Krebs Cycle Calculators

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The Krebs cycle (also called the tricarboxylic acid cycle or TCA cycle, citric acid cycle) is a series of eight enzymatic reactions occurring in the mitochondrial matrix that oxidize acetyl-CoA to CO₂, generating high-energy electron carriers (NADH and FADH₂) that feed into the electron transport chain. Each turn of the cycle produces: 3 NADH, 1 FADH₂, 1 GTP (or ATP), and 2 CO₂. Because glucose produces 2 acetyl-CoA (via glycolysis and pyruvate decarboxylation), the cycle turns twice per glucose molecule. The cycle was elucidated by Hans Krebs in 1937, for which he received the Nobel Prize in 1953.

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TCA Cycle Overview

Starting material: acetyl-CoA (2C) enters by combining with oxaloacetate (4C) → citrate (6C). 8 enzyme-catalyzed steps → regenerates oxaloacetate (4C), releases 2 CO₂, generates high-energy carriers.

Products Per Turn

  • 3 NADH (at isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase steps)
  • 1 FADH₂ (at succinate dehydrogenase)
  • 1 GTP/ATP (substrate-level phosphorylation at succinyl-CoA synthetase)
  • 2 CO₂ (released at isocitrate dehydrogenase and α-ketoglutarate dehydrogenase)

Per glucose: 2 turns → 6 NADH + 2 FADH₂ + 2 GTP + 4 CO₂.

Key TCA Cycle Enzymes

  • Citrate synthase: condensation of acetyl-CoA + OAA → citrate; regulated by NADH, succinyl-CoA, ATP
  • Isocitrate dehydrogenase: first CO₂ release; produces NADH; activated by ADP, Ca²⁺; inhibited by NADH, ATP
  • α-Ketoglutarate dehydrogenase: second CO₂; produces NADH; similar regulation to PDH complex
  • Succinate dehydrogenase (Complex II): embedded in inner mitochondrial membrane; also part of ETC

Cycle Functions Beyond ATP Production

Biosynthetic precursors: α-ketoglutarate → amino acids; succinyl-CoA → heme; OAA → amino acids, gluconeogenesis; citrate → fatty acid synthesis (exported to cytoplasm). The TCA cycle is amphibolic — both catabolic and anabolic.

Glossary

Krebs Cycle (TCA Cycle)
Eight reactions in the mitochondrial matrix oxidizing acetyl-CoA to CO₂; per turn: 3 NADH + 1 FADH₂ + 1 GTP + 2 CO₂; turns twice per glucose; elucidated by Hans Krebs (Nobel 1953).
Acetyl-CoA
A 2-carbon acetyl group linked to coenzyme A; the main fuel entering the Krebs cycle; produced from pyruvate (glycolysis), fatty acid β-oxidation, and amino acid catabolism.
Amphibolic Pathway
A metabolic pathway that is both catabolic (generates energy) and anabolic (provides biosynthetic precursors); the TCA cycle is amphibolic — provides ATP, NADH, and building blocks for amino acids, heme, and fatty acids.

Frequently Asked Questions

Each turn of the Krebs (TCA) cycle produces: 3 NADH (at isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase steps). 1 FADH₂ (at succinate dehydrogenase). 1 GTP (substrate-level phosphorylation at succinyl-CoA synthetase; in some tissues, ATP directly). 2 CO₂ (at isocitrate dehydrogenase and α-ketoglutarate dehydrogenase). Since glucose yields 2 acetyl-CoA, the cycle turns twice per glucose → total TCA cycle products per glucose: 6 NADH + 2 FADH₂ + 2 GTP + 4 CO₂. NADH and FADH₂ donate electrons to the electron transport chain → ~28 ATP per glucose from oxidative phosphorylation.

The TCA cycle is regulated at three key points corresponding to large free energy drops: (1) Citrate synthase: inhibited by ATP, NADH, succinyl-CoA, citrate; activated by ADP and OAA availability. (2) Isocitrate dehydrogenase: inhibited by ATP and NADH (high energy state → slow cycle); activated by ADP and Ca²⁺ (low energy → speed up cycle). (3) α-Ketoglutarate dehydrogenase: inhibited by succinyl-CoA, NADH, and ATP; activated by Ca²⁺. General principle: cycle accelerates when ATP/ADP ratio is low (energy needed) and decelerates when ATP and NADH are abundant (energy sufficient). Pyruvate dehydrogenase complex (PDH): regulated similarly, controls entry of acetyl-CoA into the cycle.

The TCA cycle is amphibolic — both catabolic (breaking down fuels) and anabolic (providing biosynthetic precursors): Outputs used for biosynthesis: α-ketoglutarate → glutamate → other amino acids. Succinyl-CoA → heme, porphyrins. Oxaloacetate (OAA) → aspartate, asparagine; gluconeogenesis. Citrate (exported to cytoplasm) → acetyl-CoA + OAA → fatty acid and cholesterol synthesis. Inputs from other pathways: amino acid catabolism: alanine → pyruvate → acetyl-CoA; aspartate/asparagine → OAA; glutamate/glutamine → α-ketoglutarate. Odd-chain fatty acid and some amino acid catabolism → succinyl-CoA. Anaplerosis: replenishment of TCA intermediates withdrawn for biosynthesis, primarily through pyruvate carboxylase (pyruvate + CO₂ → OAA).

Hans Krebs (1900–1981), a German-born British biochemist, elucidated the cycle in 1937 while working at the University of Sheffield. His key insight: he measured the rates of oxidation of various organic acids by minced pigeon breast muscle and discovered that citrate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, and oxaloacetate formed a cycle — adding catalytic amounts of any one accelerated total respiration far beyond what the added compound alone could account for (only catalytic amounts needed). He submitted his findings to Nature, which rejected the paper (too long!); it was published in Enzymologia. For this work, he shared the Nobel Prize in Physiology or Medicine in 1953 with Fritz Lipmann (who discovered coenzyme A). The cycle is also known as the citric acid cycle (after its first product) or TCA cycle (tricarboxylic acid, referring to the three carboxyl groups of citrate and isocitrate).