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Abstract
The membrane-integral glycerol 3-phosphate (G3P) acyltransferase PlsY catalyses the committed and essential step in bacterial phospholipid biosynthesis by acylation of G3P, forming lysophosphatidic acid. It contains no known acyltransferase motifs, lacks eukaryotic homologs, and uses the unusual acyl-phosphate as acyl donor, as opposed to acyl-CoA or acyl-carrier protein for other acyltransferases. Previous studies have identified several PlsY inhibitors as potential antimicrobials. Here we determine the crystal structure of PlsY at 1.48 Å resolution, revealing a seven-transmembrane helix fold. Four additional substrate- and product-bound structures uncover the atomic details of its relatively inflexible active site. Structure and mutagenesis suggest a different acylation mechanism of ‘substrate-assisted catalysis’ that, unlike other acyltransferases, does not require a proteinaceous catalytic base to complete. The structure data and a high-throughput enzymatic assay developed in this work should prove useful for virtual and experimental screening of inhibitors against this vital bacterial enzyme.
Highlights
The membrane-integral glycerol 3-phosphate (G3P) acyltransferase PlsY catalyses the committed and essential step in bacterial phospholipid biosynthesis by acylation of G3P, forming lysophosphatidic acid
PlsX generates acylP, which is used by PlsY for lysophosphatidic acid (lysoPA) production
Without substrates/productsbound structures or mutagenesis data, the active site architecture and catalytic mechanism remain unclear, a hydrophobic groove at the dimer interface has been proposed as the active site[38]
Summary
The membrane-integral glycerol 3-phosphate (G3P) acyltransferase PlsY catalyses the committed and essential step in bacterial phospholipid biosynthesis by acylation of G3P, forming lysophosphatidic acid It contains no known acyltransferase motifs, lacks eukaryotic homologs, and uses the unusual acyl-phosphate as acyl donor, as opposed to acyl-CoA or acyl-carrier protein for other acyltransferases. The recently identified membrane-integral PlsY exists exclusively and ubiquitously in bacteria, and uses an unusual acyl donor, namely the acyl-phosphate (acylP)[5], representing a unique class of acyltransferase. It is the sole and essential GPAT in most Gram-positive bacteria[1,5,6,7] such as Enterococcus faecium and Streptococcus pneumoniae, identified by the World Health Organization as the most dangerous multi-drug resistant pathogens. The liganded structures, along with extensive mutagenesis data, 1/v 16 : 0-P a Microplate well
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