Coenzyme A (CoA) esters of short fatty acids (acyl-CoAs) function as key precursors for the biosynthesis of various natural products and the dominant donors for lysine acylation. Herein, we investigated the functional interplay between beneficial and adverse effects of acyl-CoA supplements on the production of acyl-CoA-derived natural products in microorganisms by using erythromycin-biosynthesizedSaccharopolyspora erythraeaas a model: accumulation of propionyl-CoA benefited erythromycin biosynthesis, but lysine propionylation inhibited the activities of important enzymes involved in biosynthetic pathways of erythromycin. The results showed that the overexpression of NAD+-dependent deacylase could circumvent the inhibitory effects of high acyl-CoA concentrations. In addition, we demonstrated the similar lysine acylation mechanism in other acyl-CoA-derived natural product biosynthesis, such as malonyl-CoA-derived alkaloid and butyryl-CoA-derived bioalcohol. These observations systematically uncovered the important role of protein acylation on interaction between the accumulation of high concentrations of acyl-CoAs and the efficiency of their use in metabolic pathways.

中文翻译：

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蛋白质酰化是酰基辅酶A衍生的天然产物生物合成途径中的一般调节机制。

短脂肪酸的辅酶A（CoA）酯（酰基-CoA）充当各种天然产物生物合成的关键前体，以及赖氨酸酰化作用的主要供体。在这里，我们通过使用红霉素生物合成的糖多孢红霉菌模型研究了酰基辅酶A补充剂对微生物中酰基辅酶A天然产物生产的有利和不利作用之间的功能相互作用：丙酰辅酶A有益的红霉素生物合成，但赖氨酸的积累丙酰化抑制了红霉素生物合成途径中重要酶的活性。结果表明，NAD +依赖性脱酰基酶的过表达可以避免高酰基辅酶A的抑制作用。此外，我们证明了在其他酰基辅酶A衍生的天然产物生物合成中，例如丙二酰辅酶A