Which enzyme catalyzes the first committed step in ketone body synthesis from acetyl-CoA?

Explanation

## Ketone Body Synthesis Pathway **Key Point:** HMG-CoA synthase (also called 3-hydroxy-3-methylglutaryl-CoA synthase) catalyzes the first committed step of ketogenesis, condensing two acetyl-CoA molecules to form HMG-CoA in the mitochondrial matrix. ## Sequential Reactions in Ketogenesis 1. **HMG-CoA synthase** (rate-limiting): Acetyl-CoA + Acetyl-CoA → HMG-CoA 2. **HMG-CoA lyase**: HMG-CoA → Acetoacetate + Acetyl-CoA 3. **Acetoacetate reductase**: Acetoacetate ⇌ β-hydroxybutyrate (NADH-dependent) **High-Yield:** HMG-CoA synthase is the rate-limiting enzyme and is upregulated during prolonged fasting, starvation, and uncontrolled diabetes. It is inhibited by malonyl-CoA (a signal of fed state). **Mnemonic:** **HMG** = **H**ydroxy **M**ethyl **G**lutaryl — the first committed step in ketone body production. ## Regulation | Condition | HMG-CoA Synthase Activity | Outcome | | --- | --- | --- | | Fed state | ↓ (inhibited by malonyl-CoA) | Minimal ketogenesis | | Fasting | ↑ (malonyl-CoA ↓) | Increased ketogenesis | | Uncontrolled DM | ↑↑ (severe) | Diabetic ketoacidosis | **Clinical Pearl:** In diabetic ketoacidosis, loss of insulin signaling removes the brake on HMG-CoA synthase, leading to uncontrolled ketone body production and metabolic acidosis.