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Only valine, leucine & isoleucine are NOT catabolized extensively in liver; instead they go to . (peripheral) muscle where they are 1st transaminated, and then resulting branched chain -ketoacids catabolized for energy production (with large energy yield).
TPP(thiamine)
hwb - jan 2011
*** Proteins rich in proline (P), glutamate (E), serine (S) & threonine (T) - (PEST) typically have short 1/2-lives
Familiar example? HMG-CoA reductase (4 hrs)
oxidative deamination
hwb - jan 2011
Glutamate dehydrogenase: a tightly regulated enzyme oxidative deamination vs reductive amination Activate oxidation: ADP, GDP; Inhibit oxidation: ATP, GTP
Fit this into the energy charge concept; Note: 2 different coenzymes for 2 opposing reactions; Glutamate: non-essential & glucogenic
Glutamate metabolism:
red. (NADPH) amination & oxid. (NAD+) deamination
OD-ing on Glutamate
Glutamate The key turn-around AA to either glutamine (ATPutilizing synth) or -ketoglutarate (ATPyielding TCA cycle)
hwb - jan 2011
Lysines -NH2
group binds to the carbon of PLPs aldehyde group; bond is a Schiff base
hwb - jan 2011
Made from NH4+, CO2 & ATP By carbamoyl phosphate synthetase (CPS I) This enzyme has an absolute requirement for an allosteric activator N-acetyl-glutamate
hwb - jan 2011
Argininosuccinate synthase
A: X LINKED OTC MOST COMMON Features of condition: UREA CYCLE DEFICINEY Orotic acid build-up; hyperammonemia & encephalopathy; feeding problems, vomiting, lethargy or irritability, poor CNS develt, tendency for coma death Condition aggravated by dietary protein Nous waste overload *** Males with non-conservative mutations rarely survive 1st 72 h. Half of survivors die in 1st month, and half of the remaining by age 5. When treatment and diet inadequate, liver transplant may become a treatment option.
hwb - jan 2011
Overall toxic levels of NH4+ seem to interfere with very high levels of ATP production required for normal brain function.
hwb - jan 2011
Alanine, aspartate, glutamate, asparagine & glutamine All 5 - closely related to common MAJOR metabolites Typical relationships: Eg: interconversion of pyruvate & alanine by alanine aminotrasferase (transaminase)
i.e. ALT
hwb - jan 2011 16
*** Tetrahydrofolate (THF) from Folic acid This cofactor/coenzyme - also related to tetrahydrobiopterin (BH4) see later Source: Vitamin B-9 folic acid
THFs synthesis from folate requires NADPH in two successive reductions by dihydrofolate reductase
NADPH + H+ NADPH + H+
Degradation of methionine
coenzyme roles:
pyridoxine (B6)
cystathionine synthase, cystathioninase (see error C&H)
folate (B9)
methyl-THF (from methylene THF);
20
A carrier of single carbon groups: Tetrahydrofolate (THF), from folic acid Vit B9, its interconversions from formyl-THF methyl-THF (know differences between formyl
(N10) methenyl, methylene (both N5-10) and methyl (N5) Note error: second reducer should also be NADPH !
hwb - jan 2011 21
SAM cycle
Through donation of its methyl group, SAM becomes Sadenosylhomocysteine (SAH); this is re-converted to homocysteine and then finally back to methionine Methylation of homocysteine methionine most important requires BOTH methyl tetrahydrofolate & cobalamin (vitamin B12) as methylcobalamin This reaction is a central feature of vitamin B12 deficiency and pernicious anemia (see this later in the vitamin story)
hwb - jan 2011 22
superficially, resembles Marfan syndrome, (also tall, thin build) but while Marfan has loose joints, in homocystinuria they are tight
hwb - jan 2011 24
Valine, Leucine & Isoleucine 1st transaminated, 2nd oxidatively decarboxylated, then 3rd FAD-linked oxidized
NB: These 3 AAs - transaminated in muscle & other extrahepatic tissues, and then catabolized BC--keto acid dehydrogenase resembles pyr. dehydrogenase; defects in PDH can cause maple syrup urine disease
hwb - jan 2011 25
Treatment: Megadoses of thiamin (why this?) can at times be effective Restrict dietary valine, leucine and isoleucine
hwb - jan 2011 26
Degradation of tryptophan
1st - oxidative cleavage of pyrrol forms N-formylkynurenine - by tryptophan pyrrolase (oxidase) requires O2, NADPH + H+ complex pathway; portion of molecule outside the ring becomes alanine & indole ring yields many products, incl acetoacetyl-CoA One product - nicotinic acid also considered a vitamin small, insufficient, amounts of related vitamin niacin can be formed in man A number of tryptophan-derived products such as kynurenate and xanthurenate cannot be degraded further but are excreted, giving urine its characteristic color
27
Tyrosinemia
Two causal Deficiencies: Types I & II (lack of I: fumaryl-acetoacetate hydrolase. homogentisate oxidase leads II: tyrosine transaminase (tyr to alkaptonuria, phenylpyruvate) a KEY SIGN IS BLACK Also note homogentisate oxidase URINE) deficiency alkaptonuria
Type I - more common patient: cabbage-like odor from accumulated organic acids built up through inhibition of early steps in degradation of tyrosine; impairment of tubular absorption & liver failure frequent death
hwb - jan 2011 29
Alanine
Oxaloacetate
Transaminase (req. PLP!!)
Aspartate
-ketoglutarate
Glutamate
-KetoGlutarate
+ NADPH!!! + NH3
Make note
Glutamate + NADP
Of the three amino acids formed via Transamination (alanine aspartate and glutamate), ONLY GLUTAMATE can be formed via REDUCTIVE AMINATION as well
GlutAMINE
Aspartate
+ NH3 (donated by glutamine!!!!!)
Asparagine
Note the succession in the formation of these three amino acids 1. Serine: Formed from 3-phosphoglycerate (3PG) of glycolysis. First - 3 phosphopyruvate is formed This is then transaminated (PLP) to 3-phosphoserine Hydrolysis of the phosphate ester creates serine
(It can also be formed by the attachment of a hydroxymethyl group to glycine carried by N5-N10 methylene tetrahydrofolate) methylene-THF** -
2. Glycine: by removal of hydroxymethyl from serine in a reaction that requires tetrahydrofolate (FH4) and PLP
(see also previous file)
We will discuss Cysteine synthesis in a few slides
hwb - sept '09
Synthesis of Serine
Transamination via PLP
SERINE
Synthesis of Glycine: from Serine Exact same reaction (directly above) but, in reverse!
