannose-6-phosphate) on glycoproteins proteins are secreted
extracellularly rather than delivered to lysosomes. Results in coarse facial features, gingival
hyperplasia, clouded corneas, restricted joint movements, claw hand deformities, kyphoscoliosis,
and high plasma levels of lysosomal enzymes. Often fatal in childhood.
Key: Signal recognition particle (SRP)
ne Abundant, cytosolic ribonucleoprotein that
mbra
Clathrin sm a me traffics proteins from the ribosome to
Pla
Secretory the RER. Absent or dysfunctional SRP
vesicle
COPI Late Early proteins accumulate in the cytosol.
endosome endosome
COPII Vesicular trafficking proteins

Lysosome COPI: Golgi Golgi (retrograde); cis-Golgi
Retrograde trans ER.
Anterograde COPII: ER cis-Golgi (anterograde).
Golgi “Two (COPII) steps forward (anterograde); one
apparatus (COPI) step back (retrograde).”
Clathrin: trans-Golgi lysosomes; plasma
membrane endosomes (receptor-
cis
mediated endocytosis [eg, LDL receptor
activity]).
Endoplasmic
reticulum
Nuclear envelope
Peroxisome Membrane-enclosed organelle involved in:

β-oxidation of very-long-chain fatty acids (VLCFA)
α-oxidation (strictly peroxisomal process)
Catabolism of branched-chain fatty acids, amino acids, and ethanol
Synthesis of cholesterol, bile acids, and plasmalogens (important membrane phospholipid,
especially in white matter of brain)
Zellweger syndrome—autosomal recessive disorder of peroxisome biogenesis due to mutated PEX
genes. Hypotonia, seizures, hepatomegaly, early death.
Refsum disease—autosomal recessive disorder of α-oxidation → phytanic acid not metabolized
to pristanic acid. Scaly skin, ataxia, cataracts/night blindness, shortening of 4th toe, epiphyseal
dysplasia. Treatment: diet, plasmapheresis.
Adrenoleukodystrophy—X-linked recessive disorder of β-oxidation → VLCFA buildup in adrenal
glands, white (leuko) matter of brain, testes. Progressive disease that can lead to adrenal gland
crisis, coma, and death.

Proteasome Barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins. Defects in the
ubiquitin-proteasome system have been implicated in some cases of Parkinson disease.
Cytoskeletal elements A network of protein fibers within the cytoplasm that supports cell structure, cell and organelle
movement, and cell division.
TYPE OF FILAMENT PREDOMINANT FUNCTION EXAMPLES
Microfilaments Muscle contraction, cytokinesis Actin, microvilli.
Intermediate Maintain cell structure Vimentin, desmin, cytokeratin, lamins, glial
filaments fibrillary acidic protein (GFAP), neurofilaments.
Microtubules Movement, cell division Cilia, flagella, mitotic spindle, axonal trafficking,
centrioles.
Microtubule Cylindrical outer structure composed of a Drugs that act on microtubules (Microtubules
Positive
helical array of polymerized heterodimers Get Constructed Very Poorly):
end (+) of α- and β-tubulin. Each dimer has 2 GTP Mebendazole (antihelminthic)
Heterodimer bound. Incorporated into flagella, cilia, mitotic Griseofulvin (antifungal)
spindles. Grows slowly, collapses quickly. Colchicine (antigout)
Also involved in slow axoplasmic transport in Vincristine/Vinblastine (anticancer)
neurons. Paclitaxel (anticancer)
Molecular motor proteins—transport cellular
Protofilament cargo toward opposite ends of microtubule
tracks.
Negative Dynein—retrograde to microtubule (+ −). Negative end Near Nucleus
end (–) Kinesin—anterograde to microtubule (− +). Positive end Points to Periphery

Biochemistry 
Cilia structure 9 doublet + 2 singlet arrangement of Kartagener syndrome (1° ciliary dyskinesia)—
microtubules A . immotile cilia due to a dynein arm defect.
Basal body (base of cilium below cell Autosomal recessive. Results in male and
membrane) consists of 9 microtubule female fertility due to immotile sperm and
triplets B with no central microtubules. dysfunctional fallopian tube cilia, respectively;
Axonemal dynein—ATPase that links peripheral risk of ectopic pregnancy. Can cause
9 doublets and causes bending of cilium by bronchiectasis, recurrent sinusitis, chronic
differential sliding of doublets. ear infections, conductive hearing loss, and
Gap junctions enable coordinated ciliary situs inversus (eg, dextrocardia on CXR C ).
movement. (Kartagener’s restaurant: take-out only, there’s
no dynein “dine-in”).
A B C
R L
Sodium-potassium Na+-K+ ATPase is located in the plasma Pumpkin = pump K+ in.

pump membrane with ATP site on cytosolic side. Ouabain (a cardiac glycoside) inhibits by
For each ATP consumed, 3Na+ go out of the binding to K+ site.
cell (pump phosphorylated) and 2K+ come into Cardiac glycosides (digoxin and digitoxin)
the cell (pump dephosphorylated). directly inhibit the Na+-K+ ATPase, which
Plasma membrane is an asymmetric lipid leads to indirect inhibition of Na+/Ca2+
bilayer containing cholesterol, phospholipids, exchange [Ca2+]i cardiac contractility.
sphingolipids, glycolipids, and proteins.
Extracellular
3Na+ 2K+
space
Plasma
membrane
P
Cytosol 2K+
3Na+ ATP ADP P

Collagen Most abundant protein in the human body. Be (So Totally) Cool, Read Books.
Extensively modified by posttranslational
modification.
Organizes and strengthens extracellular matrix.
Type I Most common (90%)—Bone (made by Type I: bone.
osteoblasts), Skin, Tendon, dentin, fascia, production in osteogenesis imperfecta type I.
cornea, late wound repair.
Type II Cartilage (including hyaline), vitreous body, Type II: cartwolage.
nucleus pulposus.
Type III Reticulin—skin, blood vessels, uterus, fetal Type III: deficient in the uncommon, vascular
tissue, granulation tissue. type of Ehlers-Danlos syndrome (ThreE D).
Type IV Basement membrane, basal lamina, lens. Type IV: under the floor (basement membrane).
Defective in Alport syndrome; targeted by
autoantibodies in Goodpasture syndrome.
Collagen synthesis and structure

S ynthesis—translation of collagen α chains
Fibroblast Preprocollagen
Pro α-chain backbone (Gly-X-Y)
(preprocollagen)—usually Gly-X-Y (X and Y
are proline or lysine). Glycine content best
Nucleus
OH
Hydroxylation of proline and reflects collagen synthesis (collagen is 1⁄3
OH lysine (requires vitamin C)
Collagen mRNA glycine).
Sugar
Glycosylation
H ydroxylation—hydroxylation of specific
Cytoplasm OH
OH proline and lysine residues. Requires vitamin
RER
C; deficiency scurvy.
Triple helix formation Glycosylation—glycosylation of pro-α-chain
Procollagen
hydroxylysine residues and formation of
Golgi
procollagen via hydrogen and disulfide
Exocytosis
bonds (triple helix of 3 collagen α chains).
Extracellular
Problems forming triple helix osteogenesis
space imperfecta.
Cleavage of procollagen Exocytosis—exocytosis of procollagen into
C- and N-terminals
extracellular space.
Tropocollagen
Proteolytic processing—cleavage of
Formation of cross-links disulfide-rich terminal regions of procollagen
(stabilized by lysyl oxidase)
insoluble tropocollagen. Problems with
cleavage Ehlers-Danlos syndrome.
Collagen fiber
C ross-linking—reinforcement of many
staggered tropocollagen molecules by
covalent lysine-hydroxylysine cross-linkage
(by copper-containing lysyl oxidase) to make
collagen fibrils. Problems with cross-linking
Ehlers-Danlos syndrome, Menkes disease.

Biochemistry 
Osteogenesis Genetic bone disorder (brittle bone May be confused with child abuse.
imperfecta disease) caused by a variety of gene defects Treat with bisphosphonates to fracture risk.
(most commonly COL1A1 and COL1A2). Patients can’t BITE:
Most common form is autosomal dominant Bones = multiple fractures
with production of otherwise normal type I I (eye) = blue sclerae
collagen. Manifestations can include: Teeth = dental imperfections
Multiple fractures with minimal Ear = hearing loss
trauma A B ; may occur during the birth
process
Blue sclerae C due to the translucent
connective tissue over choroidal veins
Some forms have tooth abnormalities,
including opalescent teeth that wear easily
due to lack of dentin (dentinogenesis
imperfecta)
Hearing loss (abnormal ossicles)
A B C
Lower Upper
body extremity
Ehlers-Danlos Faulty collagen synthesis causing hyperextensible skin A , hypermobile joints B , and tendency to
syndrome bleed (easy bruising).
A
Multiple types. Inheritance and severity vary. Can be autosomal dominant or recessive. May be
associated with joint dislocation, berry and aortic aneurysms, organ rupture.
Hypermobility type (joint instability): most common type.
Classical type (joint and skin symptoms): caused by a mutation in type V collagen (eg, COL5A1,
COL5A2).
Vascular type (fragile tissues including vessels [eg, aorta], muscles, and organs that are prone to
rupture): deficient type III procollagen.

B iochemistry—Laboratory Techniques
Menkes disease X-linked recessive connective tissue disease caused by impaired copper absorption and transport
due to defective Menkes protein (ATP7A). Leads to activity of lysyl oxidase (copper is a
necessary cofactor) defective collagen. Results in brittle, “kinky” hair, growth retardation, and
hypotonia.
Elastin Stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava
(connect vertebrae relaxed and stretched conformations).
Rich in nonhydroxylated proline, glycine, and lysine residues, vs the hydroxylated residues of
collagen.
Tropoelastin with fibrillin scaffolding.
Single elastin Cross-linking takes place extracellularly and gives elastin its elastic properties.
Stretch Relax
molecule Cross-link Broken down by elastase, which is normally inhibited by α1-antitrypsin.
α1-Antitrypsin deficiency results in unopposed elastase activity, which can cause emphysema.
Changes with aging: dermal collagen and elastin, synthesis of collagen fibrils; crosslinking
remains normal.
Marfan syndrome—autosomal dominant connective tissue disorder affecting skeleton, heart,
and eyes. FBN1 gene mutation on chromosome 15 results in defective fibrillin, a glycoprotein
that forms a sheath around elastin. Findings: tall with long extremities; pectus carinatum
(more specific) or pectus excavatum; hypermobile joints; long, tapering fingers and toes
(arachnodactyly); cystic medial necrosis of aorta; aortic incompetence and dissecting aortic
aneurysms; floppy mitral valve. Subluxation of lenses, typically upward and temporally. (Look up
at a ceiling fan.)
BIOCHEMISTRY—LABORATORY TECHNIQUES
``
Polymerase chain Molecular biology lab procedure used to amplify a desired fragment of DNA. Useful as a diagnostic
reaction tool (eg, neonatal HIV, herpes encephalitis).
5' 3' 5' 3' 5' 3'
5' 3' 3' 5'

DNA primer
dNTP
Repeat
3' 5' 5' 3'
Double-stranded DNA
3' 5' 3' 5' 3' 5'
Denaturation—DNA is heated to ~95°C to separate the strands.

Annealing—Sample is cooled to ~55°C. DNA primers, a heat-stable DNA polymerase (Taq),
and deoxynucleotide triphosphates (dNTPs) are added. DNA primers anneal to the specific
sequence to be amplified on each strand.
Elongation—Temperature is increased to ~72°C. DNA polymerase attaches dNTPs to the
strand to replicate the sequence after each primer.
Heating and cooling cycles continue until the DNA sample size is sufficient.

Biochemistry 
B iochemistry—Laboratory Techniques SEC TION II 53
CRISPR/Cas9 A genome editing tool, derived from bacteria. Composed of an endonuclease (Cas9, which cleaves
dsDNA) and a guide RNA (gRNA) sequence that binds to a complementary target DNA sequence.
Cell DNA repair machinery (nonhomologous end joining) fills in the gap introduced by the
system (knock-out) or a donor DNA can be added to the system to fill the gap (knock-in). The
gRNA can be designed to target any DNA sequence.
Blotting procedures
Southern blot 1. DNA sample is enzymatically cleaved into I: Parents
smaller pieces, which are separated on a gel
PEDIGREE
by electrophoresis, and then transferred to a
filter.
II: Children
2. Filter is exposed to radiolabeled DNA
probe that recognizes and anneals to its Aa Aa aa Aa AA Genotype
complementary strand.
SOUTHERN BLOT
3. Resulting double-stranded, labeled piece of Mutant
DNA is visualized when filter is exposed to Normal
film.
Northern blot Similar to Southern blot, except that an RNA
sample is electrophoresed. Useful for studying SNoW DRoP:
mRNA levels, which are reflective of gene Southern = DNA
expression. Northern = RNA
Western = Protein
Western blot Sample protein is separated via gel
electrophoresis and transferred to a membrane.
Labeled antibody is used to bind to relevant
protein.
Southwestern blot Identifies DNA-binding proteins (eg,
transcription factors) using labeled
oligonucleotide probes.

