(R,R)-Hymeglusin

Hymeglusin (also known as 1233A, F244, L-659-699) is a ?-lactone natural product that specifically inhibits 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS1 in eukaryotes; mvaS in bacteria). It acts via covalent modification of the active-site cysteine to form a stable thioester adduct, thereby blocking the mevalonate pathway. Enzymology and crystallography studies (e.g., Enterococcus faecalis mvaS, 1.95 ﾅ) demonstrate near-complete occlusion of the inhibitor within a narrow active-site tunnel in bacteria, explaining prolonged adduct stability relative to human HMGCS. In cancer biology, hymeglusin suppresses HMGCS1-driven mevalonate metabolism and enhances venetoclax-induced apoptosis in AML models. In MRSA, it inhibits bacterial mvaS and can circumvent ?-lactam resistance. These data establish hymeglusin as a covalent mevalonate-pathway inhibitor with antibacterial and antitumor adjuvant potential.