Structure of Escherichia coli 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase inhibitor complexes provide insight into the conformational changes required for substrate binding and catalysis
Structure of Escherichia coli 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase inhibitor complexes provide insight into the conformational changes required for substrate binding and catalysis
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DOI：
10.1074/jbc.m210836200
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发表时间：
2003-03-07
影响因子：
4.8
通讯作者：
Howell, PL
中科院分区：
文献类型：
--
作者：
Lee, JE;Cornell, KA;Howell, PL
5 '-甲基硫代腺苷/S-腺苷高半胱氨酸（MTA/S-腺苷高半胱氨酸）核苷酶是许多微生物中许多关键生物过程中的关键酶。这种核苷酶催化MTA或Hcy的N-9-C-1'键的不可逆水解，形成腺嘌呤和相应的硫代核糖。MTA/β-Hcy核苷酶在生物甲基化、多胺生物合成、甲硫氨酸再循环和细菌群体感应中的关键作用使其成为重要的抗微生物药物靶标。与过渡态类似物福霉素A（FMA）和不可水解底物类似物5 '-甲基硫代结核菌素（MTT）复合的大肠杆菌MTA/Hcy核苷酶的晶体结构已分别解到2.2埃和2.0埃分辨率。这些是在抑制剂存在下解决的第一个MTA/α-Hcy核苷酶结构。这些结构清楚地识别了活性位点中参与底物结合和催化的残基。抑制剂复合物与腺嘌呤结合的MTA/HCY核苷酶的比较（Lee，J.E.，Cornell，K.一、Riscoe，M. K.，和豪厄尔（Howell，P. L.）05 The Dog of the Dog（2001）9，941-953）结构提供了配体诱导的酶活性位点构象变化和底物偏好的证据。酶促机制已被重新审查。
5'-Methylthioadenosine/S- adenosylhomocysteine (MTA/AdoHcy) nucleosidase is a key enzyme in a number of critical biological processes in many microbes. This nucleosidase catalyzes the irreversible hydrolysis of the N-9-C-1' bond of MTA or AdoHcy to form adenine and the corresponding thioribose. The key role of the MTA/AdoHcy nucleosidase in biological methylation, polyamine biosynthesis, methionine recycling, and bacterial quorum sensing has made it an important antimicrobial drug target. The crystal structures of Escherichia coli MTA/AdoHcy nucleosidase complexed with the transition state analog, formycin A (FMA), and the nonhydrolyzable substrate analog, 5'-methylthiotubercidin (MTT) have been solved to 2.2- and 2.0-Angstrom resolution, respectively. These are the first MTA/AdoHcy nucleosidase structures to be solved in the presence of inhibitors. These structures clearly identify the residues involved in substrate binding and catalysis in the active site. Comparisons of the inhibitor complexes to the adenine-bound MTA/AdoHcy nucleosidase (Lee, J. E., Cornell, K. A., Riscoe, M. K., and Howell, P. L. (2001) Structure (Camb.) 9, 941-953) structure provide evidence for a ligand-induced conformational change in the active site and the substrate preference of the enzyme. The enzymatic mechanism has been re-examined.