Note the removal/attachment of a single-carbon group key step in interconversions of some amino acids
In the interconversion of Glycine to Serine (going from right to left on this figure): A hydroxymethyl group is being transferred from methylene-THF to Glycine to form Serine
Synthesis of cysteine from methionine & serine NB: at branch point, homocysteine; can be either (a) methylated or (b) condensed with serine to create cystathionine & on to Cysteine***
***note linked roles of
vitamins B6 & B12
B6
hwb - sept '09
B9
B12
B6
Three products of terminal reaction: 1. ammonia, 2. -ketobutyrate (to succinyl CoA), 3. cysteine
hwb - sept '09
Methyl-THF (B9)
Homocysteine
SERINE Cystathionine synthase REQ B6 Homocysteine methyltransferase REQ B12
Methionine
Cystathionine
Cystathionase REQ. B6
CYSTEINE
Tyrosine
Created by hydroxylation of phenylalanine by phenylalanine hydroxylase (PAH) Requirements: molecular O2 and key coenzyme tetrahydrobiopterin (BH4)*****; In this reaction one O atom becomes OH of tyrosine; the other is reduced to water During this reaction sequence, the tetrahydrobiopterin is oxidized and then recycled, via a reaction using NADPH *BH4 and THF use NADPH as reducing power
hwb - sept '09
Phenylalanine
Tyrosine
Tetrahydrobiopterin (BH4)
Dihydropteridine Reductase
Dihydrobiopterin (BH2)
NADP+
NADPH
Tetrahydrobiopterin and its roles in metabolism of the 3 aromatic amino acids *NO BH4* = hyperphenylalanemia, NO catecholamines, NO serotonin (from Tryptophan)
Cystine: 2 cysteines in SS- bond; transport/egress mechanism to cytosol is defective. Very poorly soluble: pure cystine 4-sided crystals; cystine-HCl prismatic needles (frequent in cornea) Clinical presentations: Does not involve metabolic breakdown; problem is in tearing, general (kidney) tubular Photophobia, retinal blindness,Transport*** dysfunction (Fanconi syndrome), acidosis, polyuria, weight loss, fevers, dehydration, muscle weakness (hypokalemia); major urinary ion losses; also glucosuria, diabetes mellitus, etc.; glomerular damage progresses dialysis or transplant essential at 6-12 yrs.
There are different points at which heme synthesis is contolled/regulated in the two main tissue types:
1. in liver control is at the first step (via allosteric negative feedback by heme)
2. in bone marrow control only at final step HIGH YIELD AS (indirectly via heme-induced inhibition of iron uptake not @#$%! allosteric in an enzymic sense. Enough complete heme means the tissue has sufficient Fe)
Biosynthesis of Porphyrins
Major sites, in the adult - as stated: 1. RBC-producing cells of bone marrow
2. liver here cytochrome P-450 enzymes are synthesized; thus major destination for heme
HIGH YIELD AS @#$%!
Initial and the last 3 steps of the process occur in the mitochondrion, - middle 4 take place in the cytosol.
Added
glycine
ALA
ALA Pb poisoning ALA dehydratase or porphobilinogen synthase (Zn2+)
Drugs that affect ALA synthase (inc activity): phenobarbitols (Symptoms of the hydantoins acute hepatic griseofulvin porphyrias are worsened by these drugs)
porphobilinogen
no light absorption 4 molecules condensed
3 porphobilinogen
CEP - AR! uroporph. III Hydroxymethylbilane = synthase Linear tetramer of Coproporphyrinogen porphobilinogen IIIMITO absorbs light cyclized to uroporphyrinogen Uroporphyrinogen III protoporphyrin can absorb light (ring)
IX
HEME
Pb poisoning
What is common to all the porphyrias? Decreased Heme synthesis increased ALA synthase in liver build up of toxic intermediates
(requires pyridoxal phosphate PLP) regulates the pathway in in liver rate-controlling step in liver Complex regulatory scheme: heme controls ALA synthase activity - 2 mechanisms
HIGH YIELD AS @#$%!
ALA synthase
1. lower [heme] raises catalytic activity & synthesis 2. higher [heme] blocks synthesis & translocation of ALA synthase from cytosol (site of synthesis) to mitochondrion (site of action)
Neg feedback by heme on ALA synthase LIVER regulation is at first step
Formation of porphobilinogen
2 -aminolevulinates (ALAs) condense to form this molecule via
requires Zn++ ; bivalent cations can competitively inhibit; very sensitive to Pb++ poisoning (Plumbism).
What would you see in a patient with lead poisoning? Anemia and elevated ALA
Formation of uroporphyrinogen
Aggregation of 4 molecules of porphobilinogen causes formation of uroporphyrinogen (hydroxymethylbilane is an
intermediate-1st to absorb light)
1st Synthasecloses the porphyrin ring/isomerization makes chain of 4 porphobilinogens (linear) 2nd Synthase creates ring from this chain; isomerizes it Final product: asymmetric uroporphyrinogen III (see side group arrangement)
if insufficiency of second enzyme (uroIII synthase), hydroxymethylbilane causes accumulation to levels that exceed the bodys capacity to excrete the molecule, cell now has a Phototoxic metabolite. What does phototoxic mean?
(patients with an enzyme defect that causes an accumulation of phototoxic metabolites will have itchy and burning skin when exposed to visible light)
Formation of heme
Through a set of oxidations and decarboxylations, Uroporphyrinogen III is modified to become protoporphyrin IX.
Final step: Fe++ inserted into ring center by ferrochelatase; Fe must be in ferrous (reduced Fe++) state **Control step in bone marrow NOT allosteric
HIGH YIELD AS @#$%!
Final product: Heme or Fe-protoporphyrin IX Ferrochelatase 2nd enzyme in this pathway sensitive to Pb inhibition / poisoning (Plumbism) Aug 20, 09: CNN Headline China, lead major smelters closed Pb poisoning in ~ 1000 children
The porphyrias (Gr. purple pigment) 1877: Felix Hoppe-Seyler (coins Biological Chemistry Biochemistry) 1889: Stokvis (Acute porphyrias)
Usually inherited may be acquired through environmental events If inherited generally autosomally dominant, except for Congenital Erythropoietic Porphyria (CEP) an autosomal recessive disease HIGH Classified as hepatic or erythropoietic Generally cause is a defect in heme synthesis;
YIELD AS @#$%!
