The place of the common catabolic pathway in metabolism
The catabolism of any biomolecules is conventionally divided into the specific pathway and the common catabolic pathway. At the specific stage, the substrate (glucose in glycolysis, fatty acids in β-oxidation, amino acids in deamination) is converted into one of two universal molecules — pyruvate or acetyl-CoA. Pyruvate, in turn, is able to convert into acetyl-CoA.
The common catabolic pathway includes two closely coupled stages:
- Tricarboxylic acid cycle (Krebs cycle, citrate cycle, citric acid cycle);
- Electron transport chain (ETC) with oxidative phosphorylation.
During the dehydrogenation reactions of the cycle, hydrogens are transferred from primary donors to secondary donors — NAD⁺ and FAD. The resulting NADH and FADH₂ are oxidized in the ETC, which provides the main yield of ATP.
Oxidative decarboxylation of pyruvate
The conversion of pyruvate to acetyl-CoA is a key linking reaction between glycolysis and the Krebs cycle. The overall equation:
CH₃–CO–COOH + HS-CoA + NAD⁺ → CH₃–CO~S-CoA + CO₂ + NADH + H⁺
The reaction is called oxidative decarboxylation of pyruvate: the release of CO₂ and dehydrogenation with the reduction of NAD⁺ occur simultaneously.
The catalyst is the pyruvate dehydrogenase complex (PDC), a multienzyme complex consisting of several subunits:
- E1 — pyruvate decarboxylase (coenzyme TPP, vitamin B1);
- E2 — dihydrolipoyl transacetylase (coenzymes lipoamide and HS-CoA, pantothenic acid);
- E3 — dihydrolipoyl dehydrogenase (coenzymes FAD and NAD⁺, vitamins B2 and PP);
- PDC kinase and PDC phosphatase — regulatory subunits.
Tricarboxylic acid cycle: reactions and energy yield
The cycle begins with the condensation of oxaloacetate with acetyl-CoA to form citrate (the enzyme is citrate synthase). One turn of the cycle includes 8 reactions and leads to the complete oxidation of the acetyl residue to 2 CO₂.
One turn involves:
- 2 decarboxylation reactions — isocitrate dehydrogenase and α-ketoglutarate dehydrogenase (2 CO₂ are released);
- 3 dehydrogenation reactions with NAD⁺ reduction → 3 NADH (isocitrate → α-ketoglutarate, α-ketoglutarate → succinyl-CoA, malate → oxaloacetate);
- 1 dehydrogenation reaction with FAD reduction → 1 FADH₂ (succinate → fumarate);
- 1 substrate-level phosphorylation reaction — succinyl-CoA synthetase forms GTP → ATP.
Energy yield of one turn:
- 3 NADH × 3 ATP = 9 ATP;
- 1 FADH₂ × 2 ATP = 2 ATP;
- 1 ATP from substrate-level phosphorylation;
- Total 12 ATP per one molecule of acetyl-CoA (11 from oxidative phosphorylation, 1 from substrate-level phosphorylation).
Anaplerotic Reactions
In addition to its energy function, the Krebs cycle performs an anaplerotic (replenishing) and amphibolic role: its metabolites serve as precursors for biosynthesis.
- α-Ketoglutarate ↔ glutamate and other amino acids;
- Oxaloacetate ↔ aspartate, as well as a substrate for gluconeogenesis;
- Succinyl-CoA is involved in heme synthesis.
The key anaplerotic reaction is the formation of oxaloacetate from pyruvate:
pyruvate + CO₂ + ATP → oxaloacetate + ADP + Pi
Catalyzed by the enzyme pyruvate carboxylase, whose coenzyme is biotin (vitamin H). Biotin deficiency disrupts anaplerosis. Maintaining oxaloacetate levels is critically important: when it is deficient, acetyl-CoA does not enter the cycle and accumulates, leading to pathological consequences (e.g., ketosis).
Regulation of the Krebs cycle
The rate of the cycle is coordinated with the rate of the ETC — a phenomenon known as respiratory control. The main signals are the ATP/ADP and NADH/NAD⁺ ratios.
- High levels of ATP and NADH (energy excess) — the cycle is inhibited;
- Accumulation of ADP and NAD⁺ (energy deficit) — the cycle is accelerated.
Three key enzymes are allosterically regulated:
- Citrate synthase — inhibited by ATP, NADH, citrate;
- Isocitrate dehydrogenase — activated by ADP, inhibited by ATP and NADH;
- α-Ketoglutarate dehydrogenase complex — inhibited by succinyl-CoA and NADH.
Regulation of the pyruvate dehydrogenase complex
PDC exists in two forms, the transition between which is ensured by regulatory subunits:
- PDC kinase phosphorylates the complex → inactive form;
- PDC phosphatase dephosphorylates the complex → active form.
Allosteric regulation of regulatory enzymes:
- Excess ATP, NADH, acetyl-CoA activates kinase → PDC is turned off;
- Accumulation of ADP, NAD⁺, pyruvate activates phosphatase → PDC is turned on.
Thus, during energy excess, pyruvate oxidation is suppressed, and during energy deficit, it is stimulated.
Clinical aspects
Conditions in which ATP synthesis is reduced are called hypoergic. These include:
- Hypovitaminoses B1, B2, PP, pantothenic acid — impair the function of PDC and α-ketoglutarate dehydrogenase, since the corresponding vitamins are part of coenzymes (TPP, FAD, NAD, CoA);
- Deficiency of biotin — blocks pyruvate carboxylase and anaplerosis;
- Hypoxia — disrupts ETC function and secondarily inhibits the Krebs cycle due to the accumulation of NADH;
- Starvation — limits the intake of substrates of the common catabolic pathway.
Key points
- The common catabolic pathway combines the Krebs cycle and the electron transport chain; universal substrates are pyruvate and acetyl-CoA.
- Oxidative decarboxylation of pyruvate is catalyzed by PDC with coenzymes TPP, lipoamide, HS-CoA, FAD, NAD⁺.
- One turn of the Krebs cycle yields 3 NADH, 1 FADH₂, 1 ATP (substrate-level phosphorylation), and 2 CO₂ — a total of 12 ATP.
- Regulatory enzymes of the cycle: citrate synthase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase complex.
- The anaplerotic reaction of pyruvate carboxylase (coenzyme biotin) replenishes the oxaloacetate pool.
- The rate of the cycle is regulated by the ATP/ADP and NADH/NAD⁺ ratios — the principle of respiratory control.
- PDK activity is determined by phosphorylation: the kinase inactivates and the phosphatase activates the complex.
- Hypovitaminosis B1, B2, PP and biotin deficiency lead to hypoergic states.