Carbohydrates metabolism important questions and answers for exam oriented
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Carbohydrate Metabolism - Exam-Oriented Questions & Answers
Sources: Lippincott's Biochemistry 8th Ed, Basic Medical Biochemistry 6th Ed, Harper's Illustrated Biochemistry 32nd Ed
SECTION 1: GLUCOSE TRANSPORT
Q1. What are the two mechanisms by which glucose enters cells?
A: Glucose cannot diffuse directly through cell membranes and enters via:
- Facilitated diffusion - Na+/ATP-independent, via GLUT transporters (uniporters)
- Active cotransport - Na+-dependent (SGLT transporters), requires energy
Q2. List the key GLUT isoforms and their tissue locations. (High-yield table)
| GLUT | Tissue | Function |
|---|---|---|
| GLUT-1 | Most tissues, RBCs, brain | Basal glucose uptake |
| GLUT-2 | Liver, pancreatic β-cells, kidneys | Glucose sensor (low affinity, high capacity) |
| GLUT-3 | Neurons | High-affinity neuronal uptake |
| GLUT-4 | Muscle, adipose tissue | Insulin-responsive uptake |
| GLUT-5 | Small intestine, sperm | Fructose transport |
GLUT-4 is the only insulin-dependent transporter - key for diabetes MCQs.
SECTION 2: GLYCOLYSIS
Q3. Define glycolysis and state where it occurs.
A: Glycolysis is the conversion of one molecule of glucose (6C) to two molecules of pyruvate (3C), occurring in the cytosol of all cells. It produces a net of 2 ATP and 2 NADH per glucose.
Q4. What are the two phases of glycolysis?
A:
- Energy-investment phase (Steps 1-5): 2 ATP consumed; glucose is phosphorylated and split into two triose phosphates
- Energy-generation phase (Steps 6-10): 4 ATP and 2 NADH produced; net gain = 2 ATP per glucose
Q5. Name the three irreversible (regulatory) enzymes of glycolysis and their key features.
A:
| Enzyme | Step | Activators | Inhibitors |
|---|---|---|---|
| Hexokinase (I-III) | Glucose → G-6-P | - | Glucose 6-phosphate (product inhibition) |
| Glucokinase (HK-IV, liver/β-cell) | Glucose → G-6-P | Glucose (high conc.) | NOT inhibited by G-6-P |
| Phosphofructokinase-1 (PFK-1) | F-6-P → F-1,6-BP | AMP, ADP, F-2,6-BP, insulin | ATP, citrate, glucagon |
| Pyruvate kinase | PEP → Pyruvate | F-1,6-BP (feedforward) | ATP, alanine, glucagon (phosphorylation) |
PFK-1 is the rate-limiting step and the most important regulatory enzyme. Fructose-2,6-bisphosphate (F-2,6-BP) is the most potent allosteric activator of PFK-1.
Q6. How does glucokinase differ from hexokinase I-III?
A:
| Feature | Hexokinase I-III | Glucokinase (HK-IV) |
|---|---|---|
| Location | Most tissues | Liver, pancreatic β-cells |
| Km for glucose | Low (high affinity) | High (low affinity) |
| Vmax | Low | High |
| Inhibited by G-6-P? | YES | NO |
| Induced by insulin? | No | YES |
| Function | Trap glucose at low conc. | Acts as glucose sensor |
Q7. What is the energy yield of aerobic vs. anaerobic glycolysis?
A:
- Anaerobic glycolysis: Net 2 ATP per glucose; pyruvate is reduced to lactate (NADH is reoxidized to NAD+)
- Aerobic glycolysis: Net 2 ATP + 2 NADH per glucose; pyruvate enters mitochondria for TCA cycle
Q8. Why do RBCs rely on anaerobic glycolysis?
A: RBCs lack mitochondria, so they cannot perform aerobic oxidation. They depend entirely on anaerobic glycolysis for ATP production, generating lactate as the end product.
Q9. What is the significance of the Rapoport-Luebering shunt in RBCs?
A: RBCs can divert 1,3-bisphosphoglycerate (1,3-BPG) to form 2,3-BPG (via bisphosphoglycerate mutase). 2,3-BPG stabilizes the deoxy (T) form of hemoglobin, decreasing O2 affinity and facilitating O2 release to tissues. This is unique to RBCs.
