Pathway

Citric acid cycle

Homo sapiens · Mitochondrial matrix (succinate dehydrogenase in inner membrane) · 8 reactions

The citric acid cycle oxidizes the acetyl group of acetyl-CoA to two carbon dioxide molecules while regenerating oxaloacetate. Each turn yields three NADH, one FADH2, and one GTP (or ATP), which feed biosynthesis and oxidative phosphorylation.

REACTOME IDENTIFIERR-HSA-71403View source record ↗

Net yield per acetyl-coa

COMPUTED FROM REACTION STOICHIOMETRY

3NADH3 made

1FADH21 made

1GTP1 made

2Carbon dioxide2 made

OVERALL REACTION

Acetyl-CoA + 2 H2O + 3 NAD+ + GDP + Pi + FAD → CoA + 4 H+ + 2 Carbon dioxide + 3 NADH + GTP + FADH2

Overview

EXPLORE BY LEVEL

Citric acid cycle is a set of connected chemical steps in human cells. The citric acid cycle oxidizes the acetyl group of acetyl-CoA to two molecules while regenerating oxaloacetate. Each turn yields three , one FADH2, and one GTP (or ATP), which feed biosynthesis and oxidative .

WHY THE FLOW CHANGES

Regulation

Compare fed and fasting

The cycle’s rate follows cellular energy demand and mitochondrial signals.

Can speed upADP and calcium in active muscle

These signals can activate key control enzymes when ATP demand rises.

Can slow downATP and NADH

High-energy and reduced-cofactor signals restrain several control points.

Context mattersOxygen supply

Oxygen is not consumed directly by TCA reactions, but the respiratory chain must reoxidize NADH and FADH2 for sustained cycling.

How to read this map

This is an instructional map of selected reactions, not a complete inventory of every reaction in the body. Some steps are grouped; transport, alternate routes, tissue differences, or full molecule balances may be summarized. The Research notes explain this map’s specific limits.

Explore the reaction map and enzyme steps

Pathway map

GENERATED FROM STRUCTURED REACTIONS

Select a molecule or enzyme to inspect it. Select a step number to open its full reaction detail.

Acetyl-CoA entry
A two-carbon acetyl group combines with oxaloacetate to make citrate.
1. Step 1Irreversible · H2O → CoA + H+
2. Step 2Reversible
First oxidative decarboxylation
Isocitrate loses one carbon as CO2 and generates NADH.
1. Step 3Irreversible · NAD+ → CO2 + NADH + H+
Second oxidative decarboxylation
2-Oxoglutarate loses a second carbon as CO2 and becomes succinyl-CoA.
1. Step 4Irreversible · CoA + NAD+ → CO2 + NADH + H+
Substrate-level phosphorylation and oxidation
Succinyl-CoA yields GTP, and succinate oxidation supplies electrons to the respiratory chain.
1. Step 5Irreversible · GDP + Pi → GTP + CoA
2. Step 6Irreversible · FAD → FADH2
Oxaloacetate regeneration
Fumarate is hydrated and malate is oxidized to restore the four-carbon acceptor.
1. Step 7Reversible · H2O → —
2. Step 8Irreversible · NAD+ → NADH + H+

Reaction steps

1Citrate formationAcetyl-CoA + Oxaloacetate → CitrateIrreversible

Citrate synthase condenses acetyl-CoA and oxaloacetate.

REACTION · PER TURN + + + +

Enzyme: EC 2.3.3.1 ↗
Cofactors: No metal cofactor listed.
Reversibility: Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa: Once
Stage: Acetyl-CoA entry

MECHANISM & CONTEXT

Hydrolysis of the thioester drives this step strongly forward and commits the acetyl group to the cycle.

Evidence for this step: Citric acid cycle (R-HSA-71403)

2Citrate isomerizationCitrate ⇌ IsocitrateReversible

Aconitase rearranges citrate through cis-aconitate to isocitrate.

REACTION · PER TURN

Enzyme: EC 4.2.1.3 ↗
Cofactors: No metal cofactor listed.
Reversibility: Reversible, operating near equilibrium in cells.
Runs per acetyl-coa: Once
Stage: Acetyl-CoA entry

MECHANISM & CONTEXT

The rearrangement moves a hydroxyl group into a position that can be oxidized and decarboxylated.

Evidence for this step: Citric acid cycle (R-HSA-71403)

3First oxidative decarboxylationIsocitrate → 2-OxoglutarateIrreversible

NAD-dependent isocitrate dehydrogenase produces 2-oxoglutarate, CO2, and NADH.