Student Problem: what happens to the porphyrins & their precursors? what accumulates & what exists at lower concentrations?
hwb - may 2011
Extra
LEAD POISONING
PORPHYRIAS SUMMARY
ferrochetalase & ALA dehydratase HMB synthase copro and ALA accumulate
porphobilinogen +ALA accumulate patients NOT photosensitive liver enyzme deficiency AUTOSOMAL RECESSIVE patients are photosensitive BM enzyme deficiency
uroporphyrinogen decarboxylase
uroporphyrin accumulates most common porphyria patents are photosensitive liver and BM enzymes affected
liver enzyme deficiency patients are photosensitive protoporphyrin accumulates BM enzyme deficiency photosensitive, build up in RBC, BM &
Porphyrias decrease HEME synthesis. In the liver, heme inhibits ALA synthase. Porphyrias causes an increase in the synthesis of ALA synthase forms porphyrin intermediates prior to defective enzyme accumulation of TOXIC intermediates
Added
1.
2.
3.
4.
5.
Degradation of Heme & formation of bilirubin RBCs life span of ~ 120 days means continual turnover; taken up & degraded by spleens reticulo-endothelial cells 1st - the spleen and 2nd liver.
~ 85% heme destined for degradation comes from RBC, remainder from immature or badly formed RBCs & cytochromes from other systems
2.
3.
4.
5.
Hemolytic Jaundice Liver normally capable of handling a heme load of over 10 times the daily rate of heme production, so generally, able to process all that comes
But on occasion, as in massive lysis of RBCs (eg: malaria or sickle cell anemia) the patient will produce bilirubin at a rate that exceeds the capacity of the liver to degrade it. Now unconjugated bilirubin levels rise sharply in blood
no mutation, defect, or deficiency quantity problem too much bilirubin a
Neonatal jaundice
Recall from our previous discussion succession of Hbs in human development: Fetal Hb is ~ 2x as concentrated as HbA (210 g/L in HbF vs ~120 g/L vs HbA) Review the functional significance of this The excess Hb is rapidly dismantled shortly after birth, giving rise to the observed neonatal jaundice
neonatal jaundice Either deficiency of bilirubin glucuronyltransferase or too much HbF breakdown (remember: baby born with more hemoglobin than present in adults levels drop shortly after birth). Unconjugated bilirubin Treat with fluorescent light & give Vit. B2 (riboflavin) b/c its destroyed by light.
obstructive jaundice obstruction of bile duct (ex: bile stones) prevents passage of bilirubin into intestine for excretion so liver regurgitates conjugated bilirubin into blood
hepatocellular jaundice damage to liver cells (ex: cirrhosis in alcoholics) decreased conjugation and the conjugated bilirubin leaks into blood
Synthesis of Creatine Universal starting materials: Glycine & guanidino group of arginine, & methyl group of Sadenosylmethionine (Ado Met / SAM). Note integration of several sequences via key compounds directly no essential nutrients
* Synthesized in liver and pancreas in significant amounts * But neither tissue contains creatine kinase So separate sites for creatine synthesis & use of phosphocreatine Uptake & concentration in myocyte by specific Na+-dependent transporter.
Arginine + NADPH + O2 Nitric oxide Histidine + pyridoxal phosphate-dependent decarboxylation (PLP/non-oxidative decarboxylation) HISTAMINE Glutamate with PLP-dependent GABA Tryptophan with BH4-dependent hydroxylation which makes 5-Hydroxytryptophan, then decarboxylation with PLP Serotonin Serotonin with acetyl-CoA and SAM ( acetyltransferase and SAM/methylation) Melatonin
Melanin The pigment that colors hair, hide & eyes. Synthesis from tyrosine, via tyrosinase a Cucontaining enzyme
a 2-step process: uses DOPA as a cofactor and produces dopaquinone Following exposure to UV light, higher levels of tyrosinase and a protein called tyrosinase related protein are induced. Albinism often caused by lack of tyrosinase
Know the main points Activators Enzymes The difference between purine and pyrimidine and not the total reaction Know regulators Know how to salvage purines
Purine nucleotide synthesis de novo Synthesized as the relevant nucleotide on a required scaffold Phosphoribosyl-pyrophosphate (PRPP)
Requirements: Precursors: 3 common AAs: aspartate, glutamine, glycine; CO2 Folic acid derivatives (vitamin B-9) as tetrahydrofolate (TH4) to donate 1-C formyl groups Ribose-5-P (via PRPP - of HMP origin) Energy from ATP: large amounts
hwb - jan 2011
Sources of atoms that comprise the purine nucleus: aspartate & glutamine donate N only; all of glycine; formyl-FH4 donates (1-C) formyl groups
hwb - jan 2011
Purine ring fabricated by series of reactions that add nitrogen and carbons to already existing PRPP (pyrophosphorylated - at C-1- of ribose-5-P, shunt sugar)
1st Step: PRPP made by: Ribose phosphate pyrophosphokinase (or PRPP synthetase which requires ATP) Note: activator (Pi) and inhibitors (ie IMP, AMP & GMP)
KNOW THIS
inhibited by the mononucleotides AMP, GMP, IMP - the pathways end products
Note: this enzyme has a Km for PRPP significantly higher than intracellular concentrations of PRPP thus any small change in [PRPP] causes a proportional change in reaction rate. Significance? PRPP a potent activator. Also, synthesis accurately reflects availability of platform
The 3rd step: ends with synthesis of inosine monophosphate (IMP) the stem (parent) purine nucleotide
nine (yes 9!) steps are involved here A derivative of tetrahydrofolate FH4 - (formyltetrahydrofolate) is required here in two key reactions that transfer 1-C groups. Inhibition here blocks purine & therefore nucleic acid synthesis Folate is essential in attachments of one-carbon groups such as formate, methyl groups, and methylene (review serine/glycine metabolism).
Note: analogues of folic acid can stop the assembly of purines, explaining their use in treatment of cancers
hwb - jan 2011
The cells investment? PRPP, 4 ATP, 2 Gln, asp, glycine, 2 formyl-THF, CO2 NO biotin needed!! Note: inhibs & activs; Antibiotics - 2 places in formyl transfers
FOLATE TRAP No Vitamin B12 OR NO HOMOCYSTEINE METHYLTRANSFERASE remember back to the Methionine pathway that in order to remake methionine you need to have vitamin B12, WITHOUT THIS YOU NO LONGER CAN REMAKE METHIONINE. ALSO, THE POINT OF THIS SLIDE, YOU CANT GENERATE TETRAHYDROFOLATE(THF) FROM METHYL THF. SO YOU HAVE TRAPPED THE FOLATE WHERE IT IS ALL STUCK IN THE METHYL THF FORM NO PURINE SYNTHESIS
4th Step: Conversion of IMP to GMP and AMP note point of action of Mycophenolate
2-steps; reciprocal energy sources (GTP for AMP; ATP for GMP); in each case 1st step is regulated
Similar to arginosuccinate synthetase back in the urea cycle =) hwb - jan 2011
en.wikipedia.org
Energetic exchange bank - base-specific. Base-specific nucleoside mono- di- phosphate kinases
Both consecutive reactions: run by xanthine oxidase (XO), which produces the ROS H2O2 in each reaction -
Hyperuricemia/gout, contd
Uric acid and its salt crystals precipitate in synovial fluid of joints arthritis & degeneration of joint Often associated with rich (DNA-purine-rich) foods: liver, sweetbreads, anchovies, red wine, often historically associated with excessively high life, ie abundance of good food, dietary protein. BUT gout can also arise from cancer chemotherapy likely due to overload of purines caused by nucleic acid degradation after death of cancer cells.