B iochemistry—Laboratory Techniques
Flow cytometry Laboratory technique to assess size, granularity, Commonly used in workup of hematologic
and protein expression (immunophenotype) of abnormalities (eg, paroxysmal nocturnal
individual cells in a sample. hemoglobinuria, fetal RBCs in mother’s blood)
and immunodeficiencies (eg, CD4 cell count
in HIV).
Cells are tagged with antibodies specific to Fluorescent

label
surface or intracellular proteins. Antibodies
Antibody
are then tagged with a unique fluorescent
dye. Sample is analyzed one cell at a time by
Anti-CD3 Ab Cell
focusing a laser on the cell and measuring
light scatter and intensity of fluorescence.
Anti-CD8 Ab
Laser
Fluorescence
is detected; r Laser makes
cto label fluoresce
labeled cells D ete
are counted
Data are plotted either as histogram (one 104

measure) or scatter plot (any two measures, as
shown). In illustration: 103
Cells in left lower quadrant ⊝ for both CD8
CD3
and CD3. 102
Cells in right lower quadrant ⊕ for CD8 and
⊝ for CD3. Right lower quadrant is empty 101
because all CD8-expressing cells also express

CD3. 100
100 101 102 103 104
Cells in left upper quadrant ⊕ for CD3 and CD8
⊝ for CD8.
Cells in right upper quadrant ⊕ for CD8
and CD3 (red + blue purple).
Microarrays Thousands of nucleic acid sequences are arranged in grids on glass or silicon. DNA or RNA probes
are hybridized to the chip, and a scanner detects the relative amounts of complementary binding.
Used to profile gene expression levels of thousands of genes simultaneously to study certain diseases
and treatments. Able to detect single nucleotide polymorphisms (SNPs) and copy number
variations (CNVs) for a variety of applications including genotyping, clinical genetic testing,
forensic analysis, cancer mutations, and genetic linkage analysis.
Enzyme-linked Immunologic test used to detect the presence of either a specific antigen (eg, HBsAg) or antibody
immunosorbent assay (eg, anti-HBs) in a patient’s blood sample. Detection involves the use of an antibody linked to
an enzyme. Added substrate reacts with enzyme, producing a detectable signal. Can have high
sensitivity and specificity, but is less specific than Western blot.
Direct ELISA tests for the antigen directly, while indirect ELISA tests for the antibody (thus
indirectly testing for the antigen).

Biochemistry 
B iochemistry—Laboratory Techniques SEC TION II 55
Karyotyping A process in which metaphase chromosomes A

are stained, ordered, and numbered according
to morphology, size, arm-length ratio, and
banding pattern (arrows in A point to extensive
abnormalities in a cancer cell).
Can be performed on a sample of blood, bone
marrow, amniotic fluid, or placental tissue.
Used to diagnose chromosomal imbalances
(eg, autosomal trisomies, sex chromosome
disorders).
Fluorescence in situ Fluorescent DNA or RNA probe binds to A

hybridization specific gene site of interest on chromosomes
(arrows in A point to abnormalities in a cancer
cell, whose karyotype is seen above; each
fluorescent color represents a chromosome-
specific probe).
Used for specific localization of genes and direct
visualization of chromosomal anomalies at the
molecular level.
Microdeletion—no fluorescence on a
chromosome compared to fluorescence at
the same locus on the second copy of that
chromosome
Translocation—fluorescence signal that
corresponds to one chromosome is found in
a different chromosome (two white arrows in
A show fragments of chromosome 17 that
have translocated to chromosome 19)
Duplication—a second copy of a
chromosome, resulting in a trisomy or
tetrasomy (two blue arrows show duplicated
chromosomes 8, resulting in a tetrasomy)
Molecular cloning Production of a recombinant DNA molecule in a bacterial host.

Steps:
1. Isolate eukaryotic mRNA (post-RNA processing) of interest.
2. Add reserve transcriptase (an RNA-dependent DNA polymerase) to produce complementary
DNA (cDNA, lacks introns).
3. Insert cDNA fragments into bacterial plasmids containing antibiotic resistance genes.
4. Transform (insert) recombinant plasmid into bacteria.
5. Surviving bacteria on antibiotic medium produce cloned DNA (copies of cDNA).

B IOCHEMISTRY—Genetics
Gene expression Transgenic strategies in mice involve: Knock-out = removing a gene, taking it out.
modifications Random insertion of gene into mouse Knock-in = inserting a gene.
genome
Targeted insertion or deletion of gene Random insertion—constitutive.
through homologous recombination with Targeted insertion—conditional.
mouse gene
Cre-lox system Can inducibly manipulate genes at specific
developmental points (eg, to study a gene
whose deletion causes embryonic death).
RNA interference dsRNA is synthesized that is complementary
to the mRNA sequence of interest. When
transfected into human cells, dsRNA separates
and promotes degradation of target mRNA,
“knocking down” gene expression.
BIOCHEMISTRY—GENETICS
``
Genetic terms
TERM DEFINITION EXAMPLE
Codominance Both alleles contribute to the phenotype of the Blood groups A, B, AB; α1-antitrypsin
heterozygote. deficiency; HLA groups.
Variable expressivity Patients with the same genotype have varying 2 patients with neurofibromatosis type 1 (NF1)
phenotypes. may have varying disease severity.
Incomplete Not all individuals with a mutant genotype BRCA1 gene mutations do not always result in
penetrance show the mutant phenotype. breast or ovarian cancer.
% penetrance × probability of inheriting
genotype = risk of expressing phenotype.
Pleiotropy One gene contributes to multiple phenotypic Untreated phenylketonuria (PKU) manifests with
effects. light skin, intellectual disability, and musty body
odor.
Anticipation Increased severity or earlier onset of disease in Trinucleotide repeat diseases (eg, Huntington
succeeding generations. disease).
Loss of heterozygosity If a patient inherits or develops a mutation in Retinoblastoma and the “two-hit hypothesis,”
a tumor suppressor gene, the complementary Lynch syndrome (HNPCC), Li-Fraumeni
allele must be deleted/mutated before cancer syndrome.
develops. This is not true of oncogenes.
Dominant negative Exerts a dominant effect. A heterozygote Mutation of a transcription factor in its allosteric
mutation produces a nonfunctional altered protein that site. Nonfunctioning mutant can still bind
also prevents the normal gene product from DNA, preventing wild-type transcription factor
functioning. from binding.
Linkage Tendency for certain alleles at 2 linked
disequilibrium loci to occur together more or less often
than expected by chance. Measured in a
population, not in a family, and often varies in
different populations.

Biochemistry 
B IOCHEMISTRY—Genetics SEC TION II 57
Genetic terms (continued)

TERM DEFINITION EXAMPLE
Mosaicism Presence of genetically distinct cell lines in the McCune-Albright syndrome—due to mutation
A
same individual. affecting G-protein signaling. Presents with
Somatic mosaicism—mutation arises from unilateral café-au-lait spots A with ragged
mitotic errors after fertilization and propagates edges, polyostotic fibrous dysplasia (bone is
through multiple tissues or organs. replaced by collagen and fibroblasts), and
Gonadal mosaicism—mutation only in egg or at least one endocrinopathy (eg, precocious
sperm cells. If parents and relatives do not puberty). Lethal if mutation occurs before
have the disease, suspect gonadal (or germline) fertilization (affecting all cells), but survivable in
mosaicism. patients with mosaicism.
Locus heterogeneity Mutations at different loci can produce a similar Albinism.
phenotype.
Allelic heterogeneity Different mutations in the same locus β-thalassemia.
produce the same phenotype.
Heteroplasmy Presence of both normal and mutated mtDNA passed from mother to all children.
mtDNA, resulting in variable expression in
mitochondrially inherited disease.
Uniparental disomy Offspring receives 2 copies of a chromosome from Uniparental is euploid (correct number of
1 parent and no copies from the other parent. chromosomes). Most occurrences of uniparental
HeterodIsomy (heterozygous) indicates a meiosis disomy (UPD) normal phenotype. Consider
I error. IsodIsomy (homozygous) indicates a UPD in an individual manifesting a recessive
meiosis II error or postzygotic chromosomal disorder when only one parent is a carrier.
duplication of one of a pair of chromosomes, Examples: Prader-Willi and Angelman
and loss of the other of the original pair. syndromes.
Hardy-Weinberg If a population is in Hardy-Weinberg Hardy-Weinberg law assumptions include:

population genetics equilibrium and if p and q are the frequencies No mutation occurring at the locus
pA qa of separate alleles, then: p2 + 2pq + q2 = 1 and Natural selection is not occurring
p + q = 1, which implies that: Completely random mating
pA
AA Aa p2 = frequency of homozygosity for allele A No net migration
p × p = p2 p×q q2 = frequency of homozygosity for allele a
Aa aa 2pq = frequency of heterozygosity (carrier
qa
p×q q × q = q2 frequency, if an autosomal recessive disease).
The frequency of an X-linked recessive disease
in males = q and in females = q2.

Disorders of imprinting Imprinting—one gene copy is silenced by methylation, and only the other copy is expressed
parent-of-origin effects.
Prader-Willi syndrome Maternally derived genes are silenced (imprinted). Associated with a mutation or deletion of
Disease occurs when the Paternal allele is chromosome 15 of paternal origin.
deleted or mutated. Results in hyperphagia, 25% of cases due to maternal uniparental
obesity, intellectual disability, hypogonadism, disomy.
and hypotonia.
AngelMan syndrome Paternally derived UBE3A gene is silenced Associated with mutation or deletion of
(imprinted). Disease occurs when the the UBE3A gene on the maternal copy of
Maternal allele is deleted or mutated. Results chromosome 15.
in inappropriate laughter (“happy puppet”), 5% of cases due to paternal uniparental disomy.
seizures, ataxia, and severe intellectual
disability.

Biochemistry 
Modes of inheritance
Autosomal dominant Often due to defects in structural genes. Many Often pleiotropic (multiple apparently unrelated
generations, both males and females are effects) and variably expressive (different
affected. between individuals). Family history crucial
to diagnosis. With one affected (heterozygous)
parent, on average, 1/2 of children affected.
Autosomal recessive Often due to enzyme deficiencies. Usually seen Commonly more severe than dominant disorders;
in only 1 generation. patients often present in childhood.
risk in consanguineous families.
With 2 carrier (heterozygous) parents, on average:
¼ of children will be affected (homozygous),
½ of children will be carriers, and ¼ of children
will be neither affected nor carriers.
X-linked recessive Sons of heterozygous mothers have a 50% Commonly more severe in males. Females
chance of being affected. No male-to-male usually must be homozygous to be affected.
carrier transmission. Skips generations.
X-linked dominant Transmitted through both parents. Mothers Hypophosphatemic rickets—formerly known as
transmit to 50% of daughters and sons; fathers vitamin D–resistant rickets. Inherited disorder
transmit to all daughters but no sons. resulting in phosphate wasting at proximal
tubule. Results in rickets-like presentation.
Other examples: fragile X syndrome, Alport
syndrome.
Mitochondrial Transmitted only through the mother. All Variable expression in a population or even
inheritance offspring of affected females may show signs of within a family due to heteroplasmy.
disease.
Mitochondrial myopathies—rare disorders;
often present with myopathy, lactic acidosis,
and CNS disease, eg, MELAS syndrome
(mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like episodes). 2° to
failure in oxidative phosphorylation. Muscle
biopsy often shows “ragged red fibers” (due to
accumulation of diseased mitochondria).
Leber hereditary optic neuropathy—cell
death in optic nerve neurons subacute
bilateral vision loss in teens/young adults, 90%
males. Usually permanent.
= unaffected male; = affected male; = unaffected female; = affected female.