SECTION 3: PYRUVATE DEHYDROGENASE COMPLEX (PDC)
Q10. What is the role of the pyruvate dehydrogenase complex and what cofactors does it require?
A: PDC is a mitochondrial multienzyme complex that irreversibly converts pyruvate → Acetyl-CoA + CO2 + NADH. It is the bridge between glycolysis and the TCA cycle.
Cofactors (mnemonic: "The Lazy Naked Fox Comes Around"):
- Thiamine pyrophosphate (TPP) - B1
- Lipoic acid
- NAD+ - B3 (niacin)
- FAD - B2 (riboflavin)
- Coenzyme A - B5 (pantothenate)
Q11. How is PDC regulated?
A:
- Inhibited by: High Acetyl-CoA, high NADH, high ATP (allosteric); PDC kinase (phosphorylates and inactivates it)
- Activated by: High AMP, CoA, NAD+, pyruvate; PDC phosphatase (dephosphorylates and activates it)
- Arsenic poisoning: Trivalent arsenite inhibits lipoic acid-containing enzymes, including PDC and α-ketoglutarate dehydrogenase
SECTION 4: TCA CYCLE (Krebs Cycle)
Q12. Summarize the net yield of one acetyl-CoA through the TCA cycle.
A: Per acetyl-CoA (2C):
- 3 NADH (at isocitrate DH, α-ketoglutarate DH, malate DH)
- 1 FADH2 (at succinate DH)
- 1 GTP (substrate-level phosphorylation at succinyl-CoA synthetase)
- 2 CO2 released
Q13. Which TCA cycle enzymes are irreversible/regulatory?
A:
- Citrate synthase (OAA + Acetyl-CoA → Citrate) - inhibited by ATP, NADH, succinyl-CoA
- Isocitrate dehydrogenase (Isocitrate → α-ketoglutarate) - rate-limiting; activated by ADP, Ca2+; inhibited by ATP, NADH
- α-Ketoglutarate dehydrogenase (α-KG → Succinyl-CoA) - same cofactors as PDC; inhibited by succinyl-CoA, NADH
Q14. What is the total ATP yield from complete oxidation of one glucose molecule?
A:
| Stage | ATP yield |
|---|---|
| Glycolysis (net) | 2 ATP + 2 NADH (~5 ATP) |
| Pyruvate dehydrogenase (×2) | 2 NADH (~5 ATP) |
| TCA cycle (×2 turns) | 2 GTP + 6 NADH + 2 FADH2 (~20 ATP) |
| Total | ~30-32 ATP |
Modern estimates: ~30-32 ATP (older textbooks state 36-38 ATP due to different P/O ratio assumptions).
SECTION 5: GLUCONEOGENESIS
Q15. Define gluconeogenesis and name the organs where it occurs.
A: Gluconeogenesis is the synthesis of new glucose from non-carbohydrate precursors. Primary site: liver (accounts for ~90%). Minor site: kidney cortex (important during prolonged starvation).
Q16. What are the gluconeogenic precursors?
A:
- Lactate (from muscle, RBCs - Cori cycle)
- Alanine (from muscle - glucose-alanine cycle)
- Glycerol (from lipolysis of triglycerides)
- Glucogenic amino acids (all except leucine and lysine, which are purely ketogenic)
- Propionate (odd-chain fatty acid oxidation)
Q17. What are the 3 bypass reactions of gluconeogenesis (where glycolysis is irreversible)?
A: Gluconeogenesis bypasses the three irreversible steps of glycolysis:
| Glycolytic step | Gluconeogenic bypass enzyme |
|---|---|
| Pyruvate kinase (PEP → pyruvate) | Pyruvate carboxylase (pyruvate → OAA) + PEPCK (OAA → PEP) |
| PFK-1 (F-6-P → F-1,6-BP) | Fructose-1,6-bisphosphatase (F-1,6-BP → F-6-P) |
| Hexokinase (Glucose → G-6-P) | Glucose-6-phosphatase (G-6-P → glucose) - liver and kidney only |
Q18. How is gluconeogenesis regulated?
