Abstract
The biosynthesis of phospholipids and glycolipids are critical pathways for virtually all cell membranes. PatA is an essential membrane associated acyltransferase involved in the biosynthesis of mycobacterial phosphatidyl-myo-inositol mannosides (PIMs). The enzyme transfers a palmitoyl moiety from palmitoyl–CoA to the 6-position of the mannose ring linked to 2-position of inositol in PIM1/PIM2. We report here the crystal structures of PatA from Mycobacterium smegmatis in the presence of its naturally occurring acyl donor palmitate and a nonhydrolyzable palmitoyl–CoA analog. The structures reveal an α/β architecture, with the acyl chain deeply buried into a hydrophobic pocket that runs perpendicular to a long groove where the active site is located. Enzyme catalysis is mediated by an unprecedented charge relay system, which markedly diverges from the canonical HX4D motif. Our studies establish the mechanistic basis of substrate/membrane recognition and catalysis for an important family of acyltransferases, providing exciting possibilities for inhibitor design.
Highlights
The biosynthesis of phospholipids and glycolipids are critical pathways for virtually all cell membranes
Acyltransferases are involved in the biosynthesis of triacylglycerols and a diverse group of naturally occurring polyesters composed of 3-hydroxyalkanoic acids, the most important storage lipids found in eukaryotes and prokaryotes, respectively[5]
The biosynthesis of phosphatidyl-myo-inositol mannosides (PIMs) is initiated by the phosphatidyl-myo-inositol mannosyltransferase PimA (Rv2610c in Mycobacterium tuberculosis (M. tuberculosis) H37Rv), which catalyses the transfer of Manp residue from GDP-Man to the 2-position of the myo-inositol ring of PI, to form phosphatidyl-myo-inositol monomannoside (PIM1) on the cytoplasmic face of the plasma membrane (Fig. 1b)[12,16]
Summary
The biosynthesis of phospholipids and glycolipids are critical pathways for virtually all cell membranes. The comparison of the three crystal structures revealed conformational flexibility in the carboxylate moiety of the palmitate (Supplementary Fig. 3), located in close proximity with the lateral chain of H126.
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