Autosomal dominant Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis,
diseases familial hypercholesterolemia, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu
syndrome), hereditary spherocytosis, Huntington disease, Li-Fraumeni syndrome, Marfan syndrome,
multiple endocrine neoplasias, myotonic muscular dystrophy, neurofibromatosis type 1 (von
Recklinghausen disease), neurofibromatosis type 2, tuberous sclerosis, von Hippel-Lindau disease.
Autosomal recessive Albinism, autosomal recessive polycystic kidney disease (ARPKD), cystic fibrosis, Friedreich ataxia,
diseases glycogen storage diseases, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses
(except Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoses (except Fabry
disease), thalassemias, Wilson disease.
Cystic fibrosis
GENETICS Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508.
Most common lethal genetic disease in Caucasian population.
PATHOPHYSIOLOGY CFTR encodes an ATP-gated Cl− channel that secretes Cl− in lungs and GI tract, and reabsorbs
Cl− in sweat glands. Most common mutation misfolded protein protein retained in RER
and not transported to cell membrane, causing Cl− (and H2O) secretion; intracellular Cl−
results in compensatory Na+ reabsorption via epithelial Na+ channels H2O reabsorption
abnormally thick mucus secreted into lungs and GI tract. Na+ reabsorption also causes more
negative transepithelial potential difference.
DIAGNOSIS Cl− concentration in pilocarpine-induced sweat test is diagnostic. Can present with contraction
alkalosis and hypokalemia (ECF effects analogous to a patient taking a loop diuretic) because
of ECF H2O/Na+ losses and concomitant renal K+/H+ wasting. immunoreactive trypsinogen
(newborn screening).
COMPLICATIONS Recurrent pulmonary infections (eg, S aureus [early infancy], P aeruginosa [adolescence]), chronic
bronchitis and bronchiectasis reticulonodular pattern on CXR, opacification of sinuses.
Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D, E,
K), biliary cirrhosis, liver disease. Meconium ileus in newborns.
Infertility in men (absence of vas deferens, spermatogenesis may be unaffected) and subfertility in
women (amenorrhea, abnormally thick cervical mucus).
Nasal polyps, clubbing of nails.
TREATMENT Multifactorial: chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), and hypertonic
saline facilitate mucus clearance. Azithromycin used as anti-inflammatory agent. Ibuprofen slows
disease progression.
In patients with Phe508 deletion: combination of lumacaftor (corrects misfolded proteins and improves
their transport to cell surface) and ivacaftor (opens Cl– channels improved chloride transport).
X-linked recessive Ornithine transcarbamylase deficiency, Fabry Oblivious Female Will Often Give Her Boys
disorders disease, Wiskott-Aldrich syndrome, Ocular Her x-Linked Disorders
albinism, G6PD deficiency, Hunter syndrome, Females with Turner syndrome (45,XO) are
Bruton agammaglobulinemia, Hemophilia more likely to have an X-linked recessive
A and B, Lesch-Nyhan syndrome, Duchenne disorder.
(and Becker) muscular dystrophy.
X-inactivation (lyonization)—female carriers
variably affected depending on the pattern of
inactivation of the X chromosome carrying the
mutant vs normal gene.

Biochemistry 
Muscular dystrophies
Duchenne X-linked disorder typically due to frameshift Duchenne = deleted dystrophin.
A
or nonsense mutations truncated or Dystrophin gene (DMD) is the largest
Muscle fiber absent dystrophin protein progressive protein-coding human gene chance of
myofiber damage. Weakness begins in pelvic spontaneous mutation. Dystrophin helps
girdle muscles and progresses superiorly. anchor muscle fibers, primarily in skeletal and
Pseudohypertrophy of calf muscles due to cardiac muscle. It connects the intracellular
fibrofatty replacement of muscle A . Waddling cytoskeleton (actin) to the transmembrane
gait. proteins α- and β-dystroglycan, which are
Onset before 5 years of age. Dilated connected to the extracellular matrix (ECM).
cardiomyopathy is common cause of death. Loss of dystrophin myonecrosis.
Gower sign—patient uses upper extremities to CK and aldolase; genetic testing confirms
help stand up. diagnosis.
Classically seen in Duchenne muscular
Calf
dystrophy, but also seen in other muscular pseudohypertrophy
dystrophies and inflammatory myopathies (eg,

polymyositis).
Lordosis
Thigh
atrophy
Pushing on legs
to stand
Becker X-linked disorder typically due to non- Deletions can cause both Duchenne and
frameshift deletions in dystrophin gene Becker muscular dystrophies. 2⁄3 of cases have
(partially functional instead of truncated). Less large deletions spanning one or more exons.
severe than Duchenne. Onset in adolescence
or early adulthood.
Myotonic type 1 Autosomal dominant. CTG trinucleotide repeat Cataracts, Toupee (early balding in men), Gonadal
expansion in the DMPK gene abnormal atrophy.
expression of myotonin protein kinase
myotonia, muscle wasting, cataracts,
testicular atrophy, frontal balding, arrhythmia.
Rett syndrome Sporadic disorder seen almost exclusively in girls (affected males die in utero or shortly after
birth). Most cases are caused by de novo mutation of MECP2 on X chromosome. Symptoms of
Rett syndrome usually appear between ages 1–4 and are characterized by regression (Retturn)
in motor, verbal, and cognitive abilities; ataxia; seizures; growth failure; and stereotyped hand-
wringing.

Fragile X syndrome X-linked dominant inheritance. Trinucleotide Trinucleotide repeat expansion [(CGG)n] occurs
repeat in FMR1 gene hypermethylation during oogenesis.
expression. Most common cause of
inherited intellectual disability and 2nd most
common cause of genetically associated
mental deficiency (after Down syndrome).
Findings: post-pubertal macroorchidism
(enlarged testes), long face with a large
jaw, large everted ears, autism, mitral valve
prolapse.
Trinucleotide repeat Huntington disease, myotonic dystrophy, Try (trinucleotide) hunting for my fragile cage-
expansion diseases fragile X syndrome, and Friedreich ataxia. free eggs (X).
May show genetic anticipation (disease severity
and age of onset in successive generations).
DISEASE TRINUCLEOTIDE REPEAT MODE OF INHERITANCE MNEMONIC
Huntington disease (CAG)n AD Caudate has ACh and GABA
Myotonic dystrophy (CTG)n AD Cataracts, Toupee (early balding in men),
Gonadal atrophy
Fragile X syndrome (CGG)n XD Chin (protruding), Giant Gonads
Friedreich ataxia (GAA)n AR Ataxic GAAit

Biochemistry 
Autosomal trisomies
Down syndrome Findings: intellectual disability, flat facies, Incidence 1:700.
(trisomy 21) prominent epicanthal folds, single palmar Drinking age (21).
crease, gap between 1st 2 toes, duodenal Most common viable chromosomal disorder and
atresia, Hirschsprung disease, congenital heart most common cause of genetic intellectual
disease (eg, atrioventricular septal defect), disability.
Brushfield spots. Associated with early-onset First-trimester ultrasound commonly shows
Alzheimer disease (chromosome 21 codes for nuchal translucency and hypoplastic nasal
amyloid precursor protein) and risk of ALL bone.
and AML. The 5 A’s of Down syndrome:
95% of cases due to meiotic nondisjunction Advanced maternal age
( with advanced maternal age; from 1:1500 in Atresia (duodenal)
women < 20 to 1:25 in women > 45 years old). Atrioventricular septal defect
4% of cases due to unbalanced Robertsonian Alzheimer disease (early onset)
translocation, most typically between AML/ALL
chromosomes 14 and 21. Only 1% of cases are
due to postfertilization mitotic error.
Edwards syndrome Findings: PRINCE Edward—Prominent Incidence 1:8000.
(trisomy 18) occiput, Rocker-bottom feet, Intellectual Election age (18).
disability, Nondisjunction, Clenched fists 2nd most common autosomal trisomy resulting
(with overlapping fingers), low-set Ears, in live birth (most common is Down syndrome).
micrognathia (small jaw), congenital heart
disease. Death usually occurs by age 1.
Patau syndrome Findings: severe intellectual disability, rocker- Incidence 1:15,000.
(trisomy 13) bottom feet, microphthalmia, microcephaly, Puberty (13).
cleft liP/Palate, holoProsencephaly,
Polydactyly, cutis aPlasia, congenital heart
disease, Polycystic kidney disease. Death
usually occurs by age 1.
Nondisjunction in meiosis I Nondisjunction in meiosis II
Serum markers
Trisomy 21 18 13
1st trimester
Meiosis I
β-hCG
PAPP-A
2nd trimester Nondisjunction
AFP N
β-hCG N
Estriol N Meiosis II
Inhibin A N N
N = normal. Nondisjunction
Gametes
n+1 n+1 n–1 n–1 n n n–1 n+1
Trisomy Monosomy Normal Monosomy Trisomy

Genetic disorders by CHROMOSOME SELECTED EXAMPLES
chromosome 3 von Hippel-Lindau disease, renal cell carcinoma

4 ADPKD (PKD2), achondroplasia, Huntington disease
5 Cri-du-chat syndrome, familial adenomatous polyposis
6 Hemochromatosis (HFE)
7 Williams syndrome, cystic fibrosis
9 Friedreich ataxia, tuberous sclerosis (TSC1)
11 Wilms tumor, β-globin gene defects (eg, sickle cell disease, β-thalassemia),
MEN1
13 Patau syndrome, Wilson disease, retinoblastoma (RB1), BRCA2
15 Prader-Willi syndrome, Angelman syndrome, Marfan syndrome
16 ADPKD (PKD1), α-globin gene defects (eg, α-thalassemia), tuberous sclerosis
(TSC2)
17 Neurofibromatosis type 1, BRCA1, p53
18 Edwards syndrome
21 Down syndrome
22 Neurofibromatosis type 2, DiGeorge syndrome (22q11)
X Fragile X syndrome, X-linked agammaglobulinemia, Klinefelter syndrome (XXY)
Robertsonian Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.
translocation One of the most common types of translocation. Occurs when the long arms of 2 acrocentric
chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2
short arms are lost.
Balanced translocations normally do not cause any abnormal phenotype. Unbalanced
translocations can result in miscarriage, stillbirth, and chromosomal imbalance (eg, Down
syndrome, Patau syndrome).
Cri-du-chat syndrome Congenital deletion on short arm of Cri du chat = cry of the cat.
chromosome 5 (46,XX or XY, 5p−).
Findings: microcephaly, moderate to severe
intellectual disability, high-pitched crying/
meowing, epicanthal folds, cardiac
abnormalities (VSD).
Williams syndrome Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene).
Findings: distinctive “elfin” facies, intellectual disability, hypercalcemia ( sensitivity to vitamin
D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems (eg,
supravalvular aortic stenosis, renal artery stenosis). Think Will Ferrell in Elf.

Biochemistry 
B IOCHEMISTRY—Nutrition SEC TION II 65
22q11 deletion Microdeletion at chromosome 22q11 variable CATCH-22.

syndromes presentations including Cleft palate, Abnormal Due to aberrant development of 3rd and 4th
facies, Thymic aplasia T-cell deficiency, branchial (pharyngeal) pouches.
Cardiac defects, and Hypocalcemia 2° to
parathyroid aplasia.
DiGeorge syndrome—thymic, parathyroid, and
cardiac defects.
Velocardiofacial syndrome—palate, facial, and
cardiac defects.
BIOCHEMISTRY—NUTRITION
``
Vitamins: fat soluble A, D, E, K. Absorption dependent on gut and Malabsorption syndromes with steatorrhea (eg,
pancreas. Toxicity more common than for cystic fibrosis and celiac disease) or mineral
water-soluble vitamins because fat-soluble oil intake can cause fat-soluble vitamin
vitamins accumulate in fat. deficiencies.
Vitamins: water B1 (thiamine: TPP) All wash out easily from body except B12 and B9
soluble B2 (riboflavin: FAD, FMN) (folate). B12 stored in liver for ~ 3–4 years. B9
B3 (niacin: NAD+) stored in liver for ~ 3–4 months.
B5 (pantothenic acid: CoA) B-complex deficiencies often result in
B6 (pyridoxine: PLP) dermatitis, glossitis, and diarrhea.
B7 (biotin) Can be coenzymes (eg, ascorbic acid) or
B9 (folate) precursors to organic cofactors (eg, FAD,
B12 (cobalamin) NAD+).
C (ascorbic acid)

B IOCHEMISTRY—Nutrition
Vitamin A Also called retinol.

FUNCTION Antioxidant; constituent of visual pigments Retinol is vitamin A, so think retin-A (used
(retinal); essential for normal differentiation topically for wrinkles and Acne).
of epithelial cells into specialized tissue Found in liver and leafy vegetables.
(pancreatic cells, mucus-secreting cells); Use oral isotretinoin to treat severe cystic acne.
prevents squamous metaplasia. Used to treat Use all-trans retinoic acid to treat acute
measles and acute promyelocytic leukemia promyelocytic leukemia.
(APL).
DEFICIENCY Night blindness (nyctalopia); dry, scaly
A
skin (xerosis cutis); corneal degeneration
(keratomalacia); Bitot spots (foamy appearance)
on conjunctiva A ; immunosuppression.
EXCESS Acute toxicity—nausea, vomiting, vertigo, and Isotretinoin is teratogenic.

blurred vision.
Chronic toxicity—alopecia, dry skin (eg,
scaliness), hepatic toxicity and enlargement,
arthralgias, and pseudotumor cerebri.
Teratogenic (cleft palate, cardiac abnormalities),
therefore a ⊝ pregnancy test and two forms of
contraception are required before isotretinoin
(vitamin A derivative) is prescribed.
Vitamin B1 Also called thiamine.