hwb - jan 2011
In severe form, this will cause a lack of T and B lymphocytes, causing Severe Combined
Extra*
Multifunctional Enzyme
3 domains of same polypeptide chain
CPS II CO2 + 2ATP + glutamine carbamoyl phosphate inhibited by UTP activated by ATP, PRPP aspartate transcarbamoylase (ATCase) carbamoyl phosphate + aspartate carbamoyl aspartate in prokaryotic cells, this is the regulatory step and is inhibited by CTP dihydroorotase carbamoyl aspartate + H2O dihydroorotate THEN dihydroorotate + NAD orotate (complete ring added) via Dihydroorotate DH orotate + PRPP OMP via Orotate phosphoribosyl transferase OMP CO2 UMP via OMP decarboxylase
last 2 enzymes: transferase & decarboxylase are separate domains on a single polypeptide UMP
This is catalyzed by CTP synthetase amido nitrogen donated by glutamine Transfering this costly amido group from glutamine to another compound hydrolysis of anhydrous phosphate (ATP, pyrophosphate, etc)
All N-ous bases stem from only 2 compounds by the simple addition or removal of functional groups:
a unifying & very cost-effective concept
Purines IMP + -NH2 (at different points) AMP or GMP Pyrimidines OMP - CO2 UMP UTP + - NH2 CTP UDP reduction dUDP - Pi dUMP dUMP + -CH3 dTMP; + 2 Pis dTTP DNA
web2.airmail.net
Note: these very similar modifications are specific for the phosphorylation status of the acceptor molecule
hwb - jan 2011
extra
UMP UDP dUDP dUMP dTMP dTTP UMP created from stem molecule of pyrimidines OMP needs to be phosphorylated to UDP in order to undergo reduction to deoxy state UDP is converted to dUDP via ribonucleotide reductase dUDP needs to return back to mono-state, dUMP in order to be methylated dUMP is methylated to dTMP via Thymidylate synthase (methyl from THF)
dTMP is converted to dTDP and then to dTTP via kinases and ATP
to put it plainly needs to be in DI-form to become deoxy needs to be in MONO-form to become methylated
aaronlogan.com
linkage of two 5-Fluorouracil inhibits enzymes required: thymidylate synthase dihydrofolate methotrexate inhibits reductase & dihydrofolate reductase thymidylate either of these 2 inhibitors synthase
results in blocking synthesis of dTMP
hwb - jan 2011
Tetrahydrofolate (H4-folate) recycled from dihydrofolate by the action of dihydrofolate reductase, which requires NADPH
Methylene H4-folate supplies the methyl group in the synthesis of dTMP from dUMP. Recall - serine donates this 1- C group, controlling TH4s role here. Clin. Corr.: Functional H4-folate essential for ultimate production of dTTP & DNA); considerable scope for cancer treatment;
eg: methotrexate (amethopterin) competitively & strongly (x100 than substrate) inhibits dihydrofolate reductase (model out LW-Burk plot for this!)
remember competitive inhibition = same binding site, decreased affinity ( Km), same Vmax
(methylene-THF)
All Pi additions require ATP - mainly of mitochondrial origin (in bacteria oxphos is on plasma membrane)
Total body stores: app 80-110 mg; liver is central l Dietary need: app 1-3 mg/day; Excretion: bile ~1.5-2 mg/day ~ 60% Cu bound to ceruloplasmin; rest bound loosely to albumin or in histidine-complex
Ceruloplasmin (cpm) abundant; 95+% plasma Cu; Glycoprotein single polypeptide with 6 Cus; 2-globulin; site of synthesis hepatocyte; -life = 5.5 d.;
Copper
Normally 10% cpm apoprotein, secreted w/o Cu, -life ~ 5 hrs; Changes in Cu or cpm synthesis easily effect Wilsons disease
Functions: In Cu-containing metalloenzymes; Generally these use either molecular O2 or an oxygen derivative as a substrate. Examples: cytochrome oxidase, dopamine -hydroxylase, tyrosinase, lysyl oxidase (compare this with lysyl hydroxylase - with its Fe++), and cytoplasmic superoxide dismutase (see Lou Gehrigs disease) *Cu necessary for SOD function
HWB - Sept '09
Some trace metals - a two-edged problem: Deficiency and Toxicity E.g.: Copper 1. Deficiency Menkes Disease (kinky hair syndrome) Rare, X-linked recessive, untreated fatal; Infants with condition, exposed to normal amounts of dietary Cu, cannot absorb & retain enough for normal metabolism; growth retardation, mental deficiency, seizures, arterial aneurysms, bone demineralization, brittle hair. Apparent cause: deficiency of ATP-dependent Cu transporter; Possibly also - improper binding to histidine & other AAs Treatment absorbable copper-histidine complex 2. Toxicity Wilsons Disease *affects liver/brain mainly (accumulation of Cu) *Kayser-Fleischer rings!
HWB - Sept '09
Zinc Key in many enzymes; Next to Fe most abundant trace mineral; Total stores ~ 1.5 2.5 g; in adult male RDA ~15 mg/day Many Zn metalloenzymes (300+ identified 2000+ proteins) Egs: carbonic anhydrase, cytoplasmic superoxide dismutase (contains both Cu & Zn), alcohol dehydrogenase, carboxypeptidases A & B, DNA & RNA polymerases Sources: meat, nuts, beans, wheat germ broad variety of foods Avg daily diet contains ~ 10-20 mg Absorption - upper reach of small intestine incomplete; depends largely upon food substances that could interfere No specific binding blood protein: transport - serum albumin Storage with metallothionein present - many tissues, synthesis induced by heavy metals : zinc, cadmium, arsenic Zn absorption follows metallothionein levels in intestinal
mucosa.*** (Q!!) Metallothionein(s) protect(s) cell from toxic effects of free, unbound metalHWB S: ions. 9
Zinc:
Zinc is transported in the blood via Albumin GI uptake via Transferrin Zinc is stored by metallothionein-- a zinc-binding protein present in many tissues Metallothioneins synthesis induced by heavy metals!!!!! Metallothioneins main role is to protect the cell from toxic effects of free, unbound metal ions. Zinc deficiency- may see Dermatitis and rare autosomal recessively inherited condition called Acrodermatitis Enteropathica
Keshan disease (cardiomyopathy endemic in some parts of Asia) caused by low Se content of locally grown foodstuffs. Se content of soils varies widely, worldwide; reflected in Se content of locally grown plants
HWB - Sept '09
Ferritin Fe storage
shell: 24 similar subunits (H 178 AAs & L 171 AAs); ratios vary. H heart, nucleated (nascent) blood cells ; L- liver, spleen
hollow core up to 4,500 Fe+++ as ferric oxide hydroxide (FeOOH) crystals; usually under 3,000. Fe/protein not constant Most abundant storage form when iron stores low small amounts of ferritin, mostly apoferritin with little bound iron, is also present in blood; released during normal cell turnover
Hemosiderin
contains FeOOH & same subunits of ferritin, soluble. Rich in Fe+++ Hemosiderin predominates when tissue stores of Fe high or Fe is in excess.
