Over the course of evolution, enzymes have developed remarkable functional diversity in catalyzing important chemical reactions across various organisms, and understanding how new enzyme functions might have evolved remains an important question in modern enzymology. To systematically annotate functions, based on their protein sequences and available biochemical studies, enzymes with similar catalytic mechanisms have been clustered together into an enzyme superfamily. Typically, enzymes within a superfamily have similar overall three-dimensional structures, conserved catalytic residues, but large variations in substrate recognition sites and residues to accommodate the diverse biochemical reactions that are catalyzed within the superfamily. The serine hydrolases are an excellent example of such an enzyme superfamily. Based on known enzymatic activities and protein sequences, they are split almost equally into the serine proteases and metabolic serine hydrolases. Within the metabolic serine hydrolases, there are two outlying members, ABHD14A and ABHD14B, that have high sequence similarity, but their biological functions remained cryptic till recently. While ABHD14A still lacks any functional annotation to date, we recently showed that ABHD14B functions as a lysine deacetylase in mammals. Given their high sequence similarity, automated databases often wrongly assign ABHD14A and ABHD14B as the same enzyme, and therefore, annotating functions to them in various organisms has been problematic. In this article, we present a bioinformatics study coupled with biochemical experiments, which identifies key sequence determinants for both ABHD14A and ABHD14B, and enable better classification for them. In addition, we map these enzymes on an evolutionary timescale and provide a much-wanted resource for studying these interesting enzymes in different organisms.

中文翻译：

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ABHD14 酶序列决定簇的鉴定

在进化过程中，酶在催化各种生物体的重要化学反应方面已经发展出显着的功能多样性，并且了解新的酶功能如何进化仍然是现代酶学中的一个重要问题。为了系统地注释功能，根据其蛋白质序列和现有的生化研究，具有相似催化机制的酶已被聚集到一个酶超家族中。通常，超家族内的酶具有相似的整体三维结构、保守的催化残基，但底物识别位点和残基存在较大差异，以适应超家族内催化的不同生化反应。丝氨酸水解酶是此类酶超家族的一个很好的例子。根据已知的酶活性和蛋白质序列，它们几乎均等地分为丝氨酸蛋白酶和代谢丝氨酸水解酶。在代谢丝氨酸水解酶中，有两个外围成员ABHD14A和ABHD14B具有很高的序列相似性，但它们的生物学功能直到最近仍然很神秘。虽然迄今为止 ABHD14A 仍缺乏任何功能注释，但我们最近表明 ABHD14B 在哺乳动物中充当赖氨酸脱乙酰酶。鉴于它们的高度序列相似性，自动化数据库经常错误地将 ABHD14A 和 ABHD14B 指定为相同的酶，因此，在各种生物体中注释它们的功能一直是个问题。在本文中，我们提出了一项与生化实验相结合的生物信息学研究，该研究确定了 ABHD14A 和 ABHD14B 的关键序列决定因素，并能够更好地对它们进行分类。此外，我们在进化时间尺度上绘制了这些酶的图谱，并为研究不同生物体中这些有趣的酶提供了急需的资源。