FUNCTION In thiamine pyrophosphate (TPP), a cofactor for Think ATP: α-ketoglutarate dehydrogenase,
several dehydrogenase enzyme reactions: Transketolase, and Pyruvate dehydrogenase.
Pyruvate dehydrogenase (links glycolysis to Spell beriberi as Ber1Ber1 to remember
TCA cycle) vitamin B1.
α-ketoglutarate dehydrogenase (TCA cycle) Wernicke-Korsakoff syndrome—confusion,
Transketolase (HMP shunt) ophthalmoplegia, ataxia (classic triad) +
Branched-chain ketoacid dehydrogenase confabulation, personality change, memory
DEFICIENCY Impaired glucose breakdown ATP depletion loss (permanent). Damage to medial dorsal
worsened by glucose infusion; highly aerobic nucleus of thalamus, mammillary bodies.
tissues (eg, brain, heart) are affected first. Dry beriberi—polyneuropathy, symmetrical
In alcoholic or malnourished patients, muscle wasting.
give thiamine before dextrose to risk of Wet beriberi—high-output cardiac failure
precipitating Wernicke encephalopathy. (dilated cardiomyopathy), edema.
Diagnosis made by in RBC transketolase
activity following vitamin B1 administration.

Biochemistry 
Vitamin B2 Also called riboflavin.

FUNCTION Component of flavins FAD and FMN, used as FAD and FMN are derived from riboFlavin
cofactors in redox reactions, eg, the succinate (B2 ≈ 2 ATP).
dehydrogenase reaction in the TCA cycle.
DEFICIENCY Cheilosis (inflammation of lips, scaling and The 2 C’s of B2.
fissures at the corners of the mouth), Corneal
vascularization.
Vitamin B3 Also called niacin.

FUNCTION Constituent of NAD+, NADP+ (used in redox NAD derived from Niacin (B3 ≈ 3 ATP).
reactions). Derived from tryptophan. Synthesis
requires vitamins B2 and B6. Used to treat
dyslipidemia; lowers levels of VLDL and raises
levels of HDL.
DEFICIENCY Glossitis. Severe deficiency leads to pellagra, The 3 D’s of B3.
A
which can also be caused by Hartnup disease, Hartnup disease—autosomal recessive.
malignant carcinoid syndrome ( tryptophan Deficiency of neutral amino acid (eg,
metabolism), and isoniazid ( vitamin B6). tryptophan) transporters in proximal renal
Symptoms of pellagra: Diarrhea, Dementia tubular cells and on enterocytes neutral
(also hallucinations), Dermatitis (C3/C4 aminoaciduria and absorption from the
dermatome circumferential “broad collar” rash gut tryptophan for conversion to niacin
[Casal necklace], hyperpigmentation of sun- pellagra-like symptoms. Treat with high-
exposed limbs A ). protein diet and nicotinic acid.
Deficiency of vitamin B3 pellagra.
EXCESS Facial flushing (induced by prostaglandin, not Excess of vitamin B3 podagra.

histamine; can avoid by taking aspirin with
niacin), hyperglycemia, hyperuricemia.
Vitamin B5 Also called pantothenic acid.

FUNCTION Essential component of coenzyme A (CoA, B5 is “pento”thenic acid.
a cofactor for acyl transfers) and fatty acid
synthase.
DEFICIENCY Dermatitis, enteritis, alopecia, adrenal
insufficiency.
Vitamin B6 Also called pyridoxine.

FUNCTION Converted to pyridoxal phosphate (PLP), a cofactor used in transamination (eg, ALT and AST),
decarboxylation reactions, glycogen phosphorylase. Synthesis of cystathionine, heme, niacin,
histamine, and neurotransmitters including serotonin, epinephrine, norepinephrine (NE),
dopamine, and GABA.
DEFICIENCY Convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by isoniazid and oral
contraceptives), sideroblastic anemias (due to impaired hemoglobin synthesis and iron excess).

Vitamin B7 Also called biotin.

FUNCTION Cofactor for carboxylation enzymes (which add
a 1-carbon group):
Pyruvate carboxylase: pyruvate (3C)
oxaloacetate (4C)
Acetyl-CoA carboxylase: acetyl-CoA (2C)
malonyl-CoA (3C)
Propionyl-CoA carboxylase: propionyl-CoA
(3C) methylmalonyl-CoA (4C)
DEFICIENCY Relatively rare. Dermatitis, enteritis, alopecia. “Avidin in egg whites avidly binds biotin.”
Caused by antibiotic use or excessive ingestion
of raw egg whites.
Vitamin B9 Also called folate.

FUNCTION Converted to tetrahydrofolic acid (THF), a Found in leafy green vegetables. Absorbed in
coenzyme for 1-carbon transfer/methylation jejunum. Folate from foliage.
reactions. Small reserve pool stored primarily in the liver.
Important for the synthesis of nitrogenous bases
in DNA and RNA.
DEFICIENCY Macrocytic, megaloblastic anemia; Deficiency can be caused by several drugs (eg,
hypersegmented polymorphonuclear cells phenytoin, sulfonamides, methotrexate).
(PMNs); glossitis; no neurologic symptoms Supplemental maternal folic acid at least 1 month
(as opposed to vitamin B12 deficiency). Labs: prior to conception and during early pregnancy
homocysteine, normal methylmalonic acid to risk of neural tube defects. Give vitamin B9
levels. Seen in alcoholism and pregnancy. for the 9 months of pregnancy.

Biochemistry 
Vitamin B12 Also called cobalamin.

FUNCTION Cofactor for methionine synthase (transfers Found in animal products.
CH3 groups as methylcobalamin) and Synthesized only by microorganisms. Very large
methylmalonyl-CoA mutase. Important for reserve pool (several years) stored primarily in
DNA synthesis. the liver. Deficiency caused by malabsorption
DEFICIENCY Macrocytic, megaloblastic anemia; (eg, sprue, enteritis, Diphyllobothrium latum,
hypersegmented PMNs; paresthesias achlorhydria, bacterial overgrowth, alcohol
and subacute combined degeneration excess), lack of intrinsic factor (eg, pernicious
(degeneration of dorsal columns, lateral anemia, gastric bypass surgery), absence of
corticospinal tracts, and spinocerebellar tracts) terminal ileum (surgical resection, eg, for
due to abnormal myelin. Associated with Crohn disease), or insufficient intake (eg,
serum homocysteine and methylmalonic veganism).
acid levels, along with 2° folate deficiency. Anti-intrinsic factor antibodies diagnostic for
Prolonged deficiency irreversible nerve pernicious anemia.
damage. Folate supplementation can mask the
hematologic symptoms of B12 deficiency, but
not the neurologic symptoms.
Protein Fatty acids with odd number of
carbons, branched-chain amino acids
THF Methionine SAM
CH3 to anabolic
pathways Methylmalonyl-CoA
Methylmalonyl-CoA
B12 Methionine synthase
S-adenosyl B12 mutase
homocysteine
Succinyl-CoA
B6
THF–CH3 Homocysteine
Heme TCA
B6 Adenosine
Cysteine
Vitamin C Also called ascorbic acid.

FUNCTION Antioxidant; also facilitates iron absorption Found in fruits and vegetables.
by reducing it to Fe2+ state. Necessary Pronounce “absorbic” acid.
for hydroxylation of proline and lysine in Ancillary treatment for methemoglobinemia by
collagen synthesis. Necessary for dopamine reducing Fe3+ to Fe2+.
β-hydroxylase, which converts dopamine to
NE.
DEFICIENCY Scurvy—swollen gums, bruising, petechiae, Vitamin C deficiency causes sCurvy due to a
hemarthrosis, anemia, poor wound healing, Collagen synthesis defect.
perifollicular and subperiosteal hemorrhages,
“corkscrew” hair.
Weakened immune response.
EXCESS Nausea, vomiting, diarrhea, fatigue, calcium
oxalate nephrolithiasis. Can iron toxicity in
predisposed individuals by increasing dietary
iron absorption (ie, can worsen hereditary
hemochromatosis or transfusion-related iron
overload).

Vitamin D D3 (cholecalciferol) from exposure of skin (stratum basale) to sun, ingestion of fish, milk, plants.
D2 (ergocalciferol) from ingestion of plants, fungi, yeasts.
Both converted to 25-OH D3 (storage form) in liver and to the active form 1,25-(OH)2 D3 (calcitriol)
in kidney.
FUNCTION intestinal absorption of Ca2+ and PO43.
bone mineralization at low levels.
bone resorption at higher levels.
REGULATION PTH, Ca2+, PO43– 1,25-(OH)2D3 production.
1,25-(OH)2D3 feedback inhibits its own production.
PTH Ca2+ reabsorption and PO43– reabsorption in the kidney.
DEFICIENCY Rickets in children (deformity, such as genu varum “bow legs” A ), osteomalacia in adults (bone
A
pain and muscle weakness), hypocalcemic tetany.
Caused by malabsorption, sun exposure, poor diet, chronic kidney disease.
Give oral vitamin D to breastfed infants.
Deficiency is exacerbated by pigmented skin, premature birth.
EXCESS Hypercalcemia, hypercalciuria, loss of appetite, stupor. Seen in granulomatous disease ( activation
of vitamin D by epithelioid macrophages).
Vitamin E Includes tocopherol, tocotrienol.

FUNCTION Antioxidant (protects RBCs and membranes High-dose supplementation may alter
from free radical damage). metabolism of vitamin K enhanced
anticoagulant effects of warfarin.
DEFICIENCY Hemolytic anemia, acanthocytosis, Neurologic presentation may appear similar

muscle weakness, posterior column and to vitamin B12 deficiency, but without
spinocerebellar tract demyelination. megaloblastic anemia, hypersegmented
neutrophils, or serum methylmalonic acid
levels.
EXCESS Risk of enterocolitis in infants.

Biochemistry 
Vitamin K Includes phytomenadione, phylloquinone, phytonadione, menaquinone.

FUNCTION Activated by epoxide reductase to the K is for Koagulation. Necessary for the
reduced form, which is a cofactor for the maturation of clotting factors II, VII, IX,
γ-carboxylation of glutamic acid residues on X, and proteins C and S. Warfarin inhibits
various proteins required for blood clotting. vitamin K–dependent synthesis of these factors
Synthesized by intestinal flora. and proteins.
DEFICIENCY Neonatal hemorrhage with PT and aPTT Not in breast milk; neonates are given vitamin
but normal bleeding time (neonates have K injection at birth to prevent hemorrhagic
sterile intestines and are unable to synthesize disease of the newborn.
vitamin K). Can also occur after prolonged use
of broad-spectrum antibiotics.
Zinc
FUNCTION Mineral essential for the activity of 100+ enzymes. Important in the formation of zinc fingers
(transcription factor motif).
DEFICIENCY Delayed wound healing, suppressed immunity, hypogonadism, adult hair (axillary, facial, pubic),
A dysgeusia, anosmia, acrodermatitis enteropathica A . May predispose to alcoholic cirrhosis.
Protein-energy malnutrition
Kwashiorkor Protein malnutrition resulting in skin lesions, A B
edema due to plasma oncotic pressure,
liver malfunction (fatty change due to
apolipoprotein synthesis). Clinical picture is
small child with swollen abdomen A .
Kwashiorkor results from protein-
deficient MEALS:
Malnutrition
Edema
Anemia
Liver (fatty)
Skin lesions (eg, hyperkeratosis,
dyspigmentation)
Marasmus Malnutrition not causing edema. Diet is
deficient in calories but no nutrients are
entirely absent.
Marasmus results in Muscle wasting B .

B IOCHEMISTRY—Metabolism
Ethanol metabolism
NADPH NADP+
CYP2E1
ROS Microsome
Fomepizole Disulfiram
– –
Alcohol dehydrogenase Acetaldehyde dehydrogenase
Ethanol Acetaldehyde Acetate
NAD +
NADH Cytosol NAD +
NADH
Mitochondria
Catalase
H2O2 H2O Peroxisome
FOMEpizole—inhibits alcohol dehydrogenase and is an antidote For Overdoses of Methanol or

Ethylene glycol.
Disulfiram—inhibits acetaldehyde dehydrogenase (acetaldehyde accumulates, contributing to
hangover symptoms), discouraging drinking.
NAD+ is the limiting reagent.
Alcohol dehydrogenase operates via zero-order kinetics.
Ethanol metabolism NADH/NAD+ ratio in +
NADH NAD NAD+
NADH
liver, causing: Pyruvate
Pyruvate Lactate
Lactate
Pyruvate lactate (lactic acidosis) Glycolysis
Glycolysis
Oxaloacetate malate (prevents +
NADH NAD NAD+
NADH
gluconeogenesis fasting hypoglycemia) Oxaloacetate Malate
Oxaloacetate Malate
Dihydroxyacetone phosphate glycerol- TCA cycle
TCA cycle
3‑phosphate (combines with fatty acids to
make triglycerides hepatosteatosis)
Additionally, NADH/NAD+ ratio disfavors
TCA production of NADH utilization of
acetyl-CoA for ketogenesis ( ketoacidosis) and
lipogenesis ( hepatosteatosis).
BIOCHEMISTRY—METABOLISM
``
Metabolism sites
Mitochondria Fatty acid oxidation (β-oxidation), acetyl-
CoA production, TCA cycle, oxidative
phosphorylation, ketogenesis.
Cytoplasm Glycolysis, HMP shunt, and synthesis of steroids
(SER), proteins (ribosomes, RER), fatty acids,
cholesterol, and nucleotides.
Both Heme synthesis, Urea cycle, Gluconeogenesis. HUGs take two (ie, both).