A:
- Activated by: glucagon, cortisol, glucagon/epinephrine (via cAMP); high Acetyl-CoA activates pyruvate carboxylase; ATP, NADH
- Inhibited by: insulin, AMP (activates PFK-1 instead), fructose-2,6-bisphosphate (inhibits F-1,6-BPase)
- Reciprocal regulation: when glycolysis is active (F-2,6-BP high), gluconeogenesis is suppressed, and vice versa
SECTION 6: GLYCOGEN METABOLISM
Q19. Outline the steps of glycogen synthesis.
A:
- Glucose → Glucose-6-phosphate (hexokinase/glucokinase)
- G-6-P → Glucose-1-phosphate (phosphoglucomutase)
- G-1-P + UTP → UDP-glucose + PPi (UDP-glucose pyrophosphorylase); PPi is hydrolyzed by pyrophosphatase (drives reaction forward)
- UDP-glucose → glycogen chain by glycogen synthase (forms α-1,4 glycosidic bonds)
- Branches added by branching enzyme (amylo-α-1,4→1,6-glucosyltransferase), forming α-1,6 bonds every 8-10 residues
Q20. Outline glycogenolysis (glycogen degradation).
A:
- Glycogen phosphorylase cleaves α-1,4 bonds (releasing G-1-P) until 4 residues remain before each branch point
- Debranching enzyme (bifunctional): transfers 3 residues to chain end (transferase activity), then hydrolyzes α-1,6 bond releasing free glucose
- G-1-P → G-6-P (phosphoglucomutase)
- In liver/kidney: G-6-P → glucose by glucose-6-phosphatase (released to blood)
- In muscle: No G-6-Pase, so G-6-P enters glycolysis directly
Q21. How is glycogen phosphorylase regulated?
A:
- Hormonal (cAMP-mediated): Glucagon/epinephrine → cAMP → PKA → phosphorylates phosphorylase kinase → activates glycogen phosphorylase b → phosphorylase a (active)
- Allosteric: AMP activates phosphorylase b in muscle; ATP and G-6-P inhibit it
- Insulin reverses hormonal activation
Q22. Name the glycogen storage diseases (GSD) - high yield for exams.
| GSD | Enzyme deficiency | Organ | Key feature |
|---|---|---|---|
| Type I (von Gierke) | Glucose-6-phosphatase | Liver, kidney | Fasting hypoglycemia, hepatomegaly |
| Type II (Pompe) | Lysosomal acid α-1,4-glucosidase | All organs | Cardiomegaly, muscle weakness |
| Type III (Cori) | Debranching enzyme | Liver, muscle | Short outer chains |
| Type IV (Anderson) | Branching enzyme | Liver | Long unbranched chains |
| Type V (McArdle) | Muscle phosphorylase | Muscle | No rise in lactate with exercise |
| Type VI (Hers) | Liver phosphorylase | Liver | Mild hypoglycemia |
SECTION 7: PENTOSE PHOSPHATE PATHWAY (HMP Shunt)
Q23. What is the pentose phosphate pathway and what are its products?
A: The PPP (also called hexose monophosphate shunt) is a cytosolic pathway that branches from glycolysis at glucose-6-phosphate. It has two phases:
- Oxidative phase: G-6-P → Ribulose-5-P + 2 NADPH + CO2 (via G-6-P dehydrogenase)
- Non-oxidative phase: Interconverts pentose phosphates with fructose-6-P and glyceraldehyde-3-P (via transketolase and transaldolase)
Key products: NADPH (for reductive biosynthesis and antioxidant defense) and Ribose-5-phosphate (for nucleotide synthesis)
Q24. What is the clinical significance of G-6-PD deficiency?
A: G-6-PD (glucose-6-phosphate dehydrogenase) deficiency is the most common enzyme deficiency worldwide. Since NADPH is needed to regenerate glutathione (GSH) - the antioxidant that protects RBCs - G-6-PD-deficient RBCs cannot protect against oxidative stress.
Triggers: Primaquine, dapsone, sulfonamides, fava beans, infections → hemolytic anemia. Heinz bodies (denatured Hb) and bite cells on peripheral smear.
Q25. Why is transketolase activity used to diagnose thiamin deficiency?
