Introduction: The Citric acid cycle (TCA or Krebs cycle) is central to mitochondrial metabolism and cellular energetics — a core topic for B. Pharm students studying drug action, metabolism, and bioenergetics. This concise guide emphasizes energetics: NADH and FADH2 generation, GTP formation, coupling to oxidative phosphorylation, and key regulatory points (PDH, isocitrate dehydrogenase, α‑ketoglutarate dehydrogenase). You will review enzyme inhibitors, anaplerotic/cataplerotic reactions, ATP equivalents per acetyl‑CoA, and clinically relevant toxins affecting the cycle. Mastery of these concepts helps predict metabolic effects of drugs and poisons. Now let’s test your knowledge with 50 MCQs on this topic.
Q1. Which cellular compartment houses the citric acid cycle enzymes?
- Mitochondrial matrix
- Cytosol
- Endoplasmic reticulum lumen
- Golgi apparatus
Correct Answer: Mitochondrial matrix
Q2. The first enzyme of the TCA cycle that condenses acetyl‑CoA with oxaloacetate is:
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- α‑Ketoglutarate dehydrogenase
Correct Answer: Citrate synthase
Q3. Which step of the TCA cycle produces GTP (or ATP) by substrate‑level phosphorylation?
- Succinyl‑CoA to succinate (succinyl‑CoA synthetase)
- Succinate to fumarate (succinate dehydrogenase)
- Malate to oxaloacetate (malate dehydrogenase)
- Citrate to isocitrate (aconitase)
Correct Answer: Succinyl‑CoA to succinate (succinyl‑CoA synthetase)
Q4. How many NADH molecules are produced per acetyl‑CoA oxidized in one turn of the TCA cycle?
- Three NADH
- Two NADH
- One NADH
- Four NADH
Correct Answer: Three NADH
Q5. Which TCA enzyme is also part of the electron transport chain (as Complex II)?
- Succinate dehydrogenase
- Malate dehydrogenase
- Isocitrate dehydrogenase
- Citrate synthase
Correct Answer: Succinate dehydrogenase
Q6. Modern energetic accounting typically assigns how many ATP equivalents to one NADH oxidized via oxidative phosphorylation?
- 2.5 ATP
- 3 ATP
- 1.5 ATP
- 2 ATP
Correct Answer: 2.5 ATP
Q7. Using current values, approximately how many ATP equivalents are generated from one acetyl‑CoA fully oxidized through TCA plus oxidative phosphorylation?
- ~10 ATP
- ~12 ATP
- ~6 ATP
- ~15 ATP
Correct Answer: ~10 ATP
Q8. Which enzyme is inhibited by fluoroacetate (after conversion to fluorocitrate)?
- Aconitase
- Citrate synthase
- Isocitrate dehydrogenase
- Malate dehydrogenase
Correct Answer: Aconitase
Q9. α‑Ketoglutarate dehydrogenase complex catalyzes a reaction most similar to which other enzyme complex?
- Pyruvate dehydrogenase complex
- ATP synthase
- Hexokinase
- Glucokinase
Correct Answer: Pyruvate dehydrogenase complex
Q10. Which cofactor is NOT required by α‑ketoglutarate dehydrogenase complex?
- NADPH
- Thiamine pyrophosphate (TPP)
- Lipoic acid
- FAD
Correct Answer: NADPH
Q11. Which metabolite accumulates when succinate dehydrogenase is inhibited by malonate?
- Succinate
- Fumarate
- Malate
- Oxaloacetate
Correct Answer: Succinate
Q12. The conversion of malate to oxaloacetate is catalyzed by which enzyme and yields what cofactor?
- Malate dehydrogenase; NADH
- Malate synthase; NADPH
- Fumarase; FADH2
- Isocitrate dehydrogenase; NADPH
Correct Answer: Malate dehydrogenase; NADH
Q13. Which TCA cycle enzyme is regulated allosterically by ATP and NADH as negative effectors?