REACTION · PER TURN + + + +

Enzyme: EC 1.1.1.41 ↗
Cofactors: NAD+ is consumed as a co-substrate (see reaction).
Reversibility: Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa: Once
Stage: First oxidative decarboxylation

MECHANISM & CONTEXT

The mitochondrial NAD-dependent isozyme is a major control point for cycle flux.

Evidence for this step: Citric acid cycle (R-HSA-71403)

4Second oxidative decarboxylation2-Oxoglutarate → Succinyl-CoAIrreversible

The 2-oxoglutarate dehydrogenase complex forms succinyl-CoA, CO2, and NADH.

REACTION · PER TURN + + + + +

Enzyme: EC 1.2.4.2 ↗
Cofactors: NAD+ is consumed as a co-substrate (see reaction).
Reversibility: Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa: Once
Stage: Second oxidative decarboxylation

MECHANISM & CONTEXT

This irreversible oxidative step resembles the pyruvate dehydrogenase reaction and uses related cofactors.

Evidence for this step: Citric acid cycle (R-HSA-71403)

5GTP formationSuccinyl-CoA → SuccinateIrreversible

Succinyl-CoA synthetase couples thioester cleavage to GTP formation.

REACTION · PER TURN + + + +

Enzyme: EC 6.2.1.4 ↗
Cofactors: No metal cofactor listed.
Reversibility: Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa: Once
Stage: Substrate-level phosphorylation and oxidation

MECHANISM & CONTEXT

This is substrate-level phosphorylation. Some tissues express an ADP-forming isozyme and produce ATP instead of GTP.

Evidence for this step: Citric acid cycle (R-HSA-71403)

6Succinate oxidationSuccinate → FumarateIrreversible

Succinate dehydrogenase oxidizes succinate to fumarate and reduces enzyme-bound FAD.

REACTION · PER TURN + +

Enzyme: EC 1.3.5.1 ↗
Cofactors: No metal cofactor listed.
Reversibility: Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa: Once
Stage: Substrate-level phosphorylation and oxidation

MECHANISM & CONTEXT

The enzyme is also respiratory complex II. Electrons pass through its iron-sulfur centers to ubiquinone; FADH2 is not released as a freely diffusible product in vivo.

Evidence for this step: Citric acid cycle (R-HSA-71403)

7Fumarate hydrationFumarate ⇌ MalateReversible

Fumarase adds water across the double bond of fumarate to form malate.

REACTION · PER TURN +

Enzyme: EC 4.2.1.2 ↗
Cofactors: No metal cofactor listed.
Reversibility: Reversible, operating near equilibrium in cells.
Runs per acetyl-coa: Once
Stage: Oxaloacetate regeneration

MECHANISM & CONTEXT

This stereospecific hydration is reversible and is shared with the aspartate-argininosuccinate shunt.

Evidence for this step: Citric acid cycle (R-HSA-71403)

8Oxaloacetate regenerationMalate → OxaloacetateIrreversible

Malate dehydrogenase oxidizes malate to oxaloacetate and NADH.

REACTION · PER TURN + + +

Enzyme: EC 1.1.1.37 ↗
Cofactors: NAD+ is consumed as a co-substrate (see reaction).
Reversibility: Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa: Once
Stage: Oxaloacetate regeneration

MECHANISM & CONTEXT

The reaction is pulled toward oxaloacetate by its rapid consumption in citrate synthesis.

Evidence for this step: Citric acid cycle (R-HSA-71403)

Research sources, claims, and curation

Citric acid cycle (R-HSA-71403)

Reactome · Homo sapiens · Reviewed Reactome human pathway used for reaction sequence and context.

Claims

[1] Reactome · Homo sapiens

Curation notes

One turn is modeled per acetyl-CoA. Water, protons, and cofactor conventions follow a common biochemical bookkeeping scheme.
FAD is enzyme-bound at succinate dehydrogenase; the FAD/FADH2 pair is shown as an educational electron-carrier shorthand.
The cycle is amphibolic: it supplies biosynthetic intermediates, so anaplerotic reactions replenish intermediates removed for synthesis.

Net yield per acetyl-coa

Overview

Regulation

Pathway map

Acetyl-CoA entry

First oxidative decarboxylation

Second oxidative decarboxylation

Substrate-level phosphorylation and oxidation

Oxaloacetate regeneration

Reaction steps

Claims

Curation notes