Crystal structure of inositol 1-phosphate synthase from Mycobacterium tuberculosis, a key enzyme in phosphatidylinositol synthesis.
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.
Norman
Richard A
RA
Structural Biology Laboratory, Cancer Research U K, London, United Kingdom.
McAlister
Mark S B
MS
Murray-Rust
Judith
J
Movahedzadeh
Farahnaz
F
Stoker
Neil G
NG
McDonald
Neil Q
NQ
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
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D009243:NAD; C002647:inositol 1-phosphate; D003960:Diaminopimelic Acid; D010088:Oxidoreductases; D007296:Myo-Inositol-1-Phosphate Synthase; D015032:Zinc