title: Crystal structure of inositol 1-phosphate synthase from Mycobacterium tuberculosis, a key enzyme in phosphatidylinositol synthesis.
abstract: Phosphatidylinositol (PI) is essential for Mycobacterium tuberculosis viability and the enzymes involved in the PI biosynthetic pathway are potential antimycobacterial agents for which little structural information is available. The rate-limiting step in the pathway is the production of (L)-myo-inositol 1-phosphate from (D)-glucose 6-phosphate, a complex reaction catalyzed by the enzyme inositol 1-phosphate synthase. We have determined the crystal structure of this enzyme from Mycobacterium tuberculosis (tbINO) at 1.95 A resolution, bound to the cofactor NAD+. The active site is located within a deep cleft at the junction between two domains. The unexpected presence of a zinc ion here suggests a mechanistic difference from the eukaryotic inositol synthases, which are stimulated by monovalent cations, that may be exploitable in developing selective inhibitors of tbINO.
authors: Structural Biology Laboratory, Cancer Research U K, London, United Kingdom.
authors: Richard A
authors: RA
authors: Norman
authors: Mark S B
authors: MS
authors: McAlister
authors: Judith
authors: J
authors: Murray-Rust
authors: Farahnaz
authors: F
authors: Movahedzadeh
authors: Neil G
authors: NG
authors: Stoker
authors: Neil Q
authors: NQ
authors: McDonald
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003960:Diaminopimelic Acid / Q000737:chemistry; D007295:Inositol Phosphates / Q000096:biosynthesis*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D007296:Myo-Inositol-1-Phosphate Synthase / Q000737:chemistry* / Q000235:genetics; D009243:NAD / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry; D010716:Phosphatidylinositols / Q000096:biosynthesis; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015032:Zinc / Q000737:chemistry
chemical_list: D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D009243:NAD; C002647:inositol 1-phosphate; D003960:Diaminopimelic Acid; D010088:Oxidoreductases; D007296:Myo-Inositol-1-Phosphate Synthase; D015032:Zinc