Crystal structure of a bifunctional transformylase and cyclohydrolase enzyme in purine biosynthesis
Crystal structure of a bifunctional transformylase and cyclohydrolase enzyme in purine biosynthesis
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DOI：
10.1038/87555
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发表时间：
2001-05-01
期刊：
影响因子：
--
通讯作者：
Wilson, IA
中科院分区：
文献类型：
--
作者：
Greasley, SE;Horton, P;Wilson, IA
ATIC是purH基因的产物，是一种64 kDa的双功能酶，具有嘌呤从头生物合成的最后两种活性，AICAR转化酶和IMP环化水解酶。ATIC形成一个相互缠绕的二聚体，每个单体有一个大约5,000埃（2）的界面。每个单体由两个新的、独立的功能结构域组成。N-末端结构域（直到残基199）负责IMPCH活性，而AICAR Tfase活性存在于C-末端结构域（200-593）。IMPCH和AICAR Tfase结构域的活性位点相似，相距50埃，没有连接两个活性位点的隧道的结构证据。ATIC的晶体结构提供了一个框架来探测催化机制和设计用于癌症化疗和炎症的特异性抑制剂。
ATIC, the product of the purH gene, is a 64 kDa bifunctional enzyme that possesses the final two activities in denovo purine biosynthesis, AICAR transformylase and IMP cyclohydrolase, The crystal structure of avian ATIC has been determined to 1.75 Angstrom resolution by the MAD method using a Se-methionine modified enzyme. ATIC forms an intertwined dimer with an extensive interface of similar to5,000 Angstrom (2) per monomer. Each monomer is composed of two novel, separate functional domains. The N-terminal domain (up to residue 199) is responsible for the IMPCH activity, whereas the AICAR Tfase activity resides in the C-terminal domain (200-593). The active sites of the IMPCH and AICAR Tfase domains are similar to 50 Angstrom apart, with no structural evidence of a tunnel connecting the two active sites. The crystal structure of ATIC provides a framework to probe both catalytic mechanisms and to design specific inhibitors for use in cancer chemotherapy and inflammation.