- Citrate synthase
- Fumarase
- Succinyl‑CoA synthetase
- Aconitase
Correct Answer: Citrate synthase
Q14. Which ion is known to activate several dehydrogenases (PDH kinase effectors aside) and stimulate TCA flux in muscle and heart?
- Calcium (Ca2+)
- Sodium (Na+)
- Chloride (Cl−)
- Magnesium (Mg2+)
Correct Answer: Calcium (Ca2+)
Q15. Pyruvate dehydrogenase (PDH) links glycolysis to the TCA cycle by converting pyruvate to:
- Acetyl‑CoA
- Oxaloacetate
- Lactate
- Citrate
Correct Answer: Acetyl‑CoA
Q16. Which enzyme replenishes oxaloacetate via carboxylation (anaplerotic reaction) using biotin as cofactor?
- Pyruvate carboxylase
- Pyruvate dehydrogenase
- Malic enzyme
- Phosphoenolpyruvate carboxykinase
Correct Answer: Pyruvate carboxylase
Q17. Which statement best describes the amphibolic nature of the TCA cycle?
- It provides intermediates for biosynthesis and degrades acetyl units for energy
- It only produces ATP and has no biosynthetic role
- It solely synthesizes amino acids from glucose
- It only functions under anaerobic conditions
Correct Answer: It provides intermediates for biosynthesis and degrades acetyl units for energy
Q18. Which metabolite of the TCA cycle is a key precursor for amino acid (glutamate) synthesis?
- α‑Ketoglutarate
- Citrate
- Succinate
- Fumarate
Correct Answer: α‑Ketoglutarate
Q19. What is the effect of high ATP/ADP ratio on the TCA cycle?
- Decreases TCA flux by inhibiting key dehydrogenases
- Accelerates TCA flux by activating PDH
- No effect; TCA is independent of energy charge
- Converts TCA into gluconeogenesis pathway
Correct Answer: Decreases TCA flux by inhibiting key dehydrogenases
Q20. Arsenite (arsenic) inhibits which TCA‑related enzyme complex leading to impaired energy production?
- α‑Ketoglutarate dehydrogenase (and PDH) via lipoic acid interaction
- Citrate synthase by chelation of magnesium
- Fumarase by covalent modification
- Succinate dehydrogenase by electron transfer disruption
Correct Answer: α‑Ketoglutarate dehydrogenase (and PDH) via lipoic acid interaction
Q21. The glycerol‑3‑phosphate shuttle transfers reducing equivalents from cytosolic NADH to mitochondrial:
- FAD, producing FADH2 (lower ATP yield)
- NADH directly (higher ATP yield)
- ATP synthase
- Oxaloacetate
Correct Answer: FAD, producing FADH2 (lower ATP yield)
Q22. Which TCA cycle intermediate condenses with acetyl‑CoA to form citrate?
- Oxaloacetate
- Malate
- Succinate
- α‑Ketoglutarate
Correct Answer: Oxaloacetate
Q23. Isocitrate dehydrogenase catalyzes what type of reaction?
- Oxidative decarboxylation producing NADH and CO2
- Hydration of fumarate to malate
- Substrate‑level phosphorylation producing ATP
- Transamination producing glutamate
Correct Answer: Oxidative decarboxylation producing NADH and CO2
Q24. Which step is the first oxidative decarboxylation in the TCA cycle?
- Isocitrate → α‑ketoglutarate
- Citrate → isocitrate
- α‑Ketoglutarate → succinyl‑CoA
- Succinate → fumarate
Correct Answer: Isocitrate → α‑ketoglutarate
Q25. Fumarase catalyzes which reaction in the TCA cycle?
- Fumarate → malate (hydration)
- Malate → oxaloacetate (oxidation)
- Succinate → fumarate (oxidation)
- Citrate → isocitrate (isomerization)
Correct Answer: Fumarate → malate (hydration)
Q26. Which drug or toxin directly inhibits complex I and indirectly affects NADH oxidation from TCA?
