UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) (MurA)

UDP-N-acetylglucosamine 1-carboxyvinyltransferase, commonly known as MurA, is a cytoplasmic enzyme (EC 2.5.1.7) that catalyzes the first committed step in bacterial peptidoglycan biosynthesis by transferring the enolpyruvyl moiety from phosphoenolpyruvate to UDP-N-acetylglucosamine, forming UDP-N-acetylenolpyruvylglucosamine. This reaction is essential for bacterial cell wall integrity and occurs exclusively in bacteria (e.g., Escherichia coli, UniProt P0A749), making MurA absent in humans and a selective antibacterial target. The enzyme consists of two similar domains with the active site in a cleft between them; key catalytic residues include Cys115 (site of irreversible inhibition), Glu305, and Asp305, which facilitate nucleophilic addition, proton transfer, and elimination. Structurally, MurA resembles EPSP synthase and binds UDP-GlcNAc via hydrogen bonds while coordinating the tetrahedral intermediate. Fosfomycin, an antibiotic, covalently alkylates Cys115, blocking catalysis and peptidoglycan synthesis, which leads to bacterial cell lysis. MurA inhibitors are of interest for novel antibiotics, especially against Gram-negative pathogens, though resistance via MurA mutations (e.g., Cys115 variants) has been noted. Two phylogenetic classes exist (MurA1 widespread, MurA2 in low-G+C Gram-positives), but both are druggable. No human homologs or associated safety concerns are reported, supporting its therapeutic potential in combating antibiotic-resistant infections.

Other names

MurAUDP-N-acetylglucosamine enolpyruvyl transferaseEnoylpyruvate transferaseEPTmurZ

Covalent binding to Cys115, inhibiting enolpyruvyl transfer from phosphoenolpyruvate to UDP-N-acetylglucosamine