GTP cyclohydrolase II structure and mechanism
GTP cyclohydrolase II structure and mechanism
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DOI：
10.1074/jbc.m507725200
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发表时间：
2005-11-04
影响因子：
4.8
通讯作者：
Stammers, DK
中科院分区：
文献类型：
--
作者：
Ren, J;Kotaka, M;Stammers, DK
GTP环化水解酶II将GTP转化为2，5-二氨基-6-β-核糖基-4（3 H）-嘧啶酮5 '-磷酸、甲酸和焦磷酸，这是核黄素生物合成的第一步。核黄素在代谢中的重要作用以及在高等真核生物中缺乏GTP环化水解酶II使其成为潜在的新型选择性抗微生物药物靶标。GTP环化水解酶II催化与GTP环化水解酶I不同的整体反应;后者将GTP转化为二氢新蝶呤三磷酸，用于叶酸和四氢生物蝶呤的生物合成。在1.54埃分辨率下确定的GTP环化水解酶II的结构揭示了与GTP环化水解酶I不同的蛋白质折叠和GTP独特的分子识别决定簇;尽管在这两种酶中存在结合的催化锌。GTP环化水解酶II中心点GMPCPP复合物结构显示Arg（128）与α-膦酸酯相互作用，因此在GTP的情况下，Arg（128）被定位为充当焦磷酸盐释放和形成所提出的共价鸟苷酰-GTP环化水解酶II中间体的亲核试剂。Tyr（105）被鉴定为在GTP开环中起关键作用;它与锌活化的水分子氢键结合，后者被定位为对鸟嘌呤C-8原子进行亲核攻击。虽然GTP环化水解酶I和GTP环化水解酶II都使用锌离子来进行GTP开环和甲酸盐释放，但在每种情况下都使用不同的残基来催化该反应步骤。
GTP cyclohydrolase II converts GTP to 2,5-diamino-6-beta-ribosyl-4( 3H)-pyrimidinone 5'-phosphate, formate and pyrophosphate, the first step in riboflavin biosynthesis. The essential role of riboflavin in metabolism and the absence of GTP cyclohydrolase II in higher eukaryotes makes it a potential novel selective antimicrobial drug target. GTP cyclohydrolase II catalyzes a distinctive overall reaction from GTP cyclohydrolase I; the latter converts GTP to dihydroneopterin triphosphate, utilized in folate and tetrahydrobiopterin biosynthesis. The structure of GTP cyclohydrolase II determined at 1.54-angstrom resolution reveals both a different protein fold to GTP cyclohydrolase I and distinctive molecular recognition determinants for GTP; although in both enzymes there is a bound catalytic zinc. The GTP cyclohydrolase II center dot GMPCPP complex structure shows Arg(128) interacting with the alpha-phosphonate, and thus in the case of GTP, Arg(128) is positioned to act as the nucleophile for pyrophosphate release and formation of the proposed covalent guanylyl-GTP cyclohydrolase II intermediate. Tyr(105) is identified as playing a key role in GTP ring opening; it is hydrogen-bonded to the zinc-activated water molecule, the latter being positioned for nucleophilic attack on the guanine C-8 atom. Although GTP cyclohydrolase I and GTP cyclohydrolase II both use a zinc ion for the GTP ring opening and formate release, different residues are utilized in each case to catalyze this reaction step.