Biochemistry 
B IOCHEMISTRY—Metabolism SEC TION II 73
Enzyme terminology An enzyme’s name often describes its function. For example, glucokinase is an enzyme that
catalyzes the phosphorylation of glucose using a molecule of ATP. The following are commonly
used enzyme descriptors.
Kinase Catalyzes transfer of a phosphate group from a high-energy molecule (usually ATP) to a substrate
(eg, phosphofructokinase).
Phosphorylase Adds inorganic phosphate onto substrate without using ATP (eg, glycogen phosphorylase).
Phosphatase Removes phosphate group from substrate (eg, fructose-1,6-bisphosphatase).
Dehydrogenase Catalyzes oxidation-reduction reactions (eg, pyruvate dehydrogenase).
Hydroxylase Adds hydroxyl group (−OH) onto substrate (eg, tyrosine hydroxylase).
Carboxylase Transfers CO2 groups with the help of biotin (eg, pyruvate carboxylase).
Mutase Relocates a functional group within a molecule (eg, vitamin B12–dependent methylmalonyl-CoA
mutase).
Synthase/synthetase Joins two molecules together using a source of energy (eg, ATP, acetyl CoA, nucleotide sugar).
Rate-determining enzymes of metabolic processes

PROCESS ENZYME REGULATORS
Glycolysis Phosphofructokinase-1 (PFK-1) AMP ⊕, fructose-2,6-bisphosphate ⊕
ATP ⊝, citrate ⊝
Gluconeogenesis Fructose-1,6-bisphosphatase Citrate ⊕
AMP ⊝, fructose-2,6-bisphosphate ⊝
TCA cycle Isocitrate dehydrogenase ADP ⊕
ATP ⊝, NADH ⊝
Glycogenesis Glycogen synthase Glucose-6-phosphate ⊕, insulin ⊕, cortisol ⊕
Epinephrine ⊝, glucagon ⊝
Glycogenolysis Glycogen phosphorylase Epinephrine ⊕, glucagon ⊕, AMP ⊕
Glucose-6-phosphate ⊝, insulin ⊝, ATP ⊝
HMP shunt Glucose-6-phosphate dehydrogenase (G6PD) NADP+ ⊕
NADPH ⊝
De novo pyrimidine Carbamoyl phosphate synthetase II ATP ⊕, PRPP ⊕
synthesis UTP ⊝
De novo purine Glutamine-phosphoribosylpyrophosphate AMP ⊝, inosine monophosphate (IMP) ⊝,
synthesis (PRPP) amidotransferase GMP ⊝
Urea cycle Carbamoyl phosphate synthetase I N-acetylglutamate ⊕
Fatty acid synthesis Acetyl-CoA carboxylase (ACC) Insulin ⊕, citrate ⊕
Glucagon ⊝, palmitoyl-CoA ⊝
Fatty acid oxidation Carnitine acyltransferase I Malonyl-CoA ⊝
Ketogenesis HMG-CoA synthase
Cholesterol synthesis HMG-CoA reductase Insulin ⊕, thyroxine ⊕
Glucagon ⊝, cholesterol ⊝

Summary of pathways
Galactokinase (mild galactosemia) Galactose metabolism

Galactose-1-phosphate Galactose B Requires biotin cofactor
uridyltransferase
(severe galactosemia) T Requires thiamine cofactor (TPP)
Glycolysis # Irreversible, important point of regulation
Hexokinase/glucokinase Galactose-1-phosphate Glucose
Glycogen
Glucose-6-phosphatase HMP shunt
(von Gierke disease)
UDP-glucose Glucose-1-phosphate Glucose-6-phosphate 6-phosphogluconolactone
Glucose-6-phosphate
dehydrogenase Glycogenesis / glycogenolysis
Transketolase Fructose-6-phosphate Ribulose-5-phosphate
T
Phosphofructokinase-1 Gluconeogenesis
Fructose-1,6-bisphosphatase Fructose-1,6-bisphosphate Fructose metabolism
Fructokinase (essential fructosuria)
Aldolase B (fructose intolerance) Glyceraldehyde-3-P DHAP Fructose-1-phosphate Fructose
Aldolase B (liver), A (muscle)
Triose phosphate isomerase 1,3-bisphosphoglycerate Glyceraldehyde
Pyruvate kinase
3-phosphoglycerate Glycerol Lipid metabolism
Pyruvate dehydrogenase
Pyruvate carboxylase
2-phosphoglycerate Triglycerides
PEP carboxykinase
Citrate synthase
Phosphoenolpyruvate (PEP) Fatty acids
Isocitrate dehydrogenase
α-ketoglutarate dehydrogenase Alanine Pyruvate Lactate Cholesterol
Malonyl-CoA
Carbamoyl phosphate synthetase I T
B
Ornithine transcarbamylase B Acetyl-CoA Mevalonate
Propionyl-CoA carboxylase Acetoacetyl-CoA HMG-CoA
HMG-CoA reductase
Citrate Acetoacetate
Oxaloacetate
NH3 + CO2 Aspartate
Citrulline Isocitrate β-hydroxybutyrate
Carbamoyl phosphate Argininosuccinate

Ketogenesis
Malate TCA cycle
Ornithine Odd-chain fatty acids,
Urea cycle α-ketoglutarate branched-chain amino acids,
Fumarate methionine, and threonine
T
Arginine
Succinate Succinyl-CoA Methylmalonyl-CoA Propionyl-CoA
Urea B12 B
H2O Protein metabolism
ATP production Aerobic metabolism of one glucose molecule Arsenic causes glycolysis to produce zero net
produces 32 net ATP via malate-aspartate ATP.
shuttle (heart and liver), 30 net ATP via
glycerol-3-phosphate shuttle (muscle).
Anaerobic glycolysis produces only 2 net ATP
per glucose molecule.
ATP hydrolysis can be coupled to energetically
unfavorable reactions.

Biochemistry 
Activated carriers CARRIER MOLECULE CARRIED IN ACTIVATED FORM

ATP Phosphoryl groups
NADH, NADPH, FADH2 Electrons
CoA, lipoamide Acyl groups
Biotin CO2
Tetrahydrofolates 1-carbon units
S-adenosylmethionine (SAM) CH3 groups
TPP Aldehydes
Universal electron Nicotinamides (NAD+, NADP+ from vitamin NADPH is a product of the HMP shunt.
acceptors B3) and flavin nucleotides (FAD+ from vitamin NADPH is used in:
B2). Anabolic processes
NAD+ is generally used in catabolic processes Respiratory burst
to carry reducing equivalents away as NADH. Cytochrome P-450 system
NADPH is used in anabolic processes (eg, Glutathione reductase
steroid and fatty acid synthesis) as a supply of
reducing equivalents.
Hexokinase vs Phosphorylation of glucose to yield glucose-6-phosphate is catalyzed by glucokinase in the liver and
glucokinase hexokinase in other tissues. Hexokinase sequesters glucose in tissues, where it is used even when
glucose concentrations are low. At high glucose concentrations, glucokinase helps to store glucose
in liver.
Hexokinase Glucokinase
Location Most tissues, except liver Liver, β cells of pancreas
and pancreatic β cells
Km Lower ( affinity) Higher ( affinity)
Vmax Lower ( capacity) Higher ( capacity)
Induced by insulin No Yes
Feedback-inhibited by Yes No
glucose-6-phosphate

Glycolysis regulation, Net glycolysis (cytoplasm):

key enzymes Glucose + 2 Pi + 2 ADP + 2 NAD+ 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O.
Equation not balanced chemically, and exact balanced equation depends on ionization state of
reactants and products.
REQUIRE ATP Glucose Glucose-6-P Glucose-6-P ⊝ hexokinase.
Hexokinase/glucokinasea
Fructose-6-P ⊝ glucokinase.
Fructose-6-P
Phosphofructokinase-1
Fructose-1,6-BP AMP ⊕, fructose-2,6-bisphosphate ⊕.
(rate-limiting step)
ATP ⊝, citrate ⊝.
aGlucokinase in liver and β cells of pancreas; hexokinase
in all other tissues.
PRODUCE ATP 1,3-BPG 3-PG

Phosphoglycerate kinase
Phosphoenolpyruvate Pyruvate Fructose-1,6-bisphosphate ⊕.

Pyruvate kinase
ATP ⊝, alanine ⊝.
Regulation by FBPase-1
fructose-2,6- Gluconeogenesis Fructose-6-P Fructose-1,6-BP Glycolysis
PFK-1
bisphosphate
FBPase-2 PFK-2
(active in (active in
fasting state) fed state) +
Fructose-2,6-BP
FBPase-2 (fructose bisphosphatase-2) and PFK-2 (phosphofructokinase-2) are the same bifunctional
enzyme whose function is reversed by phosphorylation by protein kinase A.
Fasting state: glucagon cAMP protein kinase A FBPase-2, PFK-2, less glycolysis,
more gluconeogenesis.
Fed state: insulin cAMP protein kinase A FBPase-2, PFK-2, more glycolysis, less
gluconeogenesis.
Pyruvate Mitochondrial enzyme complex linking The complex is similar to the α-ketoglutarate
dehydrogenase glycolysis and TCA cycle. Differentially dehydrogenase complex (same cofactors,
complex regulated in fed/fasting states (active in fed similar substrate and action), which converts
state). α-ketoglutarate succinyl-CoA (TCA cycle).
Reaction: pyruvate + NAD+ + CoA acetyl-
CoA + CO2 + NADH.
The complex contains 3 enzymes that require 5
cofactors:
1. Thiamine pyrophosphate (B1) The Lovely Co-enzymes For Nerds.
2. Lipoic acid Arsenic inhibits lipoic acid. Arsenic poisoning
3. CoA (B5, pantothenic acid) clinical findings: imagine a vampire
4. FAD (B2, riboflavin) (pigmentary skin changes, skin cancer),
5. NAD+ (B3, niacin) vomiting and having diarrhea, running away
Activated by: from a cutie (QT prolongation) with garlic
NAD+/NADH ratio breath.
ADP
Ca2+

Biochemistry 
Pyruvate Causes a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT).
dehydrogenase X-linked.
complex deficiency
FINDINGS Neurologic defects, lactic acidosis, serum alanine starting in infancy.
TREATMENT intake of ketogenic nutrients (eg, high fat content or lysine and leucine).
Pyruvate metabolism Functions of different pyruvate metabolic

pathways (and their associated cofactors):
Glucose A lanine aminotransferase (B6): alanine
carries amino groups to the liver from
muscle
Pyruvate Pyruvate carboxylase (biotin): oxaloacetate
ALT can replenish TCA cycle or be used in
LDH
Alanine NADH gluconeogenesis
Cahill cycle Cytosol + H+ NAD+ Pyruvate dehydrogenase (B1, B2, B3, B5,
Lactate
Mitochondria Cori cycle lipoic acid): transition from glycolysis to
PC
the TCA cycle

PDH
NAD+
CO2 + ATP
Lactic acid dehydrogenase (B3): end of
CO2 anaerobic glycolysis (major pathway in
NADH RBCs, WBCs, kidney medulla, lens,
Oxaloacetate + H+
testes, and cornea)
Acetyl-CoA
TCA cycle (Krebs cycle) Pyruvate acetyl-CoA produces 1 NADH, The TCA cycle produces 3 NADH, 1 FADH2,
1 CO2. 2 CO2, 1 GTP per acetyl-CoA = 10 ATP/
Pyruvate (3C) acetyl-CoA (2× everything per glucose). TCA
ATP cycle reactions occur in the mitochondria.
PDH
* Acetyl-CoA α-ketoglutarate dehydrogenase complex

