3-hydroxy-3-methylglutaryl-CoA synthase (mvaS) (mvaS)

Bacterial HMG-CoA synthase (mvaS) is a key enzyme in the mevalonate pathway, responsible for the condensation of acetyl-CoA and acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) (PubMed: 15102830). This enzyme represents the first committed step in the biosynthesis of isoprenoids in several clinically significant Gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis (PubMed: 10913093). While most eubacteria utilize the alternative methylerythritol phosphate (MEP) pathway, these specific pathogens rely exclusively on the mevalonate pathway for the production of essential metabolites like undecaprenyl phosphate, which is required for cell wall synthesis, and menaquinones, which are vital for the respiratory chain (PubMed: 22548260). Due to its essentiality for bacterial survival and the structural differences between the bacterial and human isoforms, mvaS is considered a high-priority target for the development of novel, narrow-spectrum antibiotics (PubMed: 15102830). Inhibitors such as the natural product hymeglusin (F-244) act by forming a stable, covalent thioester adduct with a conserved active site cysteine, thereby inactivating the enzyme and halting bacterial growth (PubMed: 22548260). Although human HMG-CoA synthases (HMGCS1 and HMGCS2) perform similar functions, the bacterial mvaS possesses a more occluded active site, offering a basis for the design of selective inhibitors (PubMed: 22548260).

Other names

Hydroxymethylglutaryl-CoA synthaseHMG-CoA synthasemvaSMvaSHMGCS

Irreversible inhibition via formation of a covalent thioester adduct with the active site cysteine residue.