Krebs Cycle
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Direct answer
The Krebs (citric acid or tricarboxylic acid) cycle oxidises each acetyl-CoA to two molecules of carbon dioxide inside the mitochondrial matrix, generating 3 NADH, 1 FADH2 and 1 GTP per turn — about 10 ATP per acetyl-CoA by the modern 2.5 and 1.5 convention, or 12 by the older counting still printed in many Indian texts. Isocitrate dehydrogenase is the rate-limiting step, activated by ADP and inhibited by ATP and NADH. The cycle is amphibolic: it supplies citrate for fatty acid synthesis and succinyl-CoA for haem, so it must be topped up anaplerotically, chiefly by biotin-dependent pyruvate carboxylase converting pyruvate to oxaloacetate — the biochemical truth behind the dictum that fat burns in the flame of carbohydrate.
What you must remember
- Per acetyl-CoA: 2 carbon dioxide, 3 NADH (isocitrate, α-ketoglutarate and malate dehydrogenases), 1 FADH2 (succinate dehydrogenase) and 1 GTP at succinyl-CoA synthetase — the only substrate-level phosphorylation in the cycle.
- Complete oxidation of one glucose gives 30–32 ATP by modern accounting (36–38 in the older convention), the difference lying in shuttle and proton-pumping assumptions.
- Named poisons: fluoroacetate is converted to fluorocitrate and blocks aconitase; arsenite blocks the lipoamide enzymes pyruvate dehydrogenase and α-ketoglutarate dehydrogenase; malonate blocks succinate dehydrogenase.
- Succinate dehydrogenase is unique in doubling as complex II of the electron transport chain, which is why malonate poisoning also stalls oxidative phosphorylation at that entry point.
- Vitamin coenzymes of the cycle: thiamine at α-ketoglutarate dehydrogenase, riboflavin as FAD at succinate dehydrogenase, niacin as NAD at three steps, pantothenic acid as coenzyme A, plus lipoic acid.
- Heavy fat oxidation drains oxaloacetate and stalls the cycle unless carbohydrate replenishes it — pyruvate carboxylase, activated by acetyl-CoA, is the anaplerotic hero.
- Citrate exported to the cytosol both feeds fatty acid synthesis and inhibits PFK-1, a "well-fed" signal from mitochondrion to glycolysis.
- The two carbons entering as acetyl-CoA are not the two released as carbon dioxide in that same turn; labelled acetyl carbons reappear in the CO2 of subsequent turns — a favourite of molecular-label questions.
Numbers worth knowing: the full ATP account of one glucose
Add it up the way an examiner would. Glycolysis yields 2 ATP by substrate-level phosphorylation and 2 NADH; those cytosolic NADH enter mitochondria through the malate–aspartate shuttle in liver and heart (each worth 2.5 ATP) or the glycerol-3-phosphate shuttle in muscle and brain (each worth 1.5). Pyruvate dehydrogenase converts 2 pyruvate to 2 acetyl-CoA with 2 NADH (5 ATP). Each cycle turn then delivers 3 NADH (7.5), 1 FADH2 (1.5) and 1 GTP (1) — 10 per acetyl-CoA, 20 for two turns. The grand total is 32 ATP with the malate–aspartate shuttle and 30 with the glycerol-3-phosphate shuttle; older textbooks print 38 (or 36) using 3 ATP per NADH and 2 per FADH2, so a question's answer depends on the convention it expects — read the options. The erythrocyte is the control experiment: with no mitochondria it stops at 2 ATP per glucose, and its Rapoport–Luebering bypass even sacrifices one of those to make 2,3-BPG for oxygen transport.
Where students slip
The 10-versus-12 ATP per acetyl-CoA trap catches candidates who memorised one book; state the convention before the number. Second, "the cycle makes ATP" is loose — it makes one GTP directly, everything else arrives through oxidative phosphorylation, which is why the cycle stalls without oxygen even though no oxygen-consuming step sits inside it. Third, the rate-limiting enzyme is isocitrate dehydrogenase here but PFK-1 in glycolysis and acetyl-CoA carboxylase in fatty acid synthesis — three rate-limiting enzymes commonly cross-shuffled in stems. Fourth, biotin belongs to pyruvate carboxylase (anaplerosis), not to any cycle enzyme; gluconeogenesis questions reuse the same confusion. Fifth, succinate dehydrogenase's dual identity means its inhibition raises succinate specifically, a pattern seen in riboflavin deficiency and in the rare familial paraganglioma syndrome. Finally, thiamine deficiency disables α-ketoglutarate dehydrogenase early, which is why Wernicke encephalopathy can be viewed biochemically as focal Krebs-cycle failure in energy-hungry neurons.
Frequently asked questions
How many ATP does one turn of the Krebs cycle yield per acetyl-CoA?
About 10 ATP by the modern convention (3 NADH × 2.5 + 1 FADH2 × 1.5 + 1 GTP); older texts count 12 using 3 and 2 per NADH and FADH2.
Which cycle enzyme is simultaneously part of the electron transport chain?
Succinate dehydrogenase, which is complex II; malonate competitively inhibits it, raising succinate.
Which step is rate-limiting and how is it controlled?
Isocitrate dehydrogenase — activated by ADP and calcium, inhibited by ATP and NADH.
Why is the cycle called amphibolic?
It is both catabolic (oxidising acetyl-CoA) and anabolic (providing citrate for fatty acid synthesis, α-ketoglutarate and oxaloacetate for amino acids, succinyl-CoA for haem).
Which reaction replenishes oxaloacetate, and what activates it?
Pyruvate carboxylase, a biotin-dependent enzyme switched on by acetyl-CoA — signalling that acetyl units need a receptor.
Which cycle dehydrogenases are NAD-linked?
Isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase; succinate dehydrogenase alone uses FAD.