NADH
Acetyl-CoA (2C) requires the same cofactors as the pyruvate
ATP
dehydrogenase complex (B1, B2, B3, B5, lipoic
NADH
Oxalo- Citrate synthase
* Citrate (6C)
acid).
acetate
(4C) cis-Aconitate
Citrate Is Krebs’ Starting Substrate For Making
Malate (4C) Isocitrate (6C) Oxaloacetate.
dehydrogen ase
CO2 + NADH
Fumarate (4C) * ATP
I s o c it r a t e
NADH
ADP
FADH2 α-KG (5C)
ase
en
Succinate (4C) * dr CO2 + NADH

og
y
eh
GTP + CoA Gd
Succinyl- α-K Succinyl-CoA
CoA (4C) NADH
ATP
* Enzymes are irreversible

Electron transport NADH electrons from glycolysis enter mitochondria via the malate-aspartate or glycerol-3-
chain and oxidative phosphate shuttle. FADH2 electrons are transferred to complex II (at a lower energy level than
phosphorylation NADH). The passage of electrons results in the formation of a proton gradient that, coupled to
oxidative phosphorylation, drives the production of ATP.
ADP + Pi ATP
NADH NAD + FADH2 FAD /2O2 + 2H H2O
1 +
Mitochondrial
matrix
Inner mitochondrial
CoQ membrane
Cyto-
chrome c
Complex I Complex II Complex III Complex IV Complex V Intermembrane
(succinate space
2,4-Dinitrophenol
dehydrogenase)
Aspirin overdose
Rotenone Antimycin A Cyanide, Oligomycin

H+ H+ CO H+ H+
Azide
ATP PRODUCED VIA ATP SYNTHASE

1 NADH 2.5 ATP; 1 FADH2 1.5 ATP.
OXIDATIVE PHOSPHORYLATION POISONS
Electron transport Directly inhibit electron transport, causing a Rotenone: complex one inhibitor.
inhibitors proton gradient and block of ATP synthesis. “An-3-mycin” (antimycin) A: complex 3
inhibitor.
Cyanide, carbon monoxide, azide (the -ides,
4 letters) inhibit complex IV.
ATP synthase Directly inhibit mitochondrial ATP synthase, Oligomycin.
inhibitors causing an proton gradient. No ATP is
produced because electron transport stops.
Uncoupling agents permeability of membrane, causing a proton 2,4-Dinitrophenol (used illicitly for weight
gradient and O2 consumption. ATP synthesis loss), aspirin (fevers often occur after aspirin
stops, but electron transport continues. overdose), thermogenin in brown fat (has more
Produces heat. mitochondria than white fat).
Gluconeogenesis,
irreversible enzymes Pathway Produces Fresh Glucose.
Pyruvate carboxylase In mitochondria. Pyruvate oxaloacetate. Requires biotin, ATP. Activated by acetyl-CoA.
Phosphoenolpyruvate In cytosol. Oxaloacetate Requires GTP.
carboxykinase phosphoenolpyruvate.
Fructose-1,6- In cytosol. Fructose-1,6-bisphosphate Citrate ⊕, AMP ⊝, fructose 2,6-bisphosphate ⊝.
bisphosphatase fructose-6-phosphate.
Glucose-6- In ER. Glucose-6-phosphate glucose.
phosphatase
Occurs primarily in liver; serves to maintain euglycemia during fasting. Enzymes also found in
kidney, intestinal epithelium. Deficiency of the key gluconeogenic enzymes causes hypoglycemia.
(Muscle cannot participate in gluconeogenesis because it lacks glucose-6-phosphatase).
Odd-chain fatty acids yield 1 propionyl-CoA during metabolism, which can enter the TCA cycle
(as succinyl-CoA), undergo gluconeogenesis, and serve as a glucose source. Even-chain fatty acids
cannot produce new glucose, since they yield only acetyl-CoA equivalents.

Biochemistry 
HMP shunt (pentose Provides a source of NADPH from abundantly available glucose-6-P (NADPH is required for
phosphate pathway) reductive reactions, eg, glutathione reduction inside RBCs, fatty acid and cholesterol biosynthesis).
Additionally, this pathway yields ribose for nucleotide synthesis. Two distinct phases (oxidative and
nonoxidative), both of which occur in the cytoplasm. No ATP is used or produced.
Sites: lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs.
REACTIONS KEY ENZYMES PRODUCTS
Oxidative NADP +
NADPH
(irreversible) CO2
Glucose-6-Pi 2 NADPH
Glucose-6-P dehydrogenase Ribulose-5-Pi
Rate-limiting step
Nonoxidative Phosphopentose isomerase,

transketolases Ribose-5-Pi
(reversible) Ribulose-5-Pi Glyceraldehyde-3-phosphate
Requires B1 Fructose-6-P
Glucose-6-phosphate NADPH is necessary to keep glutathione X-linked recessive disorder; most common
dehydrogenase reduced, which in turn detoxifies free radicals human enzyme deficiency; more prevalent
deficiency and peroxides. NADPH in RBCs leads to among African Americans. malarial
hemolytic anemia due to poor RBC defense resistance.
against oxidizing agents (eg, fava beans, Heinz bodies—denatured globin chains
sulfonamides, nitrofurantoin, primaquine/ precipitate within RBCs due to oxidative stress.
chloroquine, antituberculosis drugs). Infection Bite cells—result from the phagocytic removal
(most common cause) can also precipitate of Heinz bodies by splenic macrophages.
hemolysis; inflammatory response produces Think, “Bite into some Heinz ketchup.”
free radicals that diffuse into RBCs, causing
oxidative damage.
Glucose-6-P NADP+ 2 GSH H2O2
(reduced)
Glucose-6-P Glutathione Glutathione

dehydrogenase reductase peroxidase
6-phosphogluconolactone NADPH GSSG 2H2O

(oxidized)

Disorders of fructose metabolism

Essential fructosuria Involves a defect in fructokinase. Autosomal recessive. A benign, asymptomatic condition
(fructokinase deficiency is kinder), since fructose is not trapped in cells. Hexokinase becomes 1°
pathway for converting fructose to fructose-6-phosphate.
Symptoms: fructose appears in blood and urine.
Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose
metabolism.
Hereditary fructose Hereditary deficiency of aldolase B. Autosomal recessive. Fructose-1-phosphate accumulates,
intolerance causing a in available phosphate, which results in inhibition of glycogenolysis and
gluconeogenesis. Symptoms present following consumption of fruit, juice, or honey. Urine dipstick
will be ⊝ (tests for glucose only); reducing sugar can be detected in the urine (nonspecific test for
inborn errors of carbohydrate metabolism).
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.
Treatment: intake of both fructose and sucrose (glucose + fructose).
Fructose metabolism (liver)

Triose phosphate
Dihydroxyacetone-P isomerase
Fructokinase Aldolase B
Fructose Fructose-1-P se Glyceraldehyde-3-P Glycolysis
e kina
Trios
ATP ADP Glyceraldehyde
ADP
NADH ATP
NAD+
Glycerol
Disorders of galactose metabolism

Galactokinase Hereditary deficiency of galactokinase. Galactitol accumulates if galactose is present in diet.
deficiency Relatively mild condition. Autosomal recessive.
Symptoms: galactose appears in blood (galactosemia) and urine (galactosuria); infantile cataracts.
May present as failure to track objects or to develop a social smile. Galactokinase deficiency is
kinder (benign condition).
Classic galactosemia Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive. Damage is caused by
accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).
Symptoms develop when infant begins feeding (lactose present in breast milk and routine formula)
and include failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability. Can
predispose to E coli sepsis in neonates.
Treatment: exclude galactose and lactose (galactose + glucose) from diet.
Galactose metabolism Fructose is to Aldolase B as Galactose is to
Galactokinase Uridyltransferase
UridylTransferase (FAB GUT).
Galactose Galactose-1-P Glucose-1-P The more serious defects lead to PO43− depletion.
ATP
ADP UDP-Glu UDP-Gal
Aldose
reductase
Glycolysis/glycogenesis
4-epimerase
Galactitol

Biochemistry 
Sorbitol An alternative method of trapping glucose in the cell is to convert it to its alcohol counterpart,
sorbitol, via aldose reductase. Some tissues then convert sorbitol to fructose using sorbitol
dehydrogenase; tissues with an insufficient amount/activity of this enzyme are at risk of
intracellular sorbitol accumulation, causing osmotic damage (eg, cataracts, retinopathy, and
peripheral neuropathy seen with chronic hyperglycemia in diabetes).
High blood levels of galactose also result in conversion to the osmotically active galactitol via aldose
reductase.
Liver, Ovaries, and Seminal vesicles have both enzymes (they LOSe sorbitol).
Aldose reductase Sorbitol dehydrogenase
Glucose Sorbitol Fructose
NADPH NAD+
Lens has primarily aldose reductase. Retina, Kidneys, and Schwann cells have only aldose
reductase (LuRKS).
Lactase deficiency Insufficient lactase enzyme dietary lactose intolerance. Lactase functions on the intestinal brush
border to digest lactose (in milk and milk products) into glucose and galactose.
Primary: age-dependent decline after childhood (absence of lactase-persistent allele), common in
people of Asian, African, or Native American descent.
Secondary: loss of intestinal brush border due to gastroenteritis (eg, rotavirus), autoimmune disease,
etc.
Congenital lactase deficiency: rare, due to defective gene.
Stool demonstrates pH and breath shows hydrogen content with lactose hydrogen breath test.
Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.
FINDINGS Bloating, cramps, flatulence, osmotic diarrhea.
TREATMENT Avoid dairy products or add lactase pills to diet; lactose-free milk.
Amino acids Only l-amino acids are found in proteins.

Essential PVT TIM HaLL: Phenylalanine, Valine, Tyrosine, Threonine, Isoleucine, Methionine, Histidine,
Leucine, Lysine.
Glucogenic: Methionine, histidine, valine. I met his valentine, she is so sweet (glucogenic).
Glucogenic/ketogenic: Isoleucine, phenylalanine, threonine, tyrosine.
Ketogenic: Leucine, Lysine. The onLy pureLy ketogenic amino acids.
Acidic Aspartic acid, glutamic acid.
Negatively charged at body pH.
Basic Arginine, histidine, lysine.
Arginine is most basic. Histidine has no charge at body pH.
Arginine and histidine are required during periods of growth.
Arginine and lysine are in histones which bind negatively charged DNA.
His lys (lies) are basic.

Urea cycle Amino acid catabolism results in the formation Ordinarily, Careless Crappers Are Also
of common metabolites (eg, pyruvate, acetyl- Frivolous About Urination.
CoA), which serve as metabolic fuels. Excess
nitrogen generated by this process is converted
to urea and excreted by the kidneys.
CO2 + NH3
2 ATP
synthetase I
Carbamoyl
phosphate
Aspartate
N-acetylglutamate Citrulline
2 ADP + Pi Arg
(allosteric activator) e
las
rba e
ini ynth
ATP
sca hin
my
no eta
s
tran Ornit
suc se
Carbamoyl
AMP + PPi
cina
Urea phosphate
te
NH3 NH2 Mitochondria
Ornithine Argininosuccinate
CO2 C O Cytoplasm
nase
(liver)
Aspartate NH2
u cci
To kidney Urea
A rg
nos
ina
ini
se
rg
A
H2O
Arginine
Fumarate
Transport of ammonia by alanine

ST
AR
Muscle Liver
T
Amino acids Alanine Alanine

(NH3) α-Ketoglutarate (NH3) (NH3) α-Ketoglutarate
y
Cahill cycle
lucose
Glucose Glucos
Glucose
α-Ketoacids Glutamate (NH3) Pyruvate Cori cycle Pyruvate Glutamate (NH3)
Lactate Lactate Urea (NH3) FIN

ISH
Hyperammonemia Can be acquired (eg, liver disease) or hereditary Ammonia accumulation—flapping tremor
(eg, urea cycle enzyme deficiencies). (asterixis), slurring of speech, somnolence,
Excess NH3 depletes glutamate (GABA) in the vomiting, cerebral edema, blurring of vision.
CNS and α-ketoglutarate inhibition of TCA
cycle.
Treatment: limit protein in diet.
May be given to ammonia levels:
Asterixis
Lactulose to acidify the GI tract and trap
NH4+ for excretion.
Antibiotics (eg, rifaximin, neomycin) to
colonic ammoniagenic bacteria.
Benzoate, phenylacetate, or phenylbutyrate
react with glycine or glutamine, forming
products that are renally excreted.

