FDH: An aldehyde dehydrogenase fusion enzyme in folate metabolism
FDH: An aldehyde dehydrogenase fusion enzyme in folate metabolism
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DOI：
10.1016/j.cbi.2008.09.007
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发表时间：
2009-03-16
影响因子：
5.1
通讯作者：
Krupenko, Sergey A.
中科院分区：
文献类型：
--
作者：
Krupenko, Sergey A.
FDH（10-甲酰四氢叶酸脱氢酶，Aldh 1 L1，EC 1.5.1.6）在NADP（+）依赖性反应中将10-甲酰四氢叶酸（10-甲酰-THF）转化为四氢叶酸和CO2。它是四个相同的902个氨基酸残基亚基的四聚体。蛋白质亚基是三个不相关基因的天然融合产物，由三个不同的结构域组成。FDH的N-末端结构域（残基1-310）携带叶酸结合位点，并且与利用10-甲酰基-THF作为底物的其它酶共享序列同源性和结构拓扑。在体外，它作为10-甲酰-THF水解酶发挥作用，有证据表明这种活性是整个FDH机制的一部分。FDH的C-末端结构域（残基400-902）源自醛脱氢酶相关基因，并且能够将短链醛氧化成相应的酸。类似于1类和2类醛脱氢酶，该结构域以四聚体形式存在，并定义了全长酶的寡聚体结构。两个催化结构域通过中间接头（残基311-399）连接，所述中间接头是具有4 '-磷酸泛酰巯基乙胺辅基的载体蛋白的结构和功能同源物。在FDH机制中，中间接头结构域将共价连接至磷酸泛酰巯基乙胺臂的巯基的甲酰基从N端结构域转移至C端结构域。整体FDH机制是通过底物转移步骤桥接的两个连续反应（水解酶和甲酰基脱氢酶）的偶联。在这种机制中，一个结构域提供叶酸结合位点和水解酶催化中心以从叶酸底物中除去甲酰基，另一个结构域提供催化中心之间的转移载体，第三个结构域有助于脱氢酶机制进一步将甲酰基氧化为CO2。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
FDH (10-formyltetrahydrofolate dehydrogenase, Aldh1L1, EC 1.5.1.6) converts 10-formyltetrahydrofolate (10-formyl-THF) to tetrahydrofolate and CO2 in a NADP(+)-dependent reaction. It is a tetramer of four identical 902 amino acid residue subunits. The protein subunit is a product of a natural fusion of three unrelated genes and consists of three distinct domains. The N-terminal domain of FDH (residues 1-310) carries the folate binding site and shares sequence homology and structural topology with other enzymes utilizing 10-formyl-THF as a substrate. In vitro it functions as 10-formyl-THF hydrolase, and evidence indicate that this activity is a part of the overall FDH mechanism. The C-terminal domain of FDH (residues 400-902) originated from an aldehyde dehydrogenase-related gene and is capable of oxidation of short-chain aldehydes to corresponding acids. Similar to classes 1 and 2 aldehyde dehydrogenases, this domain exists as a tetramer and defines the oligomeric structure of the full-length enzyme. The two catalytic domains are connected by an intermediate linker (residues 311-399), which is a structural and functional homolog of carrier proteins possessing a 4'-phosphopantetheine prosthetic group. In the FDH mechanism, the intermediate linker domain transfers a formyl, covalently attached to the sulfhydryl group of the phosphopantetheine arm, from the N-terminal domain to the C-terminal domain. The overall FDH mechanism is a coupling of two sequential reactions, a hydrolase and a formyl dehydrogenase, bridged by a substrate transfer step. In this mechanism, one domain provides the folate binding site and a hydrolase catalytic center to remove the formyl group from the folate substrate, another provides a transfer vehicle between catalytic centers and the third one contributes the dehydrogenase machinery further oxidizing formyl to CO2. (C) 2008 Elsevier Ireland Ltd. All rights reserved.