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Citric acid (Krebs) cycle

Subject module

Biochemistry

Rate-limiting enzymes, vitamin deficiencies, urea cycle and molecular techniques — pure recall points, taught with the logic behind them.

By the end of this module you can

  • Name the committed step of each major pathway and its physiological regulator.
  • Match a vitamin deficiency to its enzyme defect and clinical syndrome.
  • Explain hyperammonaemia from the position of the urea cycle block.
  • Choose the right molecular technique for a given diagnostic question.
Practise Biochemistry questionsLock in and study
Glycolysis, with PFK-1 as the committed step
Glycolysis, with PFK-1 as the committed stepWikimedia Commons ↗

Most metabolism questions reduce to naming the committed step and its regulator.

Why this is true

A pathway is controlled at the first irreversible step, because regulating anything later would waste intermediates already committed. That step is almost always allosterically sensitive to the pathway's end product or to the cell's energy charge. Phosphofructokinase-1 is the textbook case: ATP inhibits it (energy is plentiful), AMP activates it (energy is scarce), and fructose-2,6-bisphosphate overrides both to link glycolysis to insulin signalling. Once you know the regulator, you can predict the direction of flux in any hormonal state without memorising a table.

Key points

  • Glycolysis: phosphofructokinase-1, activated by fructose-2,6-bisphosphate and AMP, inhibited by ATP and citrate.
  • Gluconeogenesis: fructose-1,6-bisphosphatase, activated by ATP, inhibited by F-2,6-BP and AMP.
  • TCA cycle: isocitrate dehydrogenase, activated by ADP and calcium.
  • Cholesterol synthesis: HMG-CoA reductase — the statin target, and the most regulated enzyme in the body.
  • Heme synthesis: ALA synthase (mitochondrial, B6-dependent), inhibited by heme itself.
  • Urea cycle: carbamoyl phosphate synthetase I, requires N-acetylglutamate as an obligate activator.
  • Fatty acid synthesis: acetyl-CoA carboxylase (citrate activates, palmitoyl-CoA inhibits).

Fed versus fasting state

StateDominant hormonePathways onPathways off
FedInsulinGlycolysis, glycogenesis, lipogenesisGluconeogenesis, lipolysis
FastingGlucagonGlycogenolysis, gluconeogenesis, lipolysisGlycolysis, lipogenesis
StarvationGlucagon + cortisolKetogenesis, proteolysisGlycogenolysis (stores gone)

Common traps

  • Fructose-2,6-bisphosphate is not an intermediate of glycolysis — it is purely a regulator.
  • Hexokinase is inhibited by its product; glucokinase (liver) is not and has a high Km, so the liver only takes up glucose when it is abundant.

Test yourself

A child presents with microcytic anaemia and basophilic stippling. Blood lead is elevated.

High-yield

Lead inhibits ALA dehydratase and ferrochelatase → basophilic stippling on the smear.

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