thiolase

**Reaction:** Thiolase uses CoA-SH to cleave a β-ketoacyl-CoA between the α and β carbons (thiolysis), yielding acetyl-CoA plus an acyl-CoA shortened by two carbons. The reaction is reversible (Claisen condensation in reverse).

**Key isoforms/roles:** - **Mitochondrial 3-ketoacyl-CoA thiolase (β-oxidation):** Fourth and final step of fatty acid β-oxidation (after acyl-CoA dehydrogenase → enoyl-CoA hydratase → 3-hydroxyacyl-CoA dehydrogenase). Releases acetyl-CoA, and the shortened acyl-CoA re-enters the cycle. - **Mitochondrial acetoacetyl-CoA thiolase (ACAT1, T2):** Condenses 2 acetyl-CoA → acetoacetyl-CoA, the first step of ketogenesis (followed by HMG-CoA synthase, the rate-limiting step, then HMG-CoA lyase). In ketone body utilization in extrahepatic tissues (brain, muscle, heart), it works in reverse: acetoacetate → acetoacetyl-CoA (via succinyl-CoA:acetoacetate CoA transferase/thiophorase) → 2 acetyl-CoA. The liver lacks thiophorase, so it cannot use ketone bodies. - **Cytosolic acetoacetyl-CoA thiolase (ACAT2):** First step of cholesterol and isoprenoid synthesis (2 acetyl-CoA → acetoacetyl-CoA, then HMG-CoA synthase, then HMG-CoA reductase, the rate-limiting step). - **Peroxisomal thiolase:** Participates in peroxisomal β-oxidation of very-long-chain fatty acids.

**Clinical significance:** - **Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase/T2 deficiency; ACAT1 mutation):** Autosomal recessive. Presents in infancy or early childhood with episodic ketoacidosis (often triggered by fasting, infection, or a high-protein diet), vomiting, and lethargy. Impaired isoleucine catabolism and ketone utilization produce elevated 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate, and tiglylglycine in urine. Management: avoid fasting, restrict protein/isoleucine, give glucose and bicarbonate during crises. - Peroxisomal disorders (e.g., Zellweger spectrum) impair peroxisomal thiolase function and VLCFA oxidation. - Thiolase is not the same as HMG-CoA synthase (the rate-limiting step of ketogenesis) or HMG-CoA reductase (the rate-limiting step of cholesterol synthesis, inhibited by statins).

**High-yield pearls:** - Thiolase = "thiolysis": cleavage using CoA-SH at the thioester (contrast with hydrolysis). - Each β-oxidation cycle produces 1 FADH2, 1 NADH, and 1 acetyl-CoA. - Odd-chain fatty acids end with propionyl-CoA → methylmalonyl-CoA → succinyl-CoA (requires biotin and B12). - Ketone bodies: acetoacetate and β-hydroxybutyrate (the main one in DKA). Acetone is exhaled (fruity breath).