The members of the arylamine N-acetyltransferase (NAT) family of enzymes are important for their many roles in xenobiotic detoxification in bacteria and humans. However, very little is known about their roles outside of detoxification or their specificities for acyl donors larger than acetyl-CoA. Herein, we report the detailed study of PtmC, an unusual NAT homologue encoded in the biosynthetic gene cluster for thioplatensimycin, thioplatencin, and a newly reported scaffold, thioplatensilin, thioacid-containing diterpenoids and highly potent inhibitors of bacterial and mammalian fatty acid synthases. As the final enzyme of the pathway, PtmC is responsible for the selection of a thioacid arylamine over its cognate carboxylic acid and coupling to at least three large, 17-carbon ketolide-CoA substrates. Therefore, this study uses a combined approach of enzymology and molecular modeling to reveal how PtmC has evolved from the canonical NAT scaffold into a key part of a natural combinatorial biosynthetic pathway. Additionally, genome mining has revealed the presence of other related NATs located within natural product biosynthetic gene clusters. Thus, findings from this study are expected to expand our knowledge of how enzymes evolve for expanded substrate diversity and enable additional predictions about the activities of NATs involved in natural product biosynthesis and xenobiotic detoxification.

中文翻译：

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PtmC 催化硫盘霉素、硫盘菌素和硫盘菌素生物合成的最后一步，扩大芳胺 N-乙酰转移酶的范围

芳胺N的成员-乙酰转移酶 (NAT) 酶家族对于它们在细菌和人类外源性解毒中的许多作用很重要。然而，关于它们在解毒之外的作用或它们对比乙酰辅酶A大的酰基供体的特异性知之甚少。在这里，我们报告了 PtmC 的详细研究，PtmC 是一种不寻常的 NAT 同源物，在硫代盘霉素、硫盘菌素的生物合成基因簇中编码，以及新报道的支架、硫代盘菌素、含硫代二萜类化合物和细菌和哺乳动物脂肪酸合酶的高效抑制剂。作为该途径的最终酶，PtmC 负责选择硫代芳基胺而不是其同源羧酸，并与至少三个大的 17 碳酮内酯-CoA 底物偶联。所以，该研究使用酶学和分子建模的组合方法来揭示 PtmC 如何从经典的 NAT 支架演变为天然组合生物合成途径的关键部分。此外，基因组挖掘揭示了位于天然产物生物合成基因簇中的其他相关 NAT 的存在。因此，这项研究的结果有望扩展我们对酶如何进化以扩大底物多样性的了解，并能够对涉及天然产物生物合成和外源物质解毒的 NAT 的活性进行额外预测。基因组挖掘揭示了位于天然产物生物合成基因簇中的其他相关 NAT 的存在。因此，这项研究的结果有望扩展我们对酶如何进化以扩大底物多样性的了解，并能够对涉及天然产物生物合成和外源物质解毒的 NAT 的活性进行额外预测。基因组挖掘揭示了位于天然产物生物合成基因簇中的其他相关 NAT 的存在。因此，这项研究的结果有望扩展我们对酶如何进化以扩大底物多样性的了解，并能够对涉及天然产物生物合成和外源物质解毒的 NAT 的活性进行额外预测。