HWB - Sept '09
Iron:
Most Iron (2/3) is in hemoglobin; the rest is stored in Ferritin and Hemosiderin Can be very toxic in the free state can form free radicals Ferritin = storage form when Fe stores are low Hemosiderin = storage form when Fe stores are high/in excess Most common nutritional deficiency worldwide
****most common inherited metabolic disorder in Caucasian population in US. Avoid Fe- fortified foods esp males
Potentially lethal: Liver damage, diabetes mellitus from pancreatic involvement, cardiomyopathy, hyperpigmentation, joint pain Elevated Fe levels often seen in liver biopsies of patients with alcoholic cirrhosis - (alcohol stimulates Fe absorption!) *** In such cases, difficult to say if the liver disease or the alcoholism caused the condition
HWB - Sept '09
B-vitamins
B-1 (TPP)
Oxidative decarboxylations, transketolases
B-2 (riboflavin) B-3 (Niacin) B-5 (pantothenic acid) B-6 (pyroxidine PLP)
Transaminations and non-oxidative decarboxylation Carboxylations
B-12 (Cobalamine)
B-1 Deficiencies moderate GI complaints, weakness, burning feet (?!), peripheral neuropathy, reduced mental acuity and ataxia will appear
Advanced deficiency Beriberi, cardiovascular & neuromuscular disorders, weakness, delirium, muscle wasting, paralysis of eye muscles, memory loss, high venous return
Deficiencies uncommon in industrialized countries, except in the alcoholic who has impaired intestinal absorption and thus a poor dietary intake of most things Acutely - Wernicke-Korsakoff syndrome (Wernicke encephalopathy) very serious Metal derangements and amnesia irreversible **Korsakoff syndrome is the most common amnesic syndrome in the US Q) what do you give alcoholics? TPP supplements Best sources of B-1: pork, whole grains, nuts
hwb - Sept '09
B1-TPP
Coenzyme form= thiamine pyrophosphate TPP Participates in transfers of 2-carbon -keto groups to phosphorylated aldehyde sugars: For ex. In transketolase rxns of HMP And participates in oxidative decarboxylations of pyruvate, and other -ketoacids Advanced deficiency Beriberi Acutely - Wernicke-Korsakoff syndrome, seen often in alcoholics
Riboflavin B-2 Structure - dimethylalloxasine ring bound to ribitol a sugar alcohol related to ribose
Only biological function known precursor to FAD and FMN, electron acceptor; Yellow color - absorbs at 450 nm. Uptake energy dependent Dietary sources: Liver, yeast, eggs, meat, enriched bread, milk Deficiencies: Glossitis, sore throat, moist dermatitis of nose; ****destroyed by natural light (UV); therapy routinely given in hyperbilirubinemia (neonatal hwb - Sept '09 treated with phototherapy jaundice)
B2- Riboflavin
precursor to FAD and FMN Riboflavin is destroyed by UV light- which is why it needs to be supplemented in patients being treated with phototherapy for hyperbilirubinemia/neonatal jaundice who are
B3-Niacin
Precursor of NAD+ & NADP+ Only vitamin that can be made from one of our amino acids Tryptophan
B5-Pantothenic Acid
Required to synthesize Coenzyme A Essential prosthetic group of several Acyl Carrier Protein (ACP) of the fatty acid synthase complex Pantothenic acid in the form of CoA is required for acylation and acetylation rxns
B6
Active form is pyridoxal phosphate= PLP Key Prosthetic group of Aminotransferases (Transamination and Deamination) and NonOxidative Decarboxylases It is also an essential cofactor for glycogen phosphorylase (glycogneloysis)
Homocysteine + Methyl-THF methionine + THF MeTHF donmates Me group to Homocysteine, & is reconstituted as THF
**** If - a deficit in Vit B12, Methyl THF cannot give up its Me group, the THF remains locked as 5-Methyl-THF (folate trap)
Best sources: heat labile; extensive cooking can destroy it Yeast, liver, kidney, fish, fruits, green leafy vegetables (Latin folium = leaf) Low levels often seen in late pregnancy Thus (pernicious anemia) megaloblastic anemia can be precipitated in the pregnant woman who is a on a diet that is marginally low in folate
Rmbr: Methyl-tetrahydrofolate donates a methyl group to homocysteine to re-form methionine B9 Deficiency: DNA replication/cell division delayed can lead to Megaloblastic Anemia Severe deficiency in pregnant women: can impair embryonic development and lead to NEURAL TUBE DEFECTS like spina bifida and anencephaly
Vitamin B12
In mammals - only 2 reactions known to require cobalamin (15+ overall): 1. Methylation of homocysteine to methionine (homocysteine methyltransferase) and (methionine metab.) and methyl-THF 2. Methylmalonyl CoA mutase reaction (see consecutive carboxylation of propionyl-CoA to methylmalonyl-CoA and finally mutation of methylmalonyl-CoA to succinyl-CoA) Odd chain FA oxidation Deficiencies: As with folic acid, lack of this vitamin will cause megaloblastic anemia (pernicious anemia) looking just like the folate deficiency which also will cause incorporation of odd FAs in nerve membranes mechanisms? Insufficient methylations of RNA, DNA, etc via MeTHF as folate remains trapped in a sink from which it cannot escape
hwb - Sept '09
Vitamin B12 Carboxylation (biotin) of propionyl-CoA creates methylmalonyl-CoA, subsequent role of vitamin B12 in mutase reaction creating succinylCoA
B12- Cobalamin
Only coenzyme that has Cobalt--in center of a corrin ring Must come from animal products INTRINSIC FACTOR absolutely required for absorption of B12!!! (Thus, loss of intrinsic factor can cause B12 deficiency) Only 2 reactions require Cobalamin: A) Methylation of homocysteine to methionine via homocysteine methyltransferase and B) Conversion of methylmalonyl-CoA to succinyl-CoA via Methylmalonyl CoA mutase Deficiencies: can lead to megaloblastic anemia (pernicious anemia) looking just like the folate deficiency
Ascorbate
Deficiencies: Rare; switch to Vitamin C-free diet, symptoms appear after 2-3 months Dry mouth, eyes; peeling & decaying gums, small petechial hemorrhages, loose teeth, slow wound healing & scar formation; bleeding from old scars, weakness, sore legs, joint pain
Scurvy
Biotin
Deficiencies uncommon inducible diet that binds biotin, as in large consumption of raw
egg whites (12+/d!); contains Avidin - binds biotin & prevents uptake
Cooking denatures avidin & destroys its ability to bind biotin.