A: Transketolase in the non-oxidative phase of PPP requires thiamin pyrophosphate (TPP) as a cofactor. In thiamin (B1) deficiency, transketolase activity is low. Adding exogenous TPP to RBCs in vitro will greatly stimulate activity if the patient is deficient - this is the "TPP effect" test for beriberi/Wernicke's.
SECTION 8: REGULATION OVERVIEW & METABOLIC STATES
Q26. Summarize the hormonal regulation of carbohydrate metabolism (Fed vs. Fasted state).
| State | Hormone | Effect on carbohydrate metabolism |
|---|---|---|
| Fed | Insulin ↑ | Glycolysis ↑, Glycogen synthesis ↑, Gluconeogenesis ↓ |
| Fasted (early) | Glucagon ↑ | Glycogenolysis ↑ (liver), Gluconeogenesis ↑, Glycolysis ↓ |
| Stress | Epinephrine ↑ | Glycogenolysis ↑ (liver + muscle), Glycolysis ↑ (muscle) |
| Prolonged fast | Cortisol ↑ | Protein catabolism → gluconeogenic substrates; gluconeogenesis ↑ |
Q27. What is the Cori cycle and its significance?
A: The Cori cycle describes the recycling of lactate between muscle and liver:
- Muscle undergoes anaerobic glycolysis → releases lactate into blood
- Liver takes up lactate → converts it back to glucose via gluconeogenesis
- Glucose is released back into blood → taken up by muscle
Significance: allows continued muscle activity even under low O2 conditions. Net energy cost: 6 ATP consumed in liver vs. 2 ATP gained in muscle.
Q28. What is the glucose-alanine cycle?
A: Similar to the Cori cycle but uses alanine as the carrier:
- Muscle catabolizes amino acids → transfers NH3 to pyruvate via transamination → alanine
- Alanine travels to liver → transaminated back to pyruvate + used for gluconeogenesis
- Glucose returned to muscle; NH3 enters urea cycle
This safely transports amino nitrogen from muscle to liver for disposal.
SECTION 9: CLINICALLY TESTED POINTS
Q29. What happens in arsenic poisoning with respect to carbohydrate metabolism?
A: Trivalent arsenite inhibits lipoic acid-requiring enzymes:
- Pyruvate dehydrogenase → blocks Acetyl-CoA production → pyruvate accumulates
- α-Ketoglutarate dehydrogenase → TCA cycle blocked
Pentavalent arsenate substitutes for phosphate in the glyceraldehyde-3-P dehydrogenase reaction, forming 1-arseno-3-PG (instead of 1,3-BPG) → spontaneously hydrolyzes → no ATP produced. This is called arsenate uncoupling of glycolysis.
Q30. A patient develops lactic acidosis after starting metformin. What is the mechanism?
A: Metformin inhibits Complex I of the mitochondrial electron transport chain, reducing NADH oxidation. This:
- Forces cells to regenerate NAD+ via lactate dehydrogenase (LDH) → pyruvate → lactate
- Inhibits hepatic gluconeogenesis (lactate is a substrate for gluconeogenesis)
- Results in lactic acid accumulation → lactic acidosis
Risk is highest in renal failure (metformin accumulates) or hypoxic states.
QUICK REVISION: KEY MNEMONICS
| Mnemonic | What it helps remember |
|---|---|
| "Glucose Takes Priority Free Can" | GLUT-1, 2, 3, 4, 5 by tissue (general guide) |
| "Heinz ketchup is 57 varieties" | G-6-PD deficiency → Heinz bodies in RBCs |
| "The Lazy Naked Fox Comes Around" | PDC cofactors: TPP, Lipoate, NAD+, FAD, CoA |
| "Phosphofructo-1 is the PACEMAKER" | PFK-1 = rate-limiting enzyme of glycolysis |
| "Von Gierke can't Go" | Von Gierke = G-6-Pase deficiency → can't release glucose |
| "McArdle can't ride" | McArdle = muscle phosphorylase → no exercise tolerance, no lactate rise |
| "Cori Court" | Cori cycle: muscle-liver-muscle circuit via lactate |
Sources: Lippincott Illustrated Reviews: Biochemistry 8th Ed, Basic Medical Biochemistry: A Clinical Approach 6th Ed, Harper's Illustrated Biochemistry 32nd Ed
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