Fat-burning brake

The metabolic intermediate that signals fuel abundance by clamping the mitochondrial fat-import gate shut.

Energy sensing reduces it.

Merrill 1997, Am J Physiol Endocrinol Metab 273:E1107 — AMPK activation phosphorylates and inhibits acetyl-CoA carboxylase, lowering malonyl-CoA and raising fatty-acid oxidation. Verified: AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC1 at Ser-659 and Ser-1157; ACC2 at Ser212), the rate-limiting enzyme producing malonyl-CoA from acetyl-CoA. Lower malonyl-CoA relieves its allosteric block on CPT1, permitting long-chain fatty acyl-CoA entry into mitochondria for beta-oxidation. the Ser1157 phosphosite work is yeast (Snf1, the AMPK homolog); mammalian ACC numbering differs. Mechanism at the residue: AMPK phosphorylates acetyl-CoA carboxylase at ACC1 Ser79 and ACC2 Ser212, which inhibits the enzyme that produces malonyl-CoA from acetyl-CoA. Genetic proof: alanine knock-in at those exact sites renders malonyl-CoA production insensitive to AMPK, which is how the causal direction was established rather than inferred. Sources: PMC3587157; PMID 26711141; PMC8535671. PMID 26711141 · PMC3587157

It reduces Carnitine shuttle.

Ruderman 1999, Am J Physiol Endocrinol Metab 276:E1 — malonyl-CoA is the allosteric inhibitor of CPT1, the gate governing entry of long-chain fatty acyl-CoAs into mitochondria for oxidation. doi:10.1152/ajpendo.1999.276.1.E1. Malonyl-CoA is a potent direct inhibitor of mitochondrial carnitine palmitoyltransferase 1: it binds CPT1 and reduces the amount of fatty acyl-CoA entering mitochondria, limiting beta-oxidation. This is the gate that decides whether fat is stored or burned, and it is an allosteric block rather than a transcriptional one — it acts in seconds. doi 10.1152/ajpendo.1999.276.1.E1.

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