Proteolysis of Biotin-containing enzymes (in gut and tissues) yields biocytin; Biotinidase hydrolyzes biocytin & releases biotin for re-use Biotinidase Deficiency non-dietary biotin deficiency hypotonia, seizures, optic atrophy dietary supplements curative *** Biotinidase deficiency often included in newborn screening programs for treatable congenital diseases such as PKU, galactosemia, maple syrup urine disease, hypothyroidism Best sources: Yeast, liver, eggs, peanuts, milk, chocolate, fish
hwb - Sept '09
Biotin
Required as a prosthetic group of ATP-dependent carboxylases 3 major enzymes require Biotin: (1) Pyruvate carboxylase (2) Acetyl-CoA carboxylase (3) Propionyl-CoA carboxylase
Bound to the enzyme via the NH group of a lysyl residue Deficiency (dietary): though uncommon, can be caused by consumption of raw eggs (bodybuilders; Raw eggs contain Avidin which binds biotin tightly and prevents uptake Deficiency (non dietary): can also be cause by Biotinidase deficiency hydrolyzes biocytin & releases biotin for re-use
B-12 (Cobalamin)
Folic acid (B-9)
Summary
o Folate Trap Hyperhomocysteinemia o Intrinsic factor binds B-12 deficiency = pernicious anemia
B-2 (riboflavin)
o FMN/FAD co-enzymes (metabolism/energy) o Oral-ocular-genital syndrome (FYI)
Vitamin C
o Scurvy important in collagen formation (hydroxylation)
Vitamin A
Active forms: retinal, retinol, retinoic acid (trans straight form) NB: in foods of animal origin most in retino(y)l ester between retinol & long-chain FA Esters hydrolyzed by pancreatic enzymes, with aid of bile salts, Free retinol absorbed @ ~ 40 80% efficiency
In mucosal cell, most retinol - re-esterified with long-chain FA to retinyl esters; incorporated into chylomicrons then as cargo of chylomicron remnants reach liver; esters temporarily stored in stellate cells.
hwb -jan 2011
Metabolism of Vitamin A: Important bio-forms: retinoic acid (at level of gene), retinal (vision)
Retinol - initially in cis form (bent) Small amount oxidized irreversibly to retinoic acid Retinoic acids main target cells: epithelial cells - oxidize retinol, retinal to retinoic acid Retinals function: prosthetic group of rhodopsins visual pigment of rods & cones How light is sensed 1. Its long fatty tail imbeds retinal in retinas plasma membrane; 2. Light absorption changes cis- to trans- (straight) form 3. configuration change sensed by opsin, which holds retinal at its center 4. Change in shape triggers action potential, informs brain that the cell has just seen a photon of light. Deficiency of vitamin A night blindness
Pathway from retinol to retinoic acid to the gene Retinoic acid binds nuclear receptor proteins; Receptor-Retinoic Acid complex regulates gene expression after binding to Response elements on DNA;
Deficiencies: Transformation of columnar epithelia into heavily keratinized squamous epithelia (gooseflesh look)
In extreme cases: conjunctiva of eye loses mucus-secreting cells and becomes keratinized Loss of glycoprotein content of tears leading to xerophthalmia (dry eyes) which may lead to infections, and blindness Leading cause of blindness in developing countries
hwb -jan 2011
VITAMIN A: Retinoic acid acts like steroid hormone & regulates of epithelial membrane maintenance Retinal is used in the retina Vitamin A deficiency = night blindness (rods not working). Retinol is Vitamin A. RBP = retinol binding protein (carries vitamin A)
RXNS OCCUR!
In (1st) Liver & (2nd) kidney transformed to active 1, 25 dihydroxycholecalciferol (calcitriol) by 2 successive hydroxylations Calcitriol hormone-like action
hwb -jan 2011
Synthesis of Vitamin D
1st step - 25 hydroxylation is NOT rate limiting or regulatory major circulating form - 25-hydroxy-D3. Last step producing calcitriol - 1-hydroxylase - is regulatory tight control by parathyroid hormone (PTH) & the 2 linked states of hypocalcemia & hypophosphatemia.
Note 25-hydroxy-D3 & cholecalciferol have half-lives of ~ 30-40 days; on the other hand --mature calcitriol persists for only 2-4 hours (why so short?); single known action: up-regulate plasma [Ca++]
Vitamin D metabolism: Cholecalciferol is produced in skin by UV irradiation of 7-dehydrocholesterol; in liver a -OH is added at C-25; in kidney a second OH is added at C-1 (in the regulatory step), producing the mature molecule 1,25dihydroxycholecalciferol (calcitriol or vitamin D3)
Vitamin E -Tocopherol
VITAMIN E (TOCOPHEROL) = ANTIOXIDANT KNOW IT!!!!
Over 8 related substances, all with vit E activity, isolated from natural sources Most potent & prevalent : -tocopherol double methylated
RDA 10 mg/day for men; 8 mg/day for women Best sources: nuts, seeds, wheat germ & vegetable oils, leafy vegetables Requirement rises as intake of polyunsaturated FAs increases
Vitamin E:
Antioxidant- reduce amount of free radicals. Promote prostacyclin- vasodilate blood vessel and inhibit platelet aggregation- less thrombus occur
Vitamin K production, availability Menaquinone(K2) synthesis by bacteria in large intestine & absorbed there. Menadione - analogue after enzymic alkylation in body. Significantly menadione absorbed in absence of bile salts; thus can offset problems in natural production of Vit K due to long-term antibacterial therapy Parsley especially rich in Vit K; also meat eggs, dairy prods As with vitamin E - no specific vit K binding protein identified
Tissue Distribution: via plasma lipoproteins & chylomicrons Not stored to any extent, reserves low ~ 50 100 mg; However rapid & continual turnover Vit K - first fat-soluble vitamin to be deficient in acute fat malabsorption.
