Q2
LONG ANSWER
10M
★ High-yield
Describe the reactions of the TCA cycle with its energetics and regulation. Explain its amphibolic role and add a note on anaplerotic reactions.
Definition
Tricarboxylic acid (Krebs, citric acid) cycle = the final common oxidative pathway in which the acetyl group of acetyl-CoA is completely oxidised to CO2 and water, with the generation of reducing equivalents.
| Feature | Detail |
|---|---|
| Site | Mitochondrial matrix — except succinate dehydrogenase, which is in the inner membrane |
| Oxygen | Strictly aerobic — it stops without O2, because NADH cannot be reoxidised |
| Absent in | RBC (no mitochondria) |
| Nature | Amphibolic — both catabolic and anabolic |
Reactions
Acetyl-CoA (2C) + Oxaloacetate (4C) → Citrate synthase → Citrate (6C) → Aconitase → Isocitrate → isocitrate dehydrogenase — NADH + CO2; rate-limiting → α-Ketoglutarate (5C) → α-KG dehydrogenase — NADH + CO2 → Succinyl-CoA (4C) → Succinate thiokinase — GTP (substrate-level) → Succinate → Succinate dehydrogenase — FADH2 → Fumarate → Fumarase → Malate → Malate dehydrogenase — NADH → Oxaloacetate regenerated
Energetics
| Product | Number | ATP each | Total |
|---|---|---|---|
| NADH | 3 | 2.5 | 7.5 |
| FADH2 | 1 | 1.5 | 1.5 |
| GTP | 1 | 1 | 1 |
| Total per acetyl-CoA | — | — | 10 ATP |
- 2 CO2 are released per turn — at the isocitrate dehydrogenase and α-KG dehydrogenase steps
- The carbons released are not those of the entering acetyl group; they come from oxaloacetate
- Complete oxidation of one glucose = 32 ATP (glycolysis 7 + 2 PDH × 2.5 = 5 + TCA 2 × 10 = 20). Older texts give 38
Regulation
| Enzyme | Activated by | Inhibited by |
|---|---|---|
| Citrate synthase | ADP | ATP, NADH, succinyl-CoA, citrate |
| Isocitrate dehydrogenase | ADP, Ca2+ | ATP, NADH |
| α-KG dehydrogenase | Ca2+ | NADH, succinyl-CoA, ATP |
- The cycle is governed chiefly by the availability of NAD+ and ADP — that is, by the energy demand of the cell (respiratory control)
- Ca2+ stimulates three enzymes — linking muscle contraction directly to increased ATP production
Amphibolic Role
Catabolic — the final common pathway
- Oxidises acetyl-CoA derived from carbohydrate, fat and protein
Anabolic — intermediates are drawn off
| Intermediate | Used to synthesise |
|---|---|
| Citrate | Fatty acids and cholesterol (exported to cytosol) |
| α-Ketoglutarate | Glutamate, glutamine, proline |
| Succinyl-CoA | Haem (with glycine) |
| Oxaloacetate | Aspartate, pyrimidines, glucose (gluconeogenesis) |
| Malate | Gluconeogenesis |
Anaplerotic Reactions
Anaplerotic ("filling up") reactions = reactions that replenish TCA intermediates withdrawn for biosynthesis. Without them the cycle would grind to a halt.
| Reaction | Enzyme | Significance |
|---|---|---|
| Pyruvate + CO2 → Oxaloacetate | Pyruvate carboxylase (biotin, ATP) | The most important; activated by acetyl-CoA |
| Glutamate → α-Ketoglutarate | Glutamate dehydrogenase / transaminase | Links protein catabolism |
| Aspartate → Oxaloacetate | Transaminase | Links protein catabolism |
| Propionyl-CoA → Succinyl-CoA | Propionyl-CoA carboxylase (biotin, B12) | From odd-chain fatty acids |
CLINICAL PEARL
Acetyl-CoA activates pyruvate carboxylase. When acetyl-CoA accumulates in starvation, oxaloacetate is made to keep the cycle running — and diverted to gluconeogenesis. This single control links fat breakdown to glucose production.
Inhibitors
| Inhibitor | Enzyme blocked |
|---|---|
| Fluoroacetate (rat poison) | Aconitase (as fluorocitrate) |
| Malonate | Succinate dehydrogenase (competitive) |
| Arsenite | α-KG dehydrogenase (binds lipoic acid) |
Applied Aspects
- Fatty acids cannot be converted to glucose — the two carbons entering as acetyl-CoA are lost as CO2, so there is no net gain of oxaloacetate
- Thiamine deficiency blocks the TPP-dependent α-KG dehydrogenase → accumulation of pyruvate and lactate → the neurological and cardiac features of beri-beri
- In starvation and diabetes oxaloacetate is drained into gluconeogenesis, so acetyl-CoA cannot enter the cycle and is diverted to ketone bodies — "fat burns in the flame of carbohydrate"
- Succinate dehydrogenase mutations cause phaeochromocytoma and paraganglioma
- Fluoroacetate poisoning — converted to fluorocitrate, which blocks aconitase; citrate accumulates and the cycle stops
- Isocitrate dehydrogenase (IDH) mutations occur in gliomas and acute myeloid leukaemia and are now therapeutic targets
- The cycle cannot run without oxygen even though it uses none directly — because NADH must be reoxidised by the respiratory chain
All questions in Carbohydrate Metabolism I: Glycolysis, TCA & Gluconeogenesis
- Q1Define glycolysis. Describe its reactions, energetics and regulation. Add a note on its significance in the red blood cell. ★
- Q2Describe the reactions of the TCA cycle with its energetics and regulation. Explain its amphibolic role and add a note on anaplerotic reactions. ★
- Q3Define gluconeogenesis. Describe its substrates, the key enzymes bypassing glycolysis, and its regulation. ★
- Q4Describe the sources and fates of blood glucose. Explain the hormonal regulation of blood glucose in the fed and fasting states. ★
- Q5Describe the pyruvate dehydrogenase complex with its components, coenzymes and regulation. Explain its metabolic significance. ★
- SN1Describe the Cori cycle and its significance. Add a note on the glucose–alanine cycle. ★
- SN2Describe the Rapoport–Luebering shunt and the significance of 2,3-BPG. ★
- SN3Define substrate-level phosphorylation. Give the reactions and compare it with oxidative phosphorylation. ★
- SN4Define anaplerotic reactions. Give examples and explain their importance. ★
- SN5Classify the glycogen storage diseases. Describe Von Gierke and McArdle disease. ★
- SN6Define lactic acidosis. Describe its biochemical basis and classify its causes. ★
- SN7Describe the glucose transporters with their sites and functions.