1233B

Hymeglusin is a fungal polyketide containing a ?-lactone ring with defined stereochemistry and acts as a potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA synthase. Mechanistic studies using radiolabeled hymeglusin demonstrated covalent binding to the catalytic Cys129 residue of cytosolic HMG-CoA synthase, resulting in complete enzymatic inhibition. Alkylating agents such as iodoacetamide and N-ethylmaleimide block hymeglusin binding, confirming thiol reactivity as the basis of inhibition. Biosynthetic investigations revealed that hymeglusin is assembled by a highly reducing polyketide synthase (HR-PKS), and the ketosynthase domain catalyzes ?-lactonization during chain termination. The ?-lactone moiety is essential for biological activity. Because HMG-CoA synthase catalyzes a key condensation step in the mevalonate pathway upstream of HMG-CoA reductase, hymeglusin and related derivatives such as 1233B provide mechanistically distinct tools for studying cholesterol biosynthesis, isoprenoid formation, and antimicrobial resistance modulation, including potential combination strategies against MRSA.