hwb -jan 2011
Only one known disorder: prolonged-clotting time (prothrombin time) period over which prothrombin thrombin; this converts prothrombin to make more of itself (multiplicative cascade) Newborns - esp premature very prone to Vit K deficiency; gut still sterile & maternal milk has insufficient Vit K Seen in ~ 1/400 live births: hemorrhagic disease of the newborn most common disease of the neonate Europe, most US states: neonatal Vit K prophylaxis mandatory KNOW*: HEMORRHAGIC DISEASE OF THE NEWBORN One other avenue TO USE deficiency of K AND WHAT VITAMIN can cause VITAMIN vit K (in adults): Combination of: Vit K-deficient diet & prolonged antibiotic therapy that can kill off flora in GI tract. In cases requiring extended antibiotic therapy, dietary fortification with Vit K is strongly advised.
hwb -jan 2011
Vitamin K deficiencies
Vitamin K = Koagulation! post-translational carboxylation. enzyme: Gamma-glutamyl carboxylase requires Vitamin K. deranged clotting cascade. Vit K - first fat-soluble vitamin to be deficient in acute fat malabsorption Factos II VII IX X ( always factor C and S) are Vitamin K-dependent!! Warfarin is vitamin K antagonist. most common disease of the neonate- Vitamin K deficiencies
Why the differences? the more reduced the substrate, the more O2 is consumed to produce equal amounts of CO2. Very significant!
3 Problems: i. Two equal (in Calories) diets consumed:
(a) 50 / 50 CH2O/fat (b) 75 / 25 CH2O/fat Which elicits the higher RQ? B
***A diet with more CH20 than other ingredients Higher RQ!!!
Which yields the lowest RQ? A iii. design a diet that yields All Fat 100%= lowest RQ & highest O2 uptake
hwb - jan 2011
Major factors in the livers response to CHO Hepatic GLUT 2 unaffected by insulin HIGH YIELD AS Liver retains ~ 60% of glucose after a meal - via @#$%! a. via glucokinase (high Km for glucose) b. accelerated glycogen synthesis c. increased HMP activity - from high use of NADPH in FA synthesis accounts for ~ 5-10% of G-6-P use in liver
Glucose flux increases for these reasons: a. huge standing #s of GLUT - 2s; b. Thus entry is never rate-limiting; c. glucose - rapid conversion Acetyl-CoA; in turn citrate FA synthesis d. In sum: glycolysis, HMP, TCA & ETS fully active; all power FA & triacylglycerol synthesis
Insulin is an effective antagonist of lipolysis (& breakdown of energy stores in general); -High Insulin TAGs synthesized after a meal; In contrast, TAGs are degraded during fasting/long-term work via glucagon
In turn this stimulates: . Glycogen synthesis if glycogen stores depleted by prior exercise, then glycogen synthesis; via glucose-1-phosphate, UDP-glucose - is heavily favored.
Under these conditions, glycogen phosphorylase and glycogen synthase are dephosphorylated the first is inactive and the synthase is active
Carbohydrate metabolism in brain No significant glycogen stores in brain; uses ~ 140 grams of glucose over a 24-h period; compare this to ~30 grams of glucose used by the RBC mass over the same time; why this huge difference? HIGH Brain glucose - totally oxidized to CO2 & water YIELD AS
@#$%!
Proposed: Lipostatic model for regulation of body weight involves 2 hormones: Leptin & Resistin (resistin renders adipocyte insulin resistant) can partially explain long-term relative constancy of somatic energy stores, effects of their depletion on ingestion, energy expenditure, linear growth, and fertility. Leptin - produced by adipocyte; promotes feeling of satiation & inhibits food intake Resistin produced by adipocyte; promotes resistance to insulin Output of both directly proportional to fat mass in absence of other factors
hwb - jan 2011
Well-fed State adipocyte GLUT-4 Muscle GLUT-4 Liver- Glut 2 Pancreas- Glut 2 respiratory quotient (RQ Highest= lots of carbs consume least O2 Lowest= lots of fat; consume most O2
Brain only uptake glucose ; with Glut-3, completely oxidize glucose to CO2 and water Also use ketones but in starvation mode
GAGS! Main factors cause increased secretion of insulin (mne Glucose (essentially in the well-fed state) Arginine Glucagon Secretin!!
Glucose most powerful stimulator (after uptake) Amino acids especially arginine
Gastrointestinal hormones after the ingestion of food
Liver: gluconeogenesis inhibited, glycogenolysis sharply diminished, Glucose uptake stimulated & glycogenesis stimulated (not a paradox synthesis of glucose and glycogen must not be confused) Peripheral tissues
Muscle: glucose
elevated Adipocyte: glucose uptake stimulated to produce glycerol-3-P for triacylglycerol synthesis & storage
hwb - jan 2011
2. This sets off a rapid chain of events in the -cell: accelerated catabolism ATP
(energy charge) levels rise closing of ATP-dependent K+ channels Ca++ entry membrane depolarization insulin secretion via exocytosis enhanced glucose uptake & storage in peripheral tissues
(credit Dr. M. Goodman, U. Mass) *** See upper left corner of next figure
hwb - jan 2011
Principal effect: Liver: elevation of cAMP promote glycogenolysis and inhibit both glycogen synthesis and glycolysis; this activates gluconeogenesis Adipocyte: R cAMP; protein kinase A phosphorylates hormone-sensitive lipase to yield FFAs and glycerol ( hepatic gluconeogenesis)
Glucagon, contd
From pancreatic -cells (near outer edge of Islet) Primary structure:
NH2 -His-Ser-Gln-Gly-Thr-Phe- Thr-Ser-Asp-Tyr-Ser -Lys-Tyr-Leu-Asp-Ser- Arg-Arg-Ala-Gln-AspPhe-Val-Gln-Trp-Leu- Met-Asn-ThrCOOH note
simple, small & no cysteine 12 AA residues (41 %) are essential or synthesized (Tyr) from essential AAs (40% of our 20 essential)
hwb - jan 2011
Glucagon
Stimulators of its secretion Fall in plasma [glucose] High catecholamines for some time Increased [AAs] to prevent hypoglycemia after an all-protein meal (arginine key role) Acetylcholine Cholecystokinin/pancreazymin Inhibitors of its secretion Somatostatin Insulin Control of output? Mechanism not yet understood: except that -cells seem to respond directly to changes in [glucose]
hwb - jan 2011
Leptin
Males, [leptin] are - in premenopausal females Other: pregnancy levels double; cannot cross LEPTIN - Promotes the feeling of being full and Note the placenta intake- Produced by adipose inhibits food differences!!!