Biochemistry 
Ornithine Most common urea cycle disorder. X-linked recessive (vs other urea cycle enzyme deficiencies,
transcarbamylase which are autosomal recessive). Interferes with the body’s ability to eliminate ammonia. Often
deficiency evident in the first few days of life, but may present later. Excess carbamoyl phosphate is converted
to orotic acid (part of the pyrimidine synthesis pathway).
Findings: orotic acid in blood and urine, BUN, symptoms of hyperammonemia. No
megaloblastic anemia (vs orotic aciduria).
Amino acid derivatives

Thyroxine Melanin
BH4 BH4 B6 Vitamin C SAM

Phenylalanine Tyrosine Dopa Dopamine NE Epi
B2, B6 Niacin NAD+/NADP+
Tryptophan BH4, B6
Serotonin Melatonin
B6
Histidine Histamine
B6
Glycine Porphyrin Heme
B6 GABA
Glutamate
Glutathione
Creatine
Arginine Urea
BH4 Nitric oxide
BH4 = tetrahydrobiopterin
Catecholamine synthesis/tyrosine catabolism

Phenylalanine
BH4 Phenylalanine
hydroxylase PKU
Homogentisic acid Tyrosine

BH4 Tyrosine
Alkaptonuria Homogentisate hydroxylase Albinism
oxidase
DOPA Tyrosinase
Maleylacetoacetic acid (Dihydroxyphenylalanine) Melanin
Fumarate B6 DOPA – Carbidopa

decarboxylase
Dopamine
TCA cycle Vitamin C Dopamine

β-hydroxylase
Catechol-O-methyl transferase
Norepinephrine
Phenylethanolamine-N-
SAM methyltransferase Cortisol Normetanephrine
Epinephrine Metanephrine Vanillylmandelic acid Homovanillic acid

Phenylketonuria Due to phenylalanine hydroxylase or Autosomal recessive. Incidence ≈ 1:10,000.

tetrahydrobiopterin (BH4) cofactor Screening occurs 2–3 days after birth (normal at
(malignant PKU). Tyrosine becomes essential. birth because of maternal enzyme during fetal
phenylalanine excess phenyl ketones in life).
urine. Phenyl ketones—phenylacetate, phenyllactate,
Findings: intellectual disability, growth and phenylpyruvate.
retardation, seizures, fair complexion, eczema, Disorder of aromatic amino acid metabolism
musty body odor. musty body odor.
Treatment: phenylalanine and tyrosine in PKU patients must avoid the artificial sweetener
diet, tetrahydrobiopterin supplementation. aspartame, which contains phenylalanine.
Maternal PKU—lack of proper dietary therapy
during pregnancy. Findings in infant:
microcephaly, intellectual disability, growth
retardation, congenital heart defects.
Maple syrup urine Blocked degradation of branched amino Autosomal recessive.

disease acids (Isoleucine, Leucine, Valine) due to Presentation: vomiting, poor feeding, urine
branched-chain α-ketoacid dehydrogenase smells like maple syrup/burnt sugar.
(B1). Causes α-ketoacids in the blood, I Love Vermont maple syrup from maple trees
especially those of leucine. (with B1ranches).
Causes severe CNS defects, intellectual
disability, and death.
Treatment: restriction of isoleucine, leucine,
valine in diet, and thiamine supplementation.
Alkaptonuria Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate
A pigment-forming homogentisic acid accumulates in tissue A . Autosomal recessive. Usually
benign.
Findings: bluish-black connective tissue, ear cartilage, and sclerae (ochronosis); urine turns black on
prolonged exposure to air. May have debilitating arthralgias (homogentisic acid toxic to cartilage).
Homocystinuria Types (all autosomal recessive): All forms result in excess homocysteine.
Cystathionine synthase deficiency HOMOCYstinuria: Homocysteine in
(treatment: methionine, cysteine, B6, urine, Osteoporosis, Marfanoid habitus,
B12, and folate in diet) Ocular changes (downward and inward
affinity of cystathionine synthase for lens subluxation), Cardiovascular effects
pyridoxal phosphate (treatment: B6 and (thrombosis and atherosclerosis stroke
cysteine in diet) and MI), kYphosis, intellectual disability. In
Methionine synthase (homocysteine homocystinuria, lens subluxes “down and in”
methyltransferase) deficiency (treatment: (vs Marfan, “up and fans out”).
methionine in diet)
Methionine Cystathionine
synthase synthase
Methionine Homocysteine Cystathionine Cysteine
B12 B6
Serine

Biochemistry 
Cystinuria Hereditary defect of renal PCT and intestinal Autosomal recessive. Common (1:7000).
A
amino acid transporter that prevents Urinary cyanide-nitroprusside test is diagnostic.
reabsorption of Cystine, Ornithine, Lysine,
and Arginine (COLA).
Excess cystine in the urine can lead to recurrent Cystine is made of 2 cysteines connected by a
precipitation of hexagonal cystine stones A . disulfide bond.
Treatment: urinary alkalinization (eg, potassium
citrate, acetazolamide) and chelating agents
(eg, penicillamine) solubility of cystine
stones; good hydration.
Glycogen regulation by insulin and glucagon/epinephrine

Epinephrine Epinephrine
(liver and muscle) (liver)
Insulin
(liver and muscle)
Glucagon Receptor Receptor
(liver) Tyrosine
te kinase
Adenyla
cyclase dimer
receptor
Glucagon Endoplasmic
receptor cAMP Calcium-calmodulin
ATP in muscle during reticulum
contraction
Protein kinase A Calcium
Protein kinase A
Glycogen
−
Glycogen
phosphorylase kinase
Glycogen Glycogen
phosphorylase synthase
−
Protein phosphatase
Glucose

Glycogen Branches have α-(1,6) bonds; linkages have α-(1,4) bonds.

Skeletal muscle Glycogen undergoes glycogenolysis glucose-1-phosphate glucose-6-phosphate, which is
rapidly metabolized during exercise.
Hepatocytes Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.
Glycogen phosphorylase liberates glucose-1-phosphate residues off branched glycogen until 4
glucose units remain on a branch. Then 4-α-d-glucanotransferase (debranching enzyme ) moves
3 of the 4 glucose units from the branch to the linkage. Then α-1,6-glucosidase (debranching
enzyme ) cleaves off the last residue, liberating glucose.
“Limit dextrin” refers to the one to four residues remaining on a branch after glycogen phosphorylase
has already shortened it.
Glucose
I II
Lysosome only # Glycogen storage disease type
Glucose-6-P
III UDP-glucose pyrophosphorylase
Glycogen synthase
Glucose-1-P Branching enzyme
Glycogen phosphorylase
UDP-glucose Debranching enzyme
(4-α-D-glucanotransferase)
Debranching enzyme
(α-1,6-glucosidase)
Glycogen V Limit dextrin α-1,4-glucosidase
Note: A small amount of glycogen is degraded in lysosomes by α-1,4-glucosidase (acid maltase).

Biochemistry 
Glycogen storage At least 15 types have been identified, all Very Poor Carbohydrate Metabolism.
diseases resulting in abnormal glycogen metabolism Types I, II, III, and V are autosomal recessive.
and an accumulation of glycogen within cells.
Periodic acid–Schiff stain identifies glycogen
and is useful in identifying these diseases.
DISEASE FINDINGS DEFICIENT ENZYME COMMENTS
Von Gierke disease Severe fasting hypoglycemia, Glucose-6-phosphatase Treatment: frequent oral
(type I) Glycogen in liver and glucose/cornstarch; avoidance
kidneys, blood lactate, of fructose and galactose
triglycerides, uric acid Impaired gluconeogenesis and
(Gout), and hepatomegaly, glycogenolysis
renomegaly. Liver does not
regulate blood glucose.
Pompe disease Cardiomegaly, hypertrophic Lysosomal acid α-1,4- PomPe trashes the PumP (1,4)
(type II) cardiomyopathy, hypotonia, glucosidase with α-1,6- (heart, liver, and muscle)
exercise intolerance, and glucosidase activity (acid
systemic findings lead to early maltase)
death.
Cori disease Milder form of von Gierke Debranching enzyme Gluconeogenesis is intact
(type III) (type I) with normal blood (α-1,6-glucosidase)
lactate levels. Accumulation
of limit dextrin–like
structures in cytosol.
McArdle disease glycogen in muscle, but Skeletal muscle glycogen Blood glucose levels typically
(type V) muscle cannot break it down phosphorylase unaffected
painful Muscle cramps, (Myophosphorylase) McArdle = Muscle
Myoglobinuria (red urine) Hallmark is a flat venous
with strenuous exercise, and lactate curve with normal
arrhythmia from electrolyte rise in ammonia levels during
abnormalities. Second-wind exercise
phenomenon noted during
exercise due to muscular
blood flow.

Lysosomal storage Each is caused by a deficiency in one of the many lysosomal enzymes. Results in an accumulation
diseases of abnormal metabolic products.
DISEASE FINDINGS DEFICIENT ENZYME ACCUMULATED SUBSTRATE INHERITANCE
Sphingolipidoses
Tay-Sachs disease Progressive neurodegeneration, HeXosaminidase A GM2 ganglioside AR
A developmental delay, “cherry-red” (“TAy-SaX”)
spot on macula A , lysosomes with
onion skin, no hepatosplenomegaly
(vs Niemann-Pick).
Fabry disease Early: Triad of episodic peripheral α-galactosidase A Ceramide XR

B neuropathy, angiokeratomas B , trihexoside
hypohidrosis. Late: progressive renal
failure, cardiovascular disease.
Metachromatic Central and peripheral demyelination Arylsulfatase A Cerebroside sulfate AR

leukodystrophy with ataxia, dementia.
Krabbe disease Peripheral neuropathy, destruction Galactocerebrosi- Galactocerebroside, AR
of oligodendrocytes, developmental dase psychosine
delay, optic atrophy, globoid cells.
Gaucher disease Most common. lucocerebrosidase Glucocerebroside
G AR
C Hepatosplenomegaly, pancytopenia, (β-glucosidase); treat
osteoporosis, avascular necrosis of with recombinant
femur, bone crises, Gaucher cells C glucocerebrosidase
(lipid-laden macrophages resembling
crumpled tissue paper).
Niemann-Pick disease Progressive neurodegeneration, Sphingomyelinase Sphingomyelin AR

D hepatosplenomegaly, foam cells
(lipid-laden macrophages) D ,
“cherry-red” spot on macula A .
Mucopolysaccharidoses
Hurler syndrome Developmental delay, gargoylism, α-l-iduronidase Heparan sulfate, AR
airway obstruction, corneal clouding, dermatan sulfate
hepatosplenomegaly.
Hunter syndrome Mild Hurler + aggressive behavior, no Iduronate-2-sulfatase Heparan sulfate, XR
corneal clouding. dermatan sulfate
GM2 Ceramide trihexoside No man picks (Niemann-Pick) his nose with

his sphinger (sphingomyelinase).
GM3 Tay-SaX lacks heXosaminidase.
Sulfatides Hunters see clearly (no corneal clouding) and
Glucocerebroside
aggressively aim for the X (X-linked recessive).
Galactocerebroside Ceramide Sphingomyelin incidence of Tay-Sachs, Niemann-Pick, and
some forms of Gaucher disease in Ashkenazi
Jews.

Biochemistry 
Fatty acid metabolism Fatty acid synthesis requires transport of citrate

from mitochondria to cytosol. Predominantly
Synthesis Degradation occurs in liver, lactating mammary glands, and
Fatty acid synthesis
adipose tissue.
(palmitate, a 16C FA) Long-chain fatty acid (LCFA) degradation
Fatty acid + CoA requires carnitine-dependent transport into the
Malonyl-CoA mitochondrial matrix.
Fatty Acyl-CoA
CO2 (biotin) synthetase “SYtrate” = SYnthesis.
Acetyl-CoA
Fatty Acyl-CoA CARnitine = CARnage of fatty acids.
ATP citrate
− Malonyl-CoA
Cell cytoplasm lyase Systemic 1° carnitine deficiency—inherited
Mitochondrial Citrate Carnitine
defect in transport of LCFAs into the
membranes shuttle shuttle mitochondria toxic accumulation. Causes
weakness, hypotonia, and hypoketotic
Mitochondrial
matrix hypoglycemia.
Citrate Fatty Acyl-CoA Medium-chain acyl-CoA dehydrogenase

β-oxidation deficiency— ability to break down fatty
(Acyl-CoA
dehydrogenases) acids into acetyl-CoA accumulation
Acetyl-CoA
of fatty acyl carnitines in the blood with
hypoketotic hypoglycemia. Causes vomiting,
Ketone TCA
lethargy, seizures, coma, liver dysfunction,
bodies cycle hyperammonemia. Can lead to sudden death
in infants or children. Treat by avoiding
fasting.

