The structure of Escherichia coli cytosine deaminase
The structure of Escherichia coli cytosine deaminase
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DOI：
10.1006/jmbi.2001.5277
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发表时间：
2002-01-25
影响因子：
5.6
通讯作者：
Stoddard, BL
中科院分区：
文献类型：
--
作者：
Ireton, GC;McDermott, G;Stoddard, BL
胞嘧啶脱氨酶（CD）催化胞嘧啶的脱氨基，产生尿嘧啶。这种酶存在于原核生物和真菌中（但不存在于多细胞真核生物中），并且是这些生物中嘧啶补救途径的重要成员。相同的酶还催化5-氟胞嘧啶转化为5-氟尿嘧啶;这种活性允许从非细胞毒性前体形成细胞毒性化疗剂。该酶在抗微生物药物设计和针对肿瘤的基因治疗应用方面都具有广泛的意义。大肠杆菌CD的结构已在存在和不存在基于结合机制的抑制剂的情况下确定。该酶形成一个（向上）桶结构，与腺苷脱氨酶具有结构相似性，在序列水平上无法检测到这种关系，与细菌胞苷脱氨酶没有相似性。该酶被包装成一个六聚体组装，通过酶亚基之间独特的结构域交换相互作用来稳定。活性位点位于酶桶的口部，并且含有与羟基亲核试剂配位的结合铁离子。底物结合涉及将反应复合物与溶剂隔离的显著构象变化。(C)北京大学出版社.
Cytosine deaminase (CD) catalyzes the deamination of cytosine, producing uracil. This enzyme is present in prokaryotes and fungi (but not multicellular eukaryotes) and is an important member of the pyrimidine salvage pathway in those organisms. The same enzyme also catalyzes the conversion of 5-fluorocytosine to 5-fluorouracil; this activity allows the formation of a cytotoxic chemotherapeutic agent from a non-cytotoxic precursor. The enzyme is of widespread interest both for antimicrobial drug design and for gene therapy applications against tumors. The structure of Esclierichia coli CD has been determined in the presence and absence of a bound mechanism-based inhibitor. The enzyme forms an (up), barrel structure with structural similarity to adenosine deaminase, a relationship that is undetectable at the sequence level, and no similarity to bacterial cytidine deaminase. The enzyme is packed into a hexameric assembly stabilized by a unique domain-swapping interaction between enzyme subunits. The active site is located in the mouth of the enzyme barrel and contains a bound iron ion that coordinates a hydroxyl nucleophile. Substrate binding involves a significant conformational change that sequesters the reaction complex from solvent. (C) 2002 Academic Press.