Structural highlights
Function
[LPXD_ECOLI] Catalyzes the N-acylation of UDP-3-O-(hydroxymyristoyl)glucosamine using 3-hydroxymyristoyl-ACP as the acyl donor. Is involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. Prefers R-3-hydroxymyristoyl-ACP over R-3-hydroxypalmitoyl-ACP as the acyl donor in vitro, which is consistent with the structure of E.coli lipid A that contains over 95% (R)-3-hydroxymyristate at the 2 and 2' positions.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
LpxD catalyzes the third step of lipid A biosynthesis, the R-3-hydroxyacyl-ACP- dependent N-acylation of UDP-3-O-(acyl)-alpha-D-glucosamine, and is a target for new antibiotic development. Here we report the 2.6 A crystal structure of the Escherichia coli LpxD homotrimer (EcLpxD). As is the case in Chlamydia trachomatis LpxD (CtLxpD), each EcLpxD chain consists of an N-terminal uridine-binding region, a left-handed parallel beta-helix (LbetaH), and a C-terminal alpha-helical domain. The backbones of the LbetaH domains of the two enzymes are similar, as are the positions of key active site residues. The N-terminal nucleotide binding domains are oriented differently relative to the LbetaH regions, but are similar when overlaid on each other. The orientation of the EcLpxcD tripeptide (residues 303-305), connecting the distal end of the LbetaH and the proximal end of the C-terminal helical domains, differs from its counterpart in CtLpxD (residues 311-312); this results in a 120 degrees rotation of the C-terminal domain relative to the LbetaH region in EcLpxD versus CtLpxD. M290 of EcLpxD appears to cap the distal end of a hydrophobic cleft that binds the acyl chain of the R-3-hydroxyacyl-ACP donor substrate. Under standard assay conditions, wild-type EcLpxD prefers R,S-3-hydroxymyristoyl-ACP over R,S-3-hydroxypalmitoyl-ACP by a factor of 3, whereas the M290A mutant has the opposite selectivity. Both wild-type and M290A EcLpxD rescue the conditional lethality of E. coli RL25, a temperature-sensitive strain harboring point mutations in lpxD. Complementation with wild-type EcLpxD restores normal lipid A containing only N-linked hydroxymyristate to RL25 at 42 degrees C, as judged by mass spectrometry, whereas the M290A mutant generates multiple lipid A species containing one or two longer hydroxy fatty acids in place of the usual R-3-hydroxymyristate at positions 2 and 2'.
Crystal Structure and Acyl Chain Selectivity of Escherichia coli LpxD, the N-Acyltransferase of Lipid A Biosynthesis.,Bartling CM, Raetz CR Biochemistry. 2009 Aug 5. PMID:19655786[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Helander IM, Lindner B, Seydel U, Vaara M. Defective biosynthesis of the lipid A component of temperature-sensitive firA (omsA) mutant of Escherichia coli. Eur J Biochem. 1993 Mar 1;212(2):363-9. PMID:8444173
- ↑ Bartling CM, Raetz CR. Crystal Structure and Acyl Chain Selectivity of Escherichia coli LpxD, the N-Acyltransferase of Lipid A Biosynthesis. Biochemistry. 2009 Aug 5. PMID:19655786 doi:10.1021/bi901025v
- ↑ Bartling CM, Raetz CR. Crystal Structure and Acyl Chain Selectivity of Escherichia coli LpxD, the N-Acyltransferase of Lipid A Biosynthesis. Biochemistry. 2009 Aug 5. PMID:19655786 doi:10.1021/bi901025v
