(R,R)-Hymeglusin (CAS: 29066-42-0)

Hymeglusin (also known as 1233A, F244, and L-659,699) is a β-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, for example on Enterococcus faecalis mvaS at 1.95 Å resolution, demonstrate near-complete occlusion of the inhibitor within a narrow active-site tunnel in bacteria, explaining the prolonged stability of the adduct relative to that in 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 β-lactam resistance. These data establish hymeglusin as a covalent mevalonate-pathway inhibitor with antibacterial and antitumor adjuvant potential.