Argueta Christopher, Parkins Andrew, Pantouris Georgios
Department of Chemistry, University of the Pacific, Stockton, CA 95211, USA.
Int J Mol Sci. 2024 Nov 24;25(23):12617. doi: 10.3390/ijms252312617.
Consisting of more than 11,000 members distributed over five families, the tautomerase superfamily (TSF) is a large collection of proteins with diverse biological functions. While much attention has been given to individual TSF enzymes, a majority remain structurally and functionally uncharacterized. Given its large size, studying a representative member of each family offers a viable approach for extracting mechanistic insights applicable to the entire superfamily. In this study, cis-3-chloroacrylic acid dehalogenase (cis-CaaD), 5-carboxymethyl-2-hydroxymuconate isomerase (CHMI), malonate semialdehyde decarboxylase (MSAD), and 4-oxalocrotonate tautomerase (4-OT) were referenced against the well-studied macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) using triplicate 1 μs molecular dynamics (MD) simulations for a total of 18 μs. Through root mean square fluctuation (RMSF) measurements, correlation analyses, and comparisons to previous crystallographic structures, we reveal key mechanistic insights that promote the understanding of the catalytic activities in TSF. Collectively, our findings from these functionally diverse TSF proteins provide key information on allosteric coupling, long-range intra- and inter-subunit communications as well as structure-activity relationships that enable new studies in the superfamily.
互变异构酶超家族（TSF）由分布在五个家族中的11000多名成员组成，是一个具有多种生物学功能的蛋白质大集合。虽然人们对单个TSF酶给予了很多关注，但大多数成员在结构和功能上仍未得到表征。鉴于其规模庞大，研究每个家族的一个代表性成员为提取适用于整个超家族的机制见解提供了一种可行的方法。在本研究中，使用一式三份的1微秒分子动力学（MD）模拟，对研究充分的巨噬细胞迁移抑制因子（MIF）和D-多巴色素互变异构酶（D-DT），参考了顺式-3-氯丙烯酸脱卤酶（cis-CaaD）、5-羧甲基-2-羟基粘康酸异构酶（CHMI）、丙二酸半醛脱羧酶（MSAD）和4-草酰巴豆酸互变异构酶（4-OT），总共进行了18微秒的模拟。通过均方根波动（RMSF）测量、相关性分析以及与先前晶体结构的比较，我们揭示了促进对TSF催化活性理解的关键机制见解。总的来说，我们从这些功能多样的TSF蛋白中获得的发现提供了关于变构偶联、亚基内和亚基间远程通讯以及结构-活性关系的关键信息，从而能够在超家族中开展新的研究。
