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Structure and reactivity of LpxD, the N-acyltransferase of lipid A biosynthesis.

Buetow L, Smith TK, Dawson A, Fyffe S, Hunter WN
Proc Natl Acad Sci U S A 104 4321-6 (2007)
Related entries: 2iu8, 2iua

Cited: 47 times
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Abstract

The external layer of the Gram-negative bacterial outer membrane is primarily composed of a protective, selectively permeable LPS. The biosynthesis of LPS relies on UDP-3-O-acyl-glucosamine N-acyltransferase (LpxD), which transfers 3-hydroxy-arachidic acid from acyl carrier protein to the 2' amine of UDP-3-O-myristoyl glucosamine in Chlamydia trachomatis. Our crystallographic study reveals that LpxD is a homotrimer, each subunit of which is constructed from a novel combination of an N-terminal uridine-binding domain, a core lipid-binding domain, and a C-terminal helical extension. Highly conserved residues dominate nucleotide binding. Phe-43 and Tyr-49 form pi-stacking interactions with uracil, and Asn-46 and His-284 form hydrogen bonds with the phosphate groups. These interactions place the glucosamine moiety at the catalytic center formed by two adjacent subunits. Here His-247 and His-284 contribute to a mechanism involving nucleophilic attack by the amine of one substrate on the carbonyl carbon of an acyl carrier protein thioester conjugate. Serendipitously, our study reveals a fatty acid (FA) binding groove near the catalytic center. MS elucidated the presence of a FA mixture binding to LpxD, with palmitic acid the most prevalent. The placement of UDP-N-acetylglucosamine and the FA provides details of N-acyltransferase ligand interactions and allows for a description of structure and reactivity at an early stage of LPS assembly.

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  1. Current Progress in the Structural and Biochemical Characterization of Proteins Involved in the Assembly of Lipopolysaccharide. Bohl TE, Aihara H. Int J Microbiol 2018 5319146 (2018)

Articles - 2iu9 mentioned but not cited (5)

  1. Structure and reactivity of LpxD, the N-acyltransferase of lipid A biosynthesis. Buetow L, Smith TK, Dawson A, Fyffe S, Hunter WN. Proc Natl Acad Sci U S A 104 4321-4326 (2007)
  2. Steady-state kinetics and mechanism of LpxD, the N-acyltransferase of lipid A biosynthesis. Bartling CM, Raetz CR. Biochemistry 47 5290-5302 (2008)
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  5. Structural basis for the acyl chain selectivity and mechanism of UDP-N-acetylglucosamine acyltransferase. Williams AH, Raetz CR. Proc Natl Acad Sci U S A 104 13543-13550 (2007)
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  7. Crystal structure and acyl chain selectivity of Escherichia coli LpxD, the N-acyltransferase of lipid A biosynthesis. Bartling CM, Raetz CR. Biochemistry 48 8672-8683 (2009)
  8. Global transcriptomic response of Leptospira interrogans serovar Copenhageni upon exposure to serum. Patarakul K, Lo M, Adler B. BMC Microbiol 10 31 (2010)
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  10. Acyl chain specificity of the acyltransferases LpxA and LpxD and substrate availability contribute to lipid A fatty acid heterogeneity in Porphyromonas gingivalis. Bainbridge BW, Karimi-Naser L, Reife R, Blethen F, Ernst RK, Darveau RP. J Bacteriol 190 4549-4558 (2008)
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  32. The structure of lipopolysaccharide transport protein B (LptB) from Burkholderia pseudomallei. Pankov G, Dawson A, Hunter WN. Acta Crystallogr F Struct Biol Commun 75 227-232 (2019)


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