title: Studies of inositol 1-phosphate analogues as inhibitors of the phosphatidylinositol phosphate synthase in mycobacteria.
abstract: We previously reported a novel pathway for the biosynthesis of phosphatidylinositol in mycobacteria via phosphatidylinositol phosphate (PIP) [Morii H., Ogawa, M., Fukuda, K., Taniguchi, H., and Koga, Y (2010) J. Biochem. 148, 593-602]. PIP synthase in the pathway is a promising target for the development of new anti-mycobacterium drugs. In the present study, we evaluated the characteristics of the PIP synthase of Mycobacterium tuberculosis. Four types of compounds were chemically synthesized based on the assumption that structural homologues of inositol 1-phosphate, a PIP synthase substrate, would act as PIP synthase inhibitors, and the results confirmed that all synthesized compounds inhibited PIP synthase activity. The phosphonate analogue of inositol 1-phosphate (Ino-C-P) had the greatest inhibitory effect among the synthesized compounds examined. Kinetic analysis indicated that Ino-C-P acted as a competitive inhibitor of inositol 1-phosphate. The IC(50) value for Ino-C-P inhibition of the PIP synthase activity was estimated to be 2.0 mM. Interestingly, Ino-C-P was utilized in the same manner as the normal PIP synthase substrate, leading to the synthesis of a phosphonate analogue of PIP (PI-C-P), which had a structure similar to that of the natural product, PIP. In addition, PI-C-P had high inhibitory activity against PIP synthase.
authors.affiliation: Department of Chemistry, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan. h-morii@health.uoeh-u.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morii
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Okauchi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nomiya
authors.forename: Midori
authors.initials: M
authors.lastname: Ogawa
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Fukuda
authors.forename: Hatsumi
authors.initials: H
authors.lastname: Taniguchi
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055162:Biocatalysis / Q000187:drug effects; D053898:Biosynthetic Pathways / Q000187:drug effects; D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D013058:Mass Spectrometry; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000378:metabolism; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D001426:Bacterial Proteins; D007295:Inositol Phosphates; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C002647:inositol 1-phosphate; D008345:Manganese; D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; D008274:Magnesium