UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) (LpxC)

UDP-3-O-acyl-N-acetylglucosamine deacetylase, commonly known as LpxC, is a zinc-dependent metalloamidase that catalyzes the committed second step in lipid A biosynthesis by hydrolyzing UDP-3-O-[(3R)-3-hydroxymyristoyl]-N-acetylglucosamine to UDP-3-O-[(3R)-3-hydroxymyristoyl]glucosamine and acetate. This process is essential for producing lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria, anchoring it and maintaining cell viability. LpxC shows no homology to mammalian enzymes, making it a selective antibacterial target. The enzyme features a zinc-binding motif in its active site cleft, with a hydrophobic tunnel for the 3-O-fatty acid chain, and operates via a general acid-base mechanism involving Glu78, His265, and zinc-bound water as nucleophile. As a bacterial-specific enzyme (EC 3.5.1.108), LpxC inhibition disrupts LPS assembly, leading to bactericidal effects against pathogens like Escherichia coli and Acinetobacter baumannii. Experimental inhibitors, including hydroxamates and acyl compounds, bind the active site to block deacetylation, highlighting its promise for novel Gram-negative antibiotics amid rising resistance. Crystal structures from Aquifex aeolicus and E. coli confirm the alpha/beta fold with duplicated domains forming the catalytic site. Metals like Co2+, Ni2+, or Mn2+ can substitute for Zn2+ but with varying efficiency, while chelators abolish activity.

Other names

LpxCUDP-3-O-[3-hydroxymyristoyl]-N-acetylglucosamine deacetylaseUDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylaseenvA

Inhibition of lipid A biosynthesis via zinc-dependent deacetylation blockade