7 min readPathway sheetOften a 10-mark answer

TCA cycle (citric acid cycle)

Acetyl-CoA from carbohydrate, fat and protein is oxidised to CO2 in the mitochondrial matrix, making NADH and FADH2: the final common pathway.

WhereMitochondrial matrix

Start → EndAcetyl-CoA → 2 CO2 (oxaloacetate is regenerated)

Per turn3 NADH + 1 FADH2 + 1 GTP

Control enzymesCitrate synthase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase

Before the cycle: the link reaction

Pyruvate from glycolysis enters the mitochondria. The pyruvate dehydrogenase (PDH) complex converts it: pyruvate + CoA + NAD+ → acetyl-CoA + CO2 + NADH. This step is one-way. PDH needs five coenzymes: TPP (from thiamine), FAD (riboflavin), NAD+ (niacin), CoA (pantothenic acid) and lipoic acid.

The 8 steps

Also called the Krebs cycle. One turn handles one acetyl-CoA; two turns run per glucose. NADH and FADH2 are carriers that take hydrogen to the electron transport chain to make ATP. Starred steps are one-way and control the cycle.

1★
Acetyl-CoA + Oxaloacetate → Citrate
Citrate synthase · 2C + 4C = 6C
2
Citrate ⇌ Isocitrate
Aconitase · via cis-aconitate · blocked by fluoroacetate (as fluorocitrate)
3★
Isocitrate → α-Ketoglutarate
Isocitrate dehydrogenase · makes NADH + CO2
4★
α-Ketoglutarate → Succinyl-CoA
α-Ketoglutarate dehydrogenase complex · makes NADH + CO2 · needs TPP, like PDH
5
Succinyl-CoA → Succinate
Succinyl-CoA synthetase (succinate thiokinase) · makes GTP directly (substrate-level phosphorylation)
6
Succinate → Fumarate
Succinate dehydrogenase · makes FADH2 · blocked by malonate
7
Fumarate → Malate
Fumarase · adds water
8
Malate → Oxaloacetate
Malate dehydrogenase · makes NADH · oxaloacetate ready for the next turn

★ one-way, controls the pace

Energy count

NADH (steps 3, 4, 8)3 NADH

FADH2 (step 6)1 FADH2

GTP (step 5)1 GTP (= 1 ATP)

ATP per turn, older values (NADH = 3, FADH2 = 2)12 ATP

ATP per turn, newer values (NADH = 2.5, FADH2 = 1.5)10 ATP

Per glucose (2 turns)24 ATP (older) or 20 ATP (newer)

Amphibolic: both breaking down and building up

Catabolic (breaking down)Burns acetyl-CoA from carbohydrate, fat and protein to CO2, giving NADH and FADH2 for energy.

Anabolic (building up)Intermediates are drawn off to make glucose (oxaloacetate), haem (succinyl-CoA), amino acids (α-ketoglutarate → glutamate; oxaloacetate → aspartate) and fatty acids (citrate carries acetyl-CoA to the cytoplasm).

Reactions that refill used-up intermediates are called anaplerotic, e.g. pyruvate carboxylase making oxaloacetate from pyruvate.

Nutrition link

Four B vitamins run the cycle and the link reaction: thiamine (B1) as TPP, riboflavin (B2) as FAD, niacin (B3) as NAD+ and pantothenic acid (B5) as CoA. In thiamine deficiency (beriberi), PDH and α-ketoglutarate dehydrogenase slow down, pyruvate and lactate build up, and the nerves and heart are affected. Polished white rice loses thiamine; parboiled rice keeps more.

Exam angle

10 marks: “Describe the citric acid cycle with its energetics.” Draw the cycle with all 8 enzymes, mark NADH, FADH2, GTP and CO2, give the ATP count and its amphibolic role.

5 marks: “Why is the TCA cycle called amphibolic?” It breaks down acetyl-CoA for energy and also supplies intermediates to make glucose, amino acids, haem and fatty acids.

2 marks: “Name the B vitamins needed for the TCA cycle.” Thiamine (TPP), riboflavin (FAD), niacin (NAD+) and pantothenic acid (CoA).

Remember it

"Citrate Is Krebs' Starting Substrate For Making Oxaloacetate": citrate, isocitrate, α-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, oxaloacetate.