Arsenate reductase (ArsC) is a superfamily of enzymes that reduce arsenate. Due to active site similarities, some ArsC can function as low-molecular weight protein tyrosine phosphatases (LMW-PTPs). Broad superfamily classifications align with redox partners (Trx- or Grx-linked). To understand this superfamily’s mechanistic diversity, the ArsC superfamily is classified on the basis of active site features utilizing the tools TuLIP (two-level iterative clustering process) and autoMISST (automated multilevel iterative sequence searching technique). This approach identified nine functionally relevant (perhaps isofunctional) protein groups. Five groups exhibit distinct ArsC mechanisms. Three are Grx-linked: group 4AA (classical ArsC), group 3AAA (YffB-like), and group 5BAA. Two are Trx-linked: groups 6AAAAA and 7AAAAAAAA. One is an Spx-like transcriptional regulatory group, group 5AAA. Three are potential LMW-PTP groups: groups 7BAAAA, and 7AAAABAA, which have not been previously identified, and the well-studied LMW-PTP family group 8AAA. Molecular dynamics simulations were utilized to explore functional site details. In several families, we confirm and add detail to literature-based mechanistic information. Mechanistic roles are hypothesized for conserved active site residues in several families. In three families, simulations of the unliganded structure sample specific conformational ensembles, which are proposed to represent either a more ligand-binding-competent conformation or a pathway toward a more binding-competent state; these active sites may be designed to traverse high-energy barriers to the lower-energy conformations necessary to more readily bind ligands. This more detailed biochemical understanding of ArsC and ArsC-like PTP mechanisms opens possibilities for further understanding of arsenate bioremediation and the LMW-PTP mechanism.

中文翻译：

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砷还原酶超家族的同构聚类和构象分析揭示了九个不同的簇。

砷酸还原酶（ArsC）是还原砷酸的酶的超家族。由于活性位点的相似性，某些ArsC可以充当低分子量蛋白酪氨酸磷酸酶（LMW-PTP）。广泛的超家族分类与氧化还原伙伴（Trx或Grx关联）保持一致。为了理解该超家族的机制多样性，使用工具TuLIP（两级迭代聚类过程）和autoMISST（自动多级迭代序列搜索技术），根据活动站点特征对ArsC超家族进行分类。这种方法确定了九个功能相关（也许同功能）的蛋白质组。五个小组展示出独特的ArsC机制。三个是Grx关联的：4AA组（经典ArsC），3AAA组（类似YffB）和5BAA组。Trx链接有两个：组6AAAAA和7AAAAAAAA。一个是Spx样的转录调节基团5AAA组。三个潜在的LMW-PTP组：先前尚未确定的组7BAAAA和7AAAABAA，以及经过充分研究的LMW-PTP家族组8AAA。利用分子动力学模拟来探索功能部位的细节。在几个家庭中，我们确认并为基于文献的机械信息增加了细节。假定了几个家族中保守的活性位点残基的机械作用。在三个家族中，对未配体结构的模拟采样了特定的构象集合体，它们被提议代表更具有配体结合能力的构象或通往更具有结合能力的状态的途径。这些活性位点可被设计为穿过高能垒，达到更容易结合配体所必需的低能构象。对ArsC和类似ArsC的PTP机制的更详细的生化理解为进一步理解砷酸盐生物修复和LMW-PTP机制提供了可能性。