Citric Acid Cycle
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Direct answer
The citric acid cycle, also called the Krebs or tricarboxylic acid (TCA) cycle, is the final common oxidative pathway for carbohydrates, fats and amino acids, and it runs in the mitochondrial matrix. Each turn oxidises one acetyl-CoA to two molecules of carbon dioxide, generating three NADH, one FADH2 and one GTP — roughly ten ATP. Its rate-limiting enzyme is isocitrate dehydrogenase, and the pathway is called amphibolic because it serves both catabolic and anabolic roles.
What you must remember
- Eight enzymes in sequence: citrate synthase (condensation of acetyl-CoA with oxaloacetate, the first committed step), aconitase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinyl-CoA synthetase, succinate dehydrogenase, fumarase and malate dehydrogenase.
- Isocitrate dehydrogenase is rate-limiting; it is activated by ADP and calcium and inhibited by ATP and NADH. Alpha-ketoglutarate dehydrogenase needs the same five cofactors as pyruvate dehydrogenase — thiamine pyrophosphate, lipoic acid, CoA, FAD and NAD+.
- Succinate dehydrogenase is the only membrane-bound enzyme and doubles as Complex II of the electron transport chain; malonate competitively inhibits it.
- Energetics per acetyl-CoA: three NADH (7.5 ATP), one FADH2 (1.5 ATP) and one GTP give about ten ATP; older textbooks using three ATP per NADH quote twelve.
- Classic inhibitors for MCQs: fluoroacetate is converted to fluorocitrate and blocks aconitase; arsenite poisons alpha-ketoglutarate dehydrogenase; malonate blocks succinate dehydrogenase.
- Amphibolic and anaplerotic role: the cycle supplies citrate for fatty acid synthesis, succinyl-CoA for haem, alpha-ketoglutarate and oxaloacetate for amino acids, and malate for gluconeogenesis.
- Pyruvate carboxylase (biotin-dependent) is the chief anaplerotic enzyme, replenishing oxaloacetate; without oxaloacetate acetyl-CoA cannot enter the cycle — the basis of ketosis in fasting and uncontrolled diabetes.
Common confusion
Students repeatedly interchange the rate-limiting enzyme (isocitrate dehydrogenase) with citrate synthase (the first committed step) — label both clearly in your answer. Another slip is assuming every dehydrogenase produces NADH; succinate dehydrogenase alone yields FADH2. Remember also that only two steps liberate carbon dioxide (isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase), and the carbons lost in a given turn are not the same ones that entered as acetyl-CoA.
Exam-focused takeaway
For theory, draw the cycle fully labelled with enzymes, cofactors, the GTP-generating step, regulation and inhibitors, then add the amphibolic and anaplerotic links. In the viva, expect "why is the TCA cycle amphibolic", "which enzyme is rate-limiting" and "what happens if oxaloacetate is deficient". MCQs repeatedly pair fluoroacetate with aconitase, malonate with succinate dehydrogenase, and test the shared cofactors of alpha-ketoglutarate dehydrogenase with pyruvate dehydrogenase. Fix the energetics — three NADH, one FADH2, one GTP per turn.
Frequently asked questions
Why is the citric acid cycle called amphibolic?
It is catabolic, oxidising acetyl-CoA to carbon dioxide, and anabolic, supplying intermediates such as citrate, succinyl-CoA and oxaloacetate for fatty acid, haem, amino acid and glucose synthesis.
Which enzymes of the cycle release carbon dioxide?
Isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase, both oxidative decarboxylations that generate NADH.
How much ATP does one turn of the cycle produce?
About ten ATP — 7.5 from three NADH, 1.5 from one FADH2 and one GTP by substrate-level phosphorylation at succinyl-CoA synthetase.
Which citric acid cycle enzyme is also part of the electron transport chain?
Succinate dehydrogenase, which is Complex II; it transfers electrons from succinate through FAD to ubiquinone.
What is an anaplerotic reaction?
A reaction that replenishes cycle intermediates; pyruvate carboxylase converting pyruvate to oxaloacetate is the most important example.