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首页> 外文期刊>Applied Microbiology >Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis
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Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis

机译：酚酰胺是De Novo核苷酸生物合成的有效抑制剂

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An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using ~(13)C-labeled sugars and [~(15)N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals.
机译：有效利用植物生物质生产生物燃料和增值化学品的一个巨大挑战是木质纤维素衍生的抑制剂对微生物发酵的影响。阐明其毒性基础的机制对于制定克服它们的策略至关重要。在这里，我们使用大肠杆菌作为模型系统，研究了氨预处理的生物质水解物中主要的酚类化合物阿魏酰酰胺和香豆酰酰胺的代谢作用和毒性机理。使用代谢组学，同位素示踪剂和生化分析，我们表明这两种酚酰胺是嘌呤和嘧啶生物合成途径的有效抑制剂和速效抑制剂。阿魏酰或香豆酰酰胺暴露会导致（i）核苷酸生物合成的关键前体5-磷酸核糖基-1-焦磷酸（PRPP）快速积累，（ii）嘧啶生物合成中间体的水平迅速下降，以及（iii）核苷酸和脱氧核苷酸水平的长期普遍下降。使用〜（13）C标记的糖和[〜（15）N]氨进行的示踪剂实验表明，这些酚酰胺抑制了碳和氮通入核苷酸和脱氧核苷酸的通量。我们发现这些作用是通过直接抑制参与核苷酸生物合成途径的谷氨酰胺酰胺转移酶介导的。尤其是，阿魏酰酰胺是谷氨酰胺PRPP酰胺基转移酶（PurF）的竞争性抑制剂，可催化从头进行嘌呤生物合成的第一步。最后，外部核苷补充剂允许通过挽救途径进行核苷酸生物合成，从而防止了酚酰胺介导的生长抑制。本文介绍的结果将有助于制定克服酚类化合物毒性的策略，并促进工程设计更高效的生物燃料和化学品的微生物生产商。

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