UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) (MurA)

UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is a key bacterial enzyme catalyzing the first committed step in peptidoglycan biosynthesis—the formation of UDP-N-acetylglucosamine enolpyruvate from phosphoenolpyruvate and UDP-N-acetylglucosamine. This reaction is critical for building the bacterial cell wall. The enzyme has two domains with an active site located between them. A conserved cysteine residue at position ~115/116 plays a central role by forming a covalent intermediate during catalysis. MurA is absent from mammalian cells but present universally among bacteria, making it an attractive target for antibiotics such as fosfomycin. Fosfomycin inhibits MurA irreversibly through covalent modification at this cysteine residue. Structural studies have elucidated substrate binding modes and inhibitor interactions that inform rational drug design efforts aimed at overcoming resistance. The catalytic mechanism involves proton transfers facilitated by conserved residues including Asp305 and Lys22 along with nucleophilic attack mediated by Cys115. Recent computational studies have provided insights into transition states and energy barriers relevant for designing novel inhibitors. Due to its essential role in maintaining bacterial viability via cell wall synthesis—and its absence from human biochemistry—MurA remains one of the most promising targets for developing new antibacterial agents against resistant pathogens such as Acinetobacter baumannii.

Other names

UDP-N-acetylglucosamine 1-carboxyvinyltransferaseUDP-N-acetylglucosamine enolpyruvyl transferaseEPTMurA enzyme

Enzymatic catalysis involves activation of UDP-N-acetyl-D-glucosamine hydroxyl group via Asp305 deprotonation followed by nucleophilic attack on PEP’s carbon-carbon double bond with involvement of Cys115 thiolate forming a covalent intermediate. Fosfomycin acts as a covalent inhibitor binding irreversibly to Cys115/116, blocking enzymatic activity.