Ketone bodies In the liver, fatty acids and amino acids Ketone bodies: acetone, acetoacetate,
are metabolized to acetoacetate and β-hydroxybutyrate.
β-hydroxybutyrate (to be used in muscle Breath smells like acetone (fruity odor).
and brain). Urine test for ketones can detect acetoacetate,
In prolonged starvation and diabetic but not β-hydroxybutyrate.
ketoacidosis, oxaloacetate is depleted for RBCs cannot utilize ketones; they strictly use
gluconeogenesis. In alcoholism, excess NADH glucose.
shunts oxaloacetate to malate. Both processes HMG-CoA lyase for ketone production.
cause a buildup of acetyl-CoA, which shunts HMG-CoA reductase for cholesterol synthesis.
glucose, amino acids, and FFAs toward the
production of ketone bodies.
Hepatocyte Blood Extrahepatic tissues

(liver) (eg, skeletal muscle)
2 Acetyl-CoA
Expired by lungs
Fatty acids, amino acids Acetoacetyl-CoA
Acetyl-CoA
TCA cycle
Acetone
HMG-CoA
Acetoacetate Acetoacetate Acetoacetate
β-Hydroxybutyrate β-Hydroxybutyrate β-Hydroxybutyrate
ATP

Biochemistry 
Metabolic fuel use

1g carb/protein (eg, whey) = 4 kcal
100%
1g alcohol = 7 kcal
1g fatty acid = 9 kcal
% Maximal energy by source
Protein (# letters = # kcal)

Stored ATP
Creatine phosphate
Anaerobic metabolism
Fat Aerobic metabolism
Overall performance
3 4 5 6 7 8 2 sec 10 sec 1 min 2 hr

Weeks of starvation
Duration of exercise
Fasting and starvation Priorities are to supply sufficient glucose to the brain and RBCs and to preserve protein.
Fed state (after a Glycolysis and aerobic respiration. Insulin stimulates storage of lipids, proteins, and
meal) glycogen.
Fasting (between Hepatic glycogenolysis (major); hepatic Glucagon and epinephrine stimulate use of fuel
meals) gluconeogenesis, adipose release of FFA reserves.
(minor).
Starvation days 1–3 Blood glucose levels maintained by: Glycogen reserves depleted after day 1.
Hepatic glycogenolysis RBCs lack mitochondria and therefore cannot
Adipose release of FFA use ketones.
Muscle and liver, which shift fuel use from 100%
12
glucose to FFA
% Maximal energy by source

Hepatic gluconeogenesis from peripheral 10 Protein
tissue lactate and alanine, and from
Stored energy (kg)
8
adipose tissue glycerol and propionyl-
Fat
CoA (from odd-chain FFA—the only 6
triacylglycerol components that contribute
4
to gluconeogenesis)
Starvation after Adipose stores (ketone bodies become the main 2
day 3 source of energy for the brain). After these are Carbohydrate
0
depleted, vital protein degradation accelerates, 0 1 2 3 4 5 6 7 8 2 sec
leading to organ failure and death. Weeks of starvation
Amount of excess stores determines survival

time.

Lipid transport
Dietary fat
+
cholesterol
Thoracic duct Chylomicron enters lymphatics

HDL transfers Apo CII and Apo E
Chylomicron Apo CII activates LPL
Liver releases VLDL
Micelles VLDL Apo CII activates LPL
Subclavian vein 6 IDL delivers to liver via Apo E
Adipocyte
7 Endocytosis of LDL
TG TG
TG
FFA Lipoprotein
Lumen Intestinal cell lipase
Systemic circulation
Apo
B-48
Peripheral cell TG TG
Hepatocyte
Adipocyte Chylomicron Chylomicron
Chol E
TG Apo CII Cholesterol
HDL TG +
TGs
Apo E
TG TG
Chylomicron
TG remnant
FFA
LDL receptor Chol E
TG
Apo
B-100 Apo E
7 VLDL receptor Bile
VLDL TG TG
Canaliculus
Chol E Chol E
LDL Chol E IDL
TG
TG
Chol E
6 HDL

Biochemistry 
Key enzymes in lipid Cholesterol ester transfer protein mediates transfer of cholesterol esters to other lipoprotein
transport particles.
Hepatic lipase Degrades TGs remaining in IDL.
Hormone-sensitive Degrades TGs stored in adipocytes.
lipase
Lecithin-cholesterol Catalyzes esterification of 2⁄3 of plasma cholesterol.
acyltransferase
Lipoprotein lipase Degrades TGs circulating chylomicrons and VLDLs. Found on vascular endothelial surface.
Pancreatic lipase Degrades dietary TGs in small intestine.
Liver
Transfer of
Nascent LCAT Mature CETP cholesterol to
HDL HDL VLDL, IDL,
LDL
Small intestine
Major apolipoproteins
Chylomicron
Apolipoprotein Function Chylomicron remnant VLDL IDL LDL HDL
E Mediates remnant uptake ✓ ✓ ✓ ✓ ✓
(Everything Except LDL)
A-I Activates LCAT ✓
C-II Lipoprotein lipase Cofactor ✓ ✓ ✓
that Catalyzes Cleavage
B-48 Mediates chylomicron ✓ ✓
secretion into lymphatics
Only on particles originating
from the intestines
B-100 Binds LDL receptor ✓ ✓ ✓
Only on particles originating
from the liver

Lipoprotein functions Lipoproteins are composed of varying

proportions of cholesterol, TGs, and
phospholipids. LDL and HDL carry the
most cholesterol.
LDL transports cholesterol from liver to tissues. LDL is Lousy.
HDL transports cholesterol from periphery to HDL is Healthy.
liver.
Cholesterol Needed to maintain cell membrane integrity and synthesize bile acid, steroids, and vitamin D.
Chylomicron Delivers dietary TGs to peripheral tissues. Delivers cholesterol to liver in the form of chylomicron
remnants, which are mostly depleted of their TGs. Secreted by intestinal epithelial cells.
VLDL Delivers hepatic TGs to peripheral tissue. Secreted by liver.
IDL Formed in the degradation of VLDL. Delivers TGs and cholesterol to liver.
LDL Delivers hepatic cholesterol to peripheral tissues. Formed by hepatic lipase modification of IDL in
the liver and peripheral tissue. Taken up by target cells via receptor-mediated endocytosis.
HDL Mediates reverse cholesterol transport from periphery to liver. Acts as a repository for
apolipoproteins C and E (which are needed for chylomicron and VLDL metabolism). Secreted
from both liver and intestine. Alcohol synthesis.
Abetalipoproteinemia Autosomal recessive. Chylomicrons, VLDL, LDL absent. Deficiency in ApoB-48, ApoB-100.
Affected infants present with severe fat malabsorption, steatorrhea, failure to thrive. Later
manifestations include retinitis pigmentosa, spinocerebellar degeneration due to vitamin E
deficiency, progressive ataxia, acanthocytosis.
Treatment: restriction of long-chain fatty acids, large doses of oral vitamin E.
Familial dyslipidemias
TYPE INHERITANCE PATHOGENESIS BLOOD LEVEL CLINICAL
I—Hyper- AR Lipoprotein lipase or Chylomicrons, TG, Pancreatitis,
chylomicronemia apolipoprotein C-II cholesterol hepatosplenomegaly, and
deficiency eruptive/pruritic xanthomas
(no risk for atherosclerosis).
Creamy layer in supernatant.
II—Familial hyper- AD Absent or defective IIa: LDL, cholesterol Heterozygotes (1:500) have
cholesterolemia LDL receptors, or IIb: LDL, cholesterol, cholesterol ≈ 300mg/dL;
defective ApoB-100 VLDL homozygotes (very rare) have
cholesterol ≈ 700+ mg/dL.
Accelerated atherosclerosis (may
have MI before age 20), tendon
(Achilles) xanthomas, and
corneal arcus.
III—Dysbeta AR Defective ApoE Chylomicrons, VLDL Premature atherosclerosis,
lipoproteinemia tuberoeruptive xanthomas,
palmar xanthomas.
IV—Hyper- AD Hepatic VLDL, TG Hypertriglyceridemia (> 1000
triglyceridemia overproduction of mg/dL) can cause acute
VLDL pancreatitis. Related to insulin
resistance.

1 Biochemistry

Încărcat de

Informații document

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

1 Biochemistry

Încărcat de

Drepturi de autor:

Formate disponibile

HIGH-YIELD PRINCIPLES IN

“Biochemistry is the study of carbon compounds that crawl.” ``Molecular 34

This high-yield material includes molecular biology, genetics, cell

FAS1_2018_01-Biochem_27-92_Indexed.indd 33 10/10/17 10:38 AM

Chromatin structure DNA exists in the condensed, chromatin form to

Heterochromatin Condensed, appears darker on EM (labeled HeteroChromatin = Highly Condensed.

Euchromatin Less condensed, appears lighter on EM (labeled Eu = true, “truly transcribed.”

FAS1_2018_01-Biochem_27-92_Indexed.indd 34 10/10/17 10:38 AM

Nucleotides NucleoSide = base + (deoxy)ribose (Sugar).

FAS1_2018_01-Biochem_27-92_Indexed.indd 35 10/10/17 10:38 AM

Hydroxyurea AMP GMP  Mycophenolate and ribavirin: inhibit inosine

FAS1_2018_01-Biochem_27-92_Indexed.indd 36 10/10/17 10:38 AM

Purine salvage deficiencies

Nucleic acids Ribose-5-phosphate Nucleic acids

Nucleotides GMP IMP AMP

ADA, adenosine deaminase; APRT, adenine phosphoribosyltransferase;

Genetic code features

FAS1_2018_01-Biochem_27-92_Indexed.indd 37 10/10/17 10:38 AM

FAS1_2018_01-Biochem_27-92_Indexed.indd 38 10/10/17 10:38 AM

AUG AUG AUG

FAS1_2018_01-Biochem_27-92_Indexed.indd 39 10/10/17 10:38 AM

Start and stop codons

FAS1_2018_01-Biochem_27-92_Indexed.indd 40 10/10/17 10:38 AM

Functional Transcription start

DNA coding strand 5′ CAAT TATAAT Exon 1 GT AG Exon 2 GT AG Exon 3 AATAAA 3′

Promoter 5′ UTR Intron 1 Intron 2 3′ UTR

Regulation of gene expression

FAS1_2018_01-Biochem_27-92_Indexed.indd 41 10/10/17 10:38 AM

Cleavage at 5′ splice site; lariat-

Cleavage at 3′ splice site; lariat

FAS1_2018_01-Biochem_27-92_Indexed.indd 42 10/10/17 10:38 AM

FAS1_2018_01-Biochem_27-92_Indexed.indd 43 10/10/17 10:38 AM

FAS1_2018_01-Biochem_27-92_Indexed.indd 44 10/10/17 10:38 AM

halts translation  completed polypeptide is 40S

FAS1_2018_01-Biochem_27-92_Indexed.indd 45 10/10/17 10:38 AM

in tumor suppressor genes can result in

FAS1_2018_01-Biochem_27-92_Indexed.indd 46 10/10/17 10:38 AM

COPII Vesicular trafficking proteins

Peroxisome Membrane-enclosed organelle involved in:

FAS1_2018_01-Biochem_27-92_Indexed.indd 47 10/10/17 10:38 AM

FAS1_2018_01-Biochem_27-92_Indexed.indd 48 10/10/17 10:38 AM

Sodium-potassium Na+-K+ ATPase is located in the plasma Pumpkin = pump K+ in.

FAS1_2018_01-Biochem_27-92_Indexed.indd 49 10/10/17 10:38 AM

Collagen synthesis and structure

FAS1_2018_01-Biochem_27-92_Indexed.indd 50 10/10/17 10:38 AM

FAS1_2018_01-Biochem_27-92_Indexed.indd 51 10/10/17 10:38 AM

5' 3' 3' 5'

Denaturation—DNA is heated to ~95°C to separate the strands.

FAS1_2018_01-Biochem_27-92_Indexed.indd 52 10/10/17 10:38 AM

DNA is visualized when filter is exposed to Normal

FAS1_2018_01-Biochem_27-92_Indexed.indd 53 10/10/17 10:38 AM

Cells are tagged with antibodies specific to Fluorescent

Data are plotted either as histogram (one 104

because all CD8-expressing cells also express

FAS1_2018_01-Biochem_27-92_Indexed.indd 54 10/10/17 10:38 AM

Karyotyping A process in which metaphase chromosomes A

Fluorescence in situ Fluorescent DNA or RNA probe binds to A

Molecular cloning Production of a recombinant DNA molecule in a bacterial host.

FAS1_2018_01-Biochem_27-92_Indexed.indd 55 10/10/17 10:38 AM

FAS1_2018_01-Biochem_27-92_Indexed.indd 56 10/10/17 10:38 AM

Genetic terms (continued)

Hardy-Weinberg If a population is in Hardy-Weinberg Hardy-Weinberg law assumptions include:

FAS1_2018_01-Biochem_27-92_Indexed.indd 57 10/10/17 10:38 AM

FAS1_2018_01-Biochem_27-92_Indexed.indd 58 10/10/17 10:38 AM

Hydroxyurea AMP GMP Mycophenolate and ribavirin: inhibit inosine

halts translation completed polypeptide is 40S

Denaturation—DNA is heated to ~95°C to separate the strands.

22q11 deletion Microdeletion at chromosome 22q11 variable CATCH-22.

EXCESS Facial flushing (induced by prostaglandin, not Excess of vitamin B3 podagra.