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Nat Commun. 2015 Oct 16;6:8505. doi: 10.1038/ncomms9505.

Structural basis for phosphatidylinositol-phosphate biosynthesis.

Author information

1
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
2
Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
3
Biology Division, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Avenida da República-EAN, 2780-157 Oeiras, Portugal.
4
NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, IL 60439, USA.

Abstract

Phosphatidylinositol is critical for intracellular signalling and anchoring of carbohydrates and proteins to outer cellular membranes. The defining step in phosphatidylinositol biosynthesis is catalysed by CDP-alcohol phosphotransferases, transmembrane enzymes that use CDP-diacylglycerol as donor substrate for this reaction, and either inositol in eukaryotes or inositol phosphate in prokaryotes as the acceptor alcohol. Here we report the structures of a related enzyme, the phosphatidylinositol-phosphate synthase from Renibacterium salmoninarum, with and without bound CDP-diacylglycerol to 3.6 and 2.5 Å resolution, respectively. These structures reveal the location of the acceptor site, and the molecular determinants of substrate specificity and catalysis. Functional characterization of the 40%-identical ortholog from Mycobacterium tuberculosis, a potential target for the development of novel anti-tuberculosis drugs, supports the proposed mechanism of substrate binding and catalysis. This work therefore provides a structural and functional framework to understand the mechanism of phosphatidylinositol-phosphate biosynthesis.

PMID:
26510127
PMCID:
PMC4634129
DOI:
10.1038/ncomms9505
[Indexed for MEDLINE]
Free PMC Article

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