Nat. Struct. Mol. Biol., published online 7 October 2012; doi:10.1038/nsmb.2393

Credit: NATURE STRUCTURAL & MOLECULAR BIOLOGY

Lipid A is the innermost component of lipopolysaccharides, which are found at the outer leaflet of the outer membrane of Gram-negative bacteria. The long fatty acyl chains of lipid A help anchor the lipopolysaccharides, which protect the bacteria from various environmental stressors, to the outer membrane. During lipid A biosynthesis, LpxI hydrolyzes the β-phosphate group of UDP-2,3-diacylglucosamine, forming lipid X, which is then converted to lipid A by several other enzymes. Metzger et al. now report two X-ray crystal structures of LpxI: a D225A mutant of the enzyme bound to UDP-2,3-diacylglucosamine and the wild-type protein bound to lipid X. The structures revealed that LpxI is a homodimer, and each monomer is made up of an N-terminal lipid-X–binding domain and a C-terminal catalytic domain. The authors determined that the homodimer observed in the crystal lattice also occurs in solution. Comparison of the two structures revealed that the lipid X–binding domains, which envelop the substrate in the substrate-bound state, 'open up' and rotate to generate the elongated conformation seen in the product-bound form of the enzyme. Biophysical experiments confirm that the substrate-bound state is more compact and spherical than the product-bound state in solution. The authors speculate that LpxI opens up after the lipid X product is formed so that the phosphodiester hydrolase can more easily transfer lipid X to the next enzyme in the lipid A biosynthetic pathway or to facilitate its release into the lipid bilayer.