tissue, like a negative feedback mechanism on eating
hwb - sept '09
Leptin
Product of adipose tissue - especially white adipose tissue (WAT); also BAT & stomach proportional to fat tissue mass 167 AAs incl 21 AA signal sequence, MW ~ 16,000. 4 helices; one essential SS bond member - cytokine family
Production - directly proportional to fat tissue mass good candidate for afferent signal from central energy stores to a peripheral receptor
Name - from leptos (Greek for thin or lean)
Food intake leptin secretion from adipose tissues Message: energy reserves sufficient - stop eating! release of appetite-suppressing (anorexigenic) hormones Effect: sensitivity to insulin (liver, muscle, fat cell) & inhibit insulin secretion (this indirectly inhibits excessive storage of food as lipid its primary storage form)*********
Additionally - complex neuronal and hormonal signals regulate food intake and conservation
**Ghrelin (stimulates hunger) from stomach ; causes
release of appetite-stimulating (orixogenic) hormones PYY from intestine & colon appetite reducer
***AMPK inhibits virtually all biosynthetic processes High AMPs message? Low energy charge !
hwb - sept '09
Ghrelin and PYYs roles in control of short-term eating behavior Ghrelin (28 AAs) & PYY3-36 34 AAs) precede a meal
Alanine
Oxaloacetate
Transaminase (req. PLP!!)
Aspartate
-ketoglutarate
Glutamate
Kwashiorkor ( protein)
Observe Deceptively plump belly due to enlarged, often fatty liver and excessive edema
hwb - sept '09
Some symptoms: stunted growth, pronounced weight loss including loss in muscle in shoulders and buttocks, hair loss, darkened skin and apathy.
hwb - sept '09
Overview: as not painful (at first) most cant appreciate how serious it will be later especially in DM II
hwb - jan 2011
Fats: hormone sens. Lipase; FA export from adipocyte; ketogenesis (liver) & ketogenic enzyme synthesis (liver); cytoplasmic carnitine acyl transferase (I); triglyceride release from liver (Basically, all the effects of glucagon in the body!)
hwb - jan 2011
1. Insulin is effectively absent in Type I diabetics; it is low in the starving 2. All diabetics show hyperglycemia, the starving individual shows near normal glucose levels in blood 3. Ketosis: in both diabetic and starveling, FA mobilization is very rapid, but 4. Ketone production - far more pronounced in the diabetic (ketoacidosis) than in the starving patient (who shows physiological ketosis)
hwb - jan 2011
INSULIN:
KETONE PRODUCTION:
Age of onset pre-or adolescent, usually 35+ yrs, any age! Nature of onset often sudden Slow, insidious Genetics specific HLA factors* no HLA connection; strongly familial Secondary factors viruses, toxins obesity -cell autoimmune? at initial episode not present Insulin secretion absent or delayed sometimes reduced? Body habitus thin to cachectic normal or obese Symptoms at onset polyuria, polydypsia often none; no ketoacidosis hunger, wt loss, ketoacidosis. Long term 2o ret-, nephro-,neuropathy Resemble Type I, often late Insulin dependency absolute occasionally, often not __________________________________________________________________ *HLA = human leukocyte antigen (genes on Chrom 6; gene aberrations here often associated with DM I & Gravess disease (hyperthyroidism)
Hypoglycemia in IDDM?
can occur if insulin dosage is inaccurately gauged or given. HIGH Frequency of hypoglycemic YIELD AS @#$%! episodes very common and may occur in more than 90% of all patients: seizures, intense sweating, hypothermia coma are common. Understand what will happen in an insulin overdose!
All the glucose in the blood will be taken up by GLUT4s in the peripheral tissues causes hypogylcemia=LOW glucose in the BLOOD
Diabetes mellitus Type II (NIDDM) Genetics & environment - major roles Very strong familial factor to susceptibility Almost 100% in identical twins; as environment in West +/- constant, genetic influence the major factor.
Hyperglycemia Effect
(polyol pathway)
HIGH YIELD AS @#$%!
cells that do NOT require insulin to import glucose include: cells of lens, retina, schwann cells, etc.
because entry is insulin independent, large amounts of glucose may enter these cells during hyperglycemia, esp in uncontrolled diabetes elevated IC [glucose] and an adequate supply of NADPH cause conversion of glucose to sorbitol via aldose reductase sorbitol cannot pass thru cell membranes and thus remains trapped inside the cell the sorbitol accumulation causes strong osmotic effects resulting in cell swelling which can then lead to damage to the above mentioned cells this is why you often see cataracts, peripheral neuropathy and vascular problems leading to nephropathy and retinopathy in diabetics
6. Diabetic neuropathy: common; varies with peripheral nerves affected. Not only peripheral nerves affected, but also cranial nerves and autonomic nerves. Symmetrical neuropathy, very common, loss of sensation in the lower extremities; patient especially prone to injury, leg and foot lesions, greatly increased incidence of gangrene & necessary amputations. Autonomic dysfunction can affect the GI tract, bladder, heart, vascular tone, even erectile function.
HIGH YIELD AS @#$%! hwb - jan 2011
CONCEPT SLIDE
Starving (low blood glucose) = Glucagon (liver) and Epinephrine (muscle & liver)
activates adenylyl cyclase cAMP PKA active (cAMP-dependent) if PKA active you get PHOSPHORYLATION of enzymes!! THUS in all enzymes involved in raising blood glucose levels, i.e. glycogen degradation, gluconeogenesis, etc. PHOSPHORYLATION ACTIVATES ex: glycogen phosphorylase is ACTIVE when phosphorylated ENZYMES
INSULIN EFFECTS
CARBOHYDRATE METABOLISM LIVER: inhibits gluconeogenesis and glycogen breakdown MUSCLE & LIVER: increases glycogen synthesis
LIPID METABOLISM ADIPOSE TISSUE: responds within minutes, significant reduction in release of Fas decreased TAG degradation: inhibits hormone-sensitive lipase in adipose (dephosph) increased TAG synthesis: increases transport & metabolism of glucose into adipocytes glucose can be converted to glycerol-3-P which is a substrate for TAG synthesis
increases synthesis of lipoprotein lipase (EC enzyme that degrades TAGs to FAs & glycerol, so that adipose tissue can take up FAs and store them as TAGs
PROTEIN SYNTHESIS MOST TISSUES: stimulates entry of AAs into cells and protein synthesis
To sum it up build stuff from glucose (glycogen, TAGs) inhibit any pathway that produces glucose (gluconeogenesis, glycogenolysis) take up FAs, AAs from blood to store as fat (TAG), protein
GLUCAGON EFFECTS
CARBOHYDRATE METABOLISM
GLUCAGON acts to maintain blood glucose during periods of potential hypoglycemia increases: glycogenolysis gluconeogenesis ketogenesis uptake of amino acids its secretion is stimulated by: low blood glucose, AAs, and epinephrine its secretion is inhibited by: elevated blood glucose and insulin