Center for Bioinformatics, Perdana University School of Data Science, Serdang, Selangor, Malaysia.
The Davies Research Centre, School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy, SA, Australia.
PLoS One. 2018 Dec 26;13(12):e0209336. doi: 10.1371/journal.pone.0209336. eCollection 2018.
Glutathione S-Transferases (GSTs) are phase II detoxification enzymes that may have evolved in response to changes of environmental substrates. GST genes formed a multigene family and in mammals, there are six classes known as Alpha, Mu, Omega, Pi, Theta, and Zeta. Recent studies in phase I detoxification system specifically the cytochrome P450s provided a general explanation on why genes from a common origin such as those in a multigene family have both phylogenetically stable and unstable genes. Genes that participate in core functions of organisms such as development and physiology are stable whereas genes that play a role in detoxification are unstable and evolve in a process known as birth-death evolution, which is characterised by frequent gene gains and losses. The generality of the birth-death model at explaining the evolution of detoxification enzymes beyond the phase I enzyme has not been comprehensively explored. This work utilized 383 Gst genes and 300 pseudogenes across 22 mammalian species to study gene gains and losses. GSTs vary greatly in their phylogenetic stability despite their overall sequence similarity. Stable Gst genes from Omega and Zeta classes do not show fluctuation in gene numbers from human to opossum. These genes play a role in biosynthesis related functions. Unstable genes that include Alpha, Mu, Pi and Theta undergo frequent gene gain and loss in a process known as birth-death evolution. Gene members of these four classes are well known for their roles in detoxification. Our positive selection screen identified five positively selected sites in mouse GSTA3. Previous studies showed two of these sites (108H and 208E) were biochemically tested as important residues that conferred catalytic activity against the toxic aflatoxin B1-8,9-epoxide. The functional significance against aflatoxin of the remaining three positively selected sites warrant further investigation.
谷胱甘肽 S-转移酶 (GSTs) 是 II 相解毒酶，可能是为了应对环境底物的变化而进化的。GST 基因形成了一个多基因家族，在哺乳动物中，有六个已知的类别，分别是 Alpha、Mu、Omega、Pi、Theta 和 Zeta。最近对 I 相解毒系统的研究，特别是细胞色素 P450s，为为什么来自共同起源的基因（如多基因家族中的基因）既有进化上稳定的基因，也有不稳定的基因提供了一个普遍的解释。参与生物体核心功能（如发育和生理）的基因是稳定的，而在解毒中发挥作用的基因是不稳定的，并在一个称为“生死进化”的过程中进化，其特征是频繁的基因获得和丢失。生死模型在解释 I 相酶以外的解毒酶进化方面的普遍性尚未得到全面探讨。这项工作利用了 22 种哺乳动物中的 383 个 Gst 基因和 300 个假基因来研究基因的获得和丢失。尽管 GSTs 的整体序列相似，但它们在系统发育稳定性上差异很大。来自 Omega 和 Zeta 类别的稳定 Gst 基因，其基因数量在人类到负鼠之间没有波动。这些基因在生物合成相关功能中发挥作用。包括 Alpha、Mu、Pi 和 Theta 在内的不稳定基因经历了频繁的基因获得和丢失，这一过程称为生死进化。这些四类基因的成员因其在解毒中的作用而广为人知。我们的正选择筛选在小鼠 GSTA3 中鉴定出了 5 个正选择位点。以前的研究表明，这两个位点（108H 和 208E）在生化上被测试为对有毒的黄曲霉毒素 B1-8,9-环氧化物具有催化活性的重要残基。其余三个正选择位点对黄曲霉毒素的功能意义值得进一步研究。
