%0 Journal Article
%T Structure of Mycobacterium tuberculosis phosphatidylinositol phosphate synthase reveals mechanism of substrate binding and metal catalysis
%J -
%D 2019
%R https://doi.org/10.1038/s42003-019-0427-1
%X Tuberculosis causes over one million yearly deaths, and drug resistance is rapidly developing. Mycobacterium tuberculosis phosphatidylinositol phosphate synthase (PgsA1) is an integral membrane enzyme involved in biosynthesis of inositol-derived phospholipids required for formation of the mycobacterial cell wall, and a potential drug target. Here we present three crystal structures of M. tuberculosis PgsA1: in absence of substrates (2.9£¿£¿), in complex with Mn2+ and citrate (1.9£¿£¿), and with the CDP-DAG substrate (1.8£¿£¿). The structures reveal atomic details of substrate binding as well as coordination and dynamics of the catalytic metal site. In addition, molecular docking supported by mutagenesis indicate a binding mode for the second substrate, D-myo-inositol-3-phosphate. Together, the data describe the structural basis for M. tuberculosis phosphatidylinositol phosphate synthesis and suggest a refined general catalytic mechanism¡ªincluding a substrate-induced carboxylate shift¡ªfor Class I CDP-alcohol phosphotransferases, enzymes essential for phospholipid biosynthesis in all domains of life
%U https://www.nature.com/articles/s42003-019-0427-1