LpxA

LpxA, short for UDP-N-acetylglucosamine acyltransferase, is an essential enzyme in the lipid A biosynthesis pathway of Gram-negative bacteria. It catalyzes the first acylation step, transferring a β-hydroxyacyl group from an acyl carrier protein (ACP) to the 3-hydroxyl group of UDP-N-acetylglucosamine (UDP-GlcNAc) to form UDP-3-O-acyl-GlcNAc and releasing ACP. In many bacteria, the preferred donor is 3-hydroxymyristoyl-ACP, providing the initial acyl chain for later lipid A assembly.

Structurally and mechanistically, LpxA belongs to the left-handed parallel beta-helix (LβH) family of acyltransferases. The protein commonly forms oligomeric assemblies, often trimers, with a hydrophobic pocket that accommodates the acyl chain and a binding site for UDP-GlcNAc. Catalysis involves conserved residues, including a histidine, which participates in activating the 3-OH group for nucleophilic acyl transfer. The LβH architecture supports repetitive interactions that shape the substrate-binding channel and contribute to substrate specificity.

Biological role and pathway context, LpxA occupies the first committed step in lipid A biosynthesis, a core component of lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria. Following LpxA, subsequent enzymes such as LpxC and LpxD continue the pathway to generate the lipid A disaccharide. The enzyme is typically cytosolic but associates with the inner membrane to access acyl-ACP substrates.

Genetics and clinical relevance, LpxA is encoded by lpxA and is essential for the viability of many Gram-negative species, making lipid A biosynthesis a potential target for antibiotics. Although several inhibitors have been studied in research settings, no LpxA-targeted antibiotic has achieved widespread clinical approval. Structural and mechanistic studies of LpxA continue to inform efforts in antimicrobial design.