TOPIC DIGEST: BIOCHEMICAL PATHWAYS SUMMARY

Prepared By: Chelsea Paris

SUMMARY OF RATE-LIMITING STEPS

Process Steps Rate-limiting Enzyme
Glycolysis Fructose-6-phosphate à Fructose-1,6-phosphate Phosphofructokinase-1 (PFK-1)
Gluconeogenesis Fructose-1,6-phosphate à Fructose-6-phosphate Fructose-1,6-bisphosphatse
TCA Cycle Isocitrate à a-ketoglutarate Isocitrate dehydrogenase
Glycogenesis UPD-glucose à Glycogen Glycogen synthase
Glycogenolysis Glycogen à Glucose-1-Phosphate Glycogen phosphorylase
HMP Shunt Glucose-6-phosphate à 6-phosphogluconolactone Glucose-6-phosphate dehydrogenase
(G6PD)
De novo pyrimidine Glutamine à Carbamoyl Phosphate Carbamoyl phosphate synthetase II
synthesis
De novo purine Ribose-5-P à PRPP Glutamine-
synthesis phosphoribosylpyrophosphate (PRPP)
amidotransferase
Urea cycle N-acetylglutamate à Carbamoyl phosphate Carbamoyl phosphate synthase I
Fatty acid synthesis Acetyl CoA à Malonyl CoA Acetyl-CoA carboxylase (ACC)
Fatty acid oxidation Conjugation of Carnitine to FA for transportation Carnitine acyltransferase I
across the mitochondrial membrane
Ketogenesis Acetoacetyl CoA à Hydroxy-B-methylglutaryl CoA HMG-CoA synthase
Cholesterol synthesis HMG-CoA à Mevalonate HMG-CoA reductase

GLYCOLYSIS
Location: Cytoplasm
Rate-Limiting Enzyme: PFK-1

ATP-Requiring Steps:
Glucose -- Hexokinase/Glucokinase à Glucose-6-P
Fructose-6-P -- PFK-1 à Fructose-1,6 -BP

ATP-Producing Steps:
1,3- BPG – Phosphoglycerate kinase à 3-PG
Phosphoenolpyruvate – Pyruvate kinase à Pyruvate

Net glycolysis:
Glucose + 2 Pi + 2 ADP + 2 NAD+ à 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O

Total ATP generated: *8 (2ATP + 2 NADH)

 TCA CYCLE
Location: Mitochondria
Rate-Limiting Enzyme = *Isocitate
dehydrogenase

Steps: Citrate Is Krebs’ Starting Substrate For

Making Oxaloacetate

CO2 Production (2): Isocitrate dehydrogenase,

a-ketoglutarate dehydrogenase
NADH production (3): Isocitrate dehydrogenase,
a-ketoglutarate dehydrogenase, Maltase
dehydrogenase
FADH2 production (1): Succinate
dehydrogenase
GTP production (1): Succinyl-CoA synthetase

Net Production:
3 NADH, 1 FADH2, 2 CO2, 1 GTP/ Acetyl CoA

Total ATP generated: 12 (3 NADH + FADH2+

GTP)

Other notes:
- α-ketoglutarate dehydrogenase complex
requires the same cofactors as the pyruvate
dehydrogenase complex (B1, B2, B3, B5,
lipoic acid)
- Aconitase is inhibited by fluoroacetate, a
compound that is used as a rat poison

ELECTRON TRANSPORT CHAIN

Location: Mitochondria Common Poisons:

ETC:
NADH: enters via Complex 1 Complex 1: Rotenone
FADH2: enters via Complex 2 Complex 3: Ant3mycin
Complex 4: Cyanide, CO
ATP Produced: ATP Synthase Inhibitors: Oligomycin
1 NADH à 2.5 ATP Uncouplers: 2,4- Dinitrophenol, Aspirin, thermogenin in
1 FADH2 à 1.5 ATP brown fat
 GLUCONEOGENESIS
Location: Primarily in the Liver
Rate-Limiting Step: Fructose-1,6-bisphosphatase

Irreversible Enzymes:
1. Pyruvate carboxylase
• Mitochondria. Pyruvate à oxaloacetate
2. Phosphoenolpyruvate carboxykinase
• Cystosol. Oxaloacetate à Phosophoenolpyruvate
3. Fructose 1,6- bisphosphatase
• Cytosol. Fructose – 1,6- bisphosphate à Fructose-6-
phosphate
4. Glucose-6-phosphatase
• ER. Glucose-6-phosphate à Glucose

Pathway Produces Fresh Glucose (Tao Le, 2017)

Gluconeogenesis serves to maintain euglycemia during fasting

Can also occur in the kidney and intestinal epithelium Deficiency in
gluconeogenic enzymes à HYPOglycemia
Only odd-chain fatty acids can undergo gluconeogenesis

GLYCOGENESIS & GLYCOGENOLYSIS

Location: Cytosolic processes

The differences between the rates of these two processes

determine the levels of stored glycogen during specific physiologic
states

Glycogenesis
Rate-limiting enzyme: Glycogen synthase

Glycogenolysis
Rate-limiting enzyme: Glycogen phosphorylase
HMP SHUNT
Aka Pentose phosphate pathway
Rate-Limiting Enzyme: G6PD
Location: Cell cytosol, in lactating mammary glands, liver,
adrenal cortex
Provides a source of NADPH from Glucose-6-P

Yields:
NADPH: Enzyme for reduction reactions (glutathione
reduction, fatty acid and cholesterol synthesis)
Ribose: Nucleotide synthesis
Glycolytic Intermediates: Glyceraldehyde-3-P, Fructose-
6-P

G6PD deficiency
- NADPH is integral in detoxifying reactions of free
radicals and peroxides
- Dec NADPH in RBCs leads to hemolytic anemia
- RBC defense against oxidizing agents (flava beans,
sulfonamides, primaquine, and anti-TB drugs)
- Most common precipitating factor of hemolysis:
INFECTION, due to oxidative damage
- X-linked recessive, most common human enzyme
deficiency
- Pathological hallmarks: Heinz bodies, Bite cells
 DE NOVO PURINE & PYRIMIDINE SYNTHESIS

Rate-Limiting Enzymes
Pyrimidine Synthesis: Carbamoyl phosphate synthase II
Purine Synthesis: PRPP synthetase

UREA CYCLE
 FATTY ACID METABOLISM

Rate-Limiting Enzymes
Fatty Acid Synthesis: Acetyl-CoA carboxylase (ACC)
Fatty Acid Oxidation: Carnitine acyltransferase I

KETOGENESIS
Location: Liver (formation of ketones), muscles and
brain (Ketones which are metabolized further and enter
the TCA cycle to generate ATP)

Rate-Limiting Enzyme: HMG-CoA Synthase

Ketone Bodies: acetone, acetoacetate, β-
hydroxybutyrate

Activated in prolonged starvation, severe

hypoglycemia, and alcoholism.

Signs of Ketoacidosis: Acetone breath (fruity odor)

Urine tests for ketones can detect acetoacetate but

NOT β-hydroxybutyrate
 CHOLESTEROL SYNTHESIS
Rate-Limiting Enzyme: HMG-CoA
Reductase

Sources:
Le, T., & Bhushan, V. (2017). First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Medical.
Harvey, Richard A., Ph. D. (2015). Lippincott's illustrated reviews: Biochemistry. Philadelphia :Wolters Kluwer Health

TOPIC DIGEST: BIOCHEMICAL PATHWAYS SUMMARY

Prepared By: Chelsea Paris