## Ketone Body Synthesis Pathway **Key Point:** HMG-CoA synthase-2 (also called mitochondrial HMG-CoA synthase or mHMG-CoA synthase) catalyzes the condensation of two acetyl-CoA molecules to form acetoacetyl-CoA, which is then converted to HMG-CoA — the first committed and rate-limiting step of ketone body synthesis. **High-Yield:** This enzyme is distinct from HMG-CoA synthase-1 (cytoplasmic), which is involved in cholesterol synthesis. The mitochondrial isoform (HMG-CoA synthase-2) is expressed primarily in liver and is upregulated during fasting, starvation, and uncontrolled diabetes. ### Sequential Steps of Ketone Synthesis 1. **Acetyl-CoA + Acetyl-CoA** → Acetoacetyl-CoA (via thiophorase) 2. **Acetoacetyl-CoA + Acetyl-CoA** → HMG-CoA (via **HMG-CoA synthase-2**) ← **Rate-limiting step** 3. **HMG-CoA** → Acetoacetate + Acetyl-CoA (via HMG-CoA lyase) 4. **Acetoacetate** ⇄ β-Hydroxybutyrate (via β-hydroxybutyrate dehydrogenase) **Clinical Pearl:** Acetoacetate and β-hydroxybutyrate are the two primary ketone bodies; acetone is a minor product formed by spontaneous decarboxylation of acetoacetate and is exhaled ("fruity breath" in DKA). **Mnemonic:** **HALS** = HMG-CoA synthase-2 (Hepatic, mitochondrial) is the **A**cetyl-CoA **L**imiting **S**tep. 
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