- Rotenone
- Malonate
- Fluoroacetate
- Arsenite
Correct Answer: Rotenone
Q27. How many CO2 molecules are released per acetyl‑CoA oxidized in one TCA turn?
- Two CO2
- One CO2
- Three CO2
- Zero CO2
Correct Answer: Two CO2
Q28. The net reducing equivalents (NADH + FADH2) produced per acetyl‑CoA in the TCA cycle are:
- 3 NADH and 1 FADH2
- 2 NADH and 2 FADH2
- 1 NADH and 3 FADH2
- 4 NADH and 0 FADH2
Correct Answer: 3 NADH and 1 FADH2
Q29. Which enzyme interconverts citrate and isocitrate via cis‑aconitate?
- Aconitase
- Isocitrate dehydrogenase
- Citrate lyase
- Fumarase
Correct Answer: Aconitase
Q30. What is the primary reason the TCA cycle is essential in drug metabolism studies for B.Pharm students?
- It supplies reducing equivalents and intermediates for biosynthesis and detoxification pathways
- Only because it synthesizes cholesterol directly
- Because it degrades most pharmaceutical compounds enzymatically
- It primarily regulates membrane transport of drugs
Correct Answer: It supplies reducing equivalents and intermediates for biosynthesis and detoxification pathways
Q31. Which cofactor is required by isocitrate dehydrogenase in mitochondria?
- NAD+ (or NADP+ in a cytosolic isoform), producing NADH
- Biotin, for carboxylation
- PLP (pyridoxal phosphate), for transamination
- NADPH, exclusively producing reducing power
Correct Answer: NAD+ (or NADP+ in a cytosolic isoform), producing NADH
Q32. During heavy muscle activity, increased ADP and AMP levels cause what effect on TCA cycle activity?
- Increase TCA flux via activation of dehydrogenases and PDH
- Decrease TCA flux via allosteric inhibition
- No change because TCA is solely substrate driven
- Induce TCA cycle shutdown and lactate accumulation only
Correct Answer: Increase TCA flux via activation of dehydrogenases and PDH
Q33. Which enzyme converts succinate to fumarate and transfers electrons directly to ubiquinone?
- Succinate dehydrogenase
- Malate dehydrogenase
- Succinate synthetase
- Fumarase
Correct Answer: Succinate dehydrogenase
Q34. Which reaction in the TCA cycle is irreversible under physiological conditions and serves as a regulatory point?
- Citrate synthase formation of citrate
- Fumarase hydration of fumarate
- Succinyl‑CoA synthetase producing GTP
- Malate dehydrogenase oxidation of malate
Correct Answer: Citrate synthase formation of citrate
Q35. Inhibitors of α‑ketoglutarate dehydrogenase are likely to cause accumulation of which intermediate?
- α‑Ketoglutarate
- Succinate
- Oxaloacetate
- Acetyl‑CoA
Correct Answer: α‑Ketoglutarate
Q36. Which enzyme produces FADH2 during the TCA cycle?
- Succinate dehydrogenase
- Isocitrate dehydrogenase
- Malate dehydrogenase
- Citrate synthase
Correct Answer: Succinate dehydrogenase
Q37. Which shuttle system transfers cytosolic NADH into mitochondria with minimal loss of ATP yield (approx. 2.5 ATP per NADH)?
- Malate‑aspartate shuttle
- Glycerol‑3‑phosphate shuttle
- Lactate shuttle
- Alanine cycle
Correct Answer: Malate‑aspartate shuttle
Q38. Which metabolic condition increases citrate efflux to cytosol for fatty acid synthesis, linking TCA to lipid biosynthesis?
- High energy (high citrate, high ATP) and abundant acetyl‑CoA
- Severe energy deficit and low acetyl‑CoA
- Hypoxic glycolysis with lactate accumulation
- Excessive proteolysis only
Correct Answer: High energy (high citrate, high ATP) and abundant acetyl‑CoA
Q39. Which intermediate is directly converted into porphyrin precursors and therefore links TCA to heme synthesis?
- Succinyl‑CoA
- Fumarate
- Citrate
- Malate
Correct Answer: Succinyl‑CoA
Q40. What is the likely effect of NADH accumulation on the TCA cycle?
- Inhibition of dehydrogenases and decreased cycle flux
- Activation of citrate synthase and increased flux
- No effect because NADH is not a regulator
- Immediate conversion of NADH to NADPH
Correct Answer: Inhibition of dehydrogenases and decreased cycle flux
Q41. Which enzyme converts citrate to isocitrate via a dehydration‑rehydration mechanism?
- Aconitase
- Citrate lyase
- Isocitrate dehydrogenase
- Malate dehydrogenase
Correct Answer: Aconitase
Q42. Which of the following is a cataplerotic reaction removing TCA intermediates for gluconeogenesis?
- Conversion of oxaloacetate to phosphoenolpyruvate by PEP carboxykinase
- Carboxylation of pyruvate to oxaloacetate
- Transamination of glutamate to form α‑ketoglutarate
- Malate to pyruvate via malic enzyme producing NADPH
Correct Answer: Conversion of oxaloacetate to phosphoenolpyruvate by PEP carboxykinase
Q43. Which TCA intermediate accumulates in fumarase deficiency and may cause severe metabolic disease?
- Fumarate
- Citrate
- Malate
- Succinyl‑CoA
Correct Answer: Fumarate
Q44. The overall free energy change for complete oxidation of acetyl‑CoA in the TCA cycle is:
- Highly exergonic, enabling ATP synthesis via oxidative phosphorylation
- Endergonic, requiring ATP input
- Neutral, no net free energy change
- Unknown and irrelevant to cellular metabolism
Correct Answer: Highly exergonic, enabling ATP synthesis via oxidative phosphorylation
Q45. How does insulin signaling affect pyruvate dehydrogenase activity and the TCA cycle in fed state?
- Activates PDH (via dephosphorylation), promoting acetyl‑CoA entry into TCA
- Inhibits PDH, blocking acetyl‑CoA formation
- Switches PDH to produce lactate
- Destroys PDH protein, stopping the TCA
Correct Answer: Activates PDH (via dephosphorylation), promoting acetyl‑CoA entry into TCA
Q46. Which metabolite is used to transport acetyl units from mitochondria to cytosol for fatty acid synthesis?
- Citrate
- Oxaloacetate
- Succinate
- Malate only
Correct Answer: Citrate
Q47. Inhibition of which TCA enzyme would directly decrease both NADH production and downstream ATP synthesis most markedly?
- Isocitrate dehydrogenase
- Fumarase
- Succinyl‑CoA synthetase
- Citrate lyase
Correct Answer: Isocitrate dehydrogenase
Q48. Which TCA enzyme requires thiamine (vitamin B1) as an essential cofactor?
- α‑Ketoglutarate dehydrogenase (and PDH complex)
- Succinate dehydrogenase
- Malate dehydrogenase
- Fumarase
Correct Answer: α‑Ketoglutarate dehydrogenase (and PDH complex)
Q49. The contribution of the TCA cycle to biosynthesis includes provision of precursors for:
- Amino acids, heme, nucleotides, and fatty acid synthesis (via citrate)
- Only carbohydrate polymers
- Only steroid hormones directly from succinate
- None; TCA is exclusively catabolic
Correct Answer: Amino acids, heme, nucleotides, and fatty acid synthesis (via citrate)
Q50. Complete oxidation of one glucose molecule (aerobic, using malate‑aspartate shuttle) yields roughly how many ATP equivalents?
- ~30–32 ATP
- ~10 ATP
- ~15 ATP
- ~40–48 ATP
Correct Answer: ~30–32 ATP
I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.
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