Here I present: Frederic L. Holmes, “Hans Krebs: Formation of a Scientific Life, 1991. CONTINUED.
Let’s go through the Hans Krebs “citrate cycle”, step by step. I’ll give both the cycle overview and the key molecules/energy outputs.
1. Purpose of the TCA Cycle
Central metabolic pathway in aerobic respiration.
Oxidizes acetyl-CoA to CO₂.
Produces reducing equivalents (NADH, FADH₂) for the electron transport chain and GTP (or ATP).
2. Steps of the TCA Cycle
1. Citrate formation
Acetyl-CoA (2C) + Oxaloacetate (4C) → Citrate (6C)
Enzyme: Citrate synthase
2. Isomerization
Citrate → Isocitrate
Enzyme: Aconitase
(via cis-Aconitate intermediate)
3. First oxidative decarboxylation
Isocitrate (6C) → α-Ketoglutarate (5C) + CO₂ + NADH
Enzyme: Isocitrate dehydrogenase
4. Second oxidative decarboxylation
α-Ketoglutarate (5C) → Succinyl-CoA (4C) + CO₂ + NADH
Enzyme: α-Ketoglutarate dehydrogenase
5. Substrate-level phosphorylation
Succinyl-CoA → Succinate
Produces GTP (or ATP)
Enzyme: Succinyl-CoA synthetase
6. Oxidation
Succinate → Fumarate + FADH₂
Enzyme: Succinate dehydrogenase
7. Hydration
Fumarate → Malate
Enzyme: Fumarase
8. Oxidation to regenerate oxaloacetate
Malate → Oxaloacetate + NADH
Enzyme: Malate dehydrogenase
3. Energy Yield per Acetyl-CoA
3 NADH → ~7.5 ATP
1 FADH₂ → ~1.5 ATP
1 GTP (or ATP) → 1 ATP
Total: ~10 ATP per acetyl-CoA
4. Krebs Cycle SMILES’ Notation. The letter A, B, C, D, E, F, G, H refer to the “tree-structure” BELOW this blog post.
A. Citrate.
C(C(=O)[O-])C(CC(=O)[O-])(C(=O)[O-])O
B. Isocitrate.
C(C(C(C(=O)O)O)C(=O)O)C(=O)O
C. Alpha-Ketoglutarate.
C(CC(=O[O-])C(=O)C(=O[O-]
D. Succinyl-Coenzyme-A.
CC(C)(COP(=O)(O)OP(=O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=NC3=C(N=CN=C32)N)O)OP(=O)(O)O)[C@H](C(=O)NCCC(=O)NCCSC(=O)CCC(=O)O)O
E. Succinate.
C(CC(=O)[O-])C(=O)[O-]
F. Fumarate.
C(=C/C(=O)[O-])\C(=O)[O-]
G. Malate.
C(C(C(=O)[O-])O)C(=O)[O-]
H. Oxaloacetate.
C(C(=O)C(=O)[O-])C(=O)[O-]
