A rate-limiting enzyme controls the speed of a metabolic pathway by catalyzing the slowest, most regulated step. Understanding these enzymes is crucial for grasping metabolic control and pharmacologic targets.
1. Glycolysis
- Rate-limiting enzyme: Phosphofructokinase-1 (PFK-1)
- Function: Converts fructose-6-phosphate to fructose-1,6-bisphosphate.
- Regulation: Activated by AMP, inhibited by ATP and citrate.
- Clinical relevance: Target for energy modulation in hypoxia and cancer metabolism (Warburg effect).
2. Gluconeogenesis
- Rate-limiting enzyme: Fructose-1,6-bisphosphatase
- Correction: NOT PEP carboxykinase (though important, it's not the rate-limiting step).
- Function: Converts fructose-1,6-bisphosphate to fructose-6-phosphate.
- Regulation: Inhibited by AMP and fructose-2,6-bisphosphate.
3. Glycogenesis (Glycogen Synthesis)
- Rate-limiting enzyme: Glycogen Synthase
- Function: Catalyzes the addition of glucose units to the growing glycogen chain.
- Regulation: Activated by insulin, inhibited by glucagon and epinephrine via phosphorylation.
4. Glycogenolysis (Glycogen Breakdown)
- Rate-limiting enzyme: Glycogen Phosphorylase
- Function: Cleaves glucose residues from glycogen.
- Regulation: Activated by glucagon (liver), epinephrine (muscle), and AMP; inhibited by insulin and ATP.
5. Citric Acid Cycle (Krebs Cycle)
- Rate-limiting enzyme: Isocitrate Dehydrogenase
- Function: Converts isocitrate to α-ketoglutarate, producing NADH.
- Regulation: Activated by ADP, inhibited by ATP and NADH.
6. Ketone Body Synthesis
- Rate-limiting enzyme: HMG-CoA Synthase (mitochondrial)
- Function: Converts acetyl-CoA into HMG-CoA, a precursor for ketogenesis.
- Clinical relevance: Upregulated in prolonged fasting and uncontrolled diabetes.
7. Cholesterol Synthesis
- Rate-limiting enzyme: HMG-CoA Reductase
- Function: Converts HMG-CoA to mevalonate.
- Regulation: Inhibited by statins and cholesterol; regulated by SREBP transcription factors.
8. Heme (Porphyrin) Synthesis
- Rate-limiting enzyme: δ-Aminolevulinic Acid Synthase (ALA Synthase)
- Function: Catalyzes condensation of glycine and succinyl-CoA to form ALA.
- Regulation: Inhibited by heme (end-product feedback).
- Clinical relevance: Defects can cause porphyrias.
9. Fatty Acid Synthesis
- Rate-limiting enzyme: Acetyl-CoA Carboxylase (ACC)
- Function: Converts acetyl-CoA to malonyl-CoA.
- Regulation: Activated by insulin and citrate; inhibited by glucagon and palmitoyl-CoA.
10. Purine Degradation (Uric Acid Synthesis)
- Rate-limiting enzyme: Xanthine Oxidase
- Function: Converts hypoxanthine → xanthine → uric acid.
- Clinical relevance: Target of allopurinol in gout treatment.
