HMG-CoA in the mitochondria is a branch point metabolite. In which two metabolic pathways does it serve as an intermediate, and which enzyme commits it to ketogenesis?

• A Mitochondrial HMG-CoA is the substrate for both ketogenesis (HMG-CoA lyase) and for leucine catabolism (as the product of leucine degradation feeding into HMG-CoA); HMG-CoA lyase commits to ketogenesis ✓
• B Mitochondrial HMG-CoA is a substrate for both cholesterol synthesis (via HMG-CoA reductase) and ketogenesis (via HMG-CoA lyase); HMG-CoA lyase commits to ketogenesis
• C Cytosolic HMG-CoA is a substrate for ketogenesis (HMG-CoA lyase) and amino acid synthesis (in transamination reactions)
• D Cytosolic HMG-CoA is utilised for both mevalonate pathway (cholesterol synthesis) and malonyl-CoA synthesis (fatty acid synthesis) with HMG-CoA reductase as the branch point enzyme

Explanation

In the mitochondrial matrix, HMG-CoA is generated from acetyl-CoA (via acetoacetyl-CoA + acetyl-CoA → HMG-CoA by HMG-CoA synthase) and also as an intermediate in leucine catabolism. Mitochondrial HMG-CoA lyase cleaves HMG-CoA to acetoacetate + acetyl-CoA, committing to ketogenesis. Cytosolic HMG-CoA (separate pool) is the substrate for HMG-CoA reductase in cholesterol/mevalonate synthesis. Importantly, HMG-CoA reductase is the rate-limiting step for cholesterol synthesis and is inhibited by statins. The compartmentation (mitochondrial for ketogenesis, cytosolic for cholesterol) is a key biochemical concept.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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