Norman Richard A, McAlister Mark S B, Murray-Rust Judith, Movahedzadeh Farahnaz, Stoker Neil G, McDonald Neil Q
Structural Biology Laboratory, Cancer Research U K, London, United Kingdom.
Structure. 2002 Mar;10(3):393-402. doi: 10.1016/s0969-2126(02)00718-9.
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.
磷脂酰肌醇（PI）对结核分枝杆菌的生存至关重要，参与PI生物合成途径的酶是潜在的抗分枝杆菌药物，但目前关于其结构的信息很少。该途径中的限速步骤是由（D）-葡萄糖6-磷酸生成（L）-肌醇1-磷酸，这是一个由肌醇1-磷酸合酶催化的复杂反应。我们已经确定了结核分枝杆菌的这种酶（tbINO）与辅因子NAD+结合时在1.95埃分辨率下的晶体结构。活性位点位于两个结构域之间交界处的一个深裂缝内。此处意外出现的锌离子表明其与真核肌醇合酶在机制上存在差异，真核肌醇合酶受单价阳离子刺激，这一差异可能有助于开发tbINO的选择性抑制剂。
