LpxC

UDP-3-O-acyl-N-acetylglucosamine deacetylase, commonly known as LpxC, is a zinc-dependent metalloenzyme that catalyzes the first committed step in the biosynthesis of lipid A, a core component of lipopolysaccharide in Gram-negative bacteria. Specifically, LpxC removes an acetyl group from UDP-3-O-acyl-N-acetylglucosamine to form UDP-3-O-acyl-glucosamine, enabling the subsequent steps that build lipid A.

Location and substrate: LpxC operates in the cytosol near the inner membrane, where its lipid A substrates accumulate; it is typically considered a soluble enzyme that associates with the inner membrane via interactions with the substrate and perhaps membrane anchors.

Mechanism and active site: It is a Zn2+-dependent deacetylase with active-site residues coordinating the metal, enabling nucleophilic attack by a water molecule on the acetyl group. The reaction is essential for the production of lipid A and proper outer membrane assembly.

Inhibition and clinical relevance: Because lipid A is essential for outer membrane integrity, LpxC is a prime target for antibiotic development. Several potent inhibitors have been described, including CHIR-090 and related compounds, which chelate or mimic the transition state at the zinc center and block lipid A biosynthesis. Inhibition generally leads to loss of LPS, outer membrane defects, and bacterial death or growth arrest. Resistance can arise via mutations in lpxC that reduce inhibitor binding, as well as other mechanisms like efflux.

Distribution and essentiality: LpxC is widely conserved among Gram-negative bacteria but is not present in Gram-positive organisms. LpxC genes are typically essential under standard growth conditions in many species and are a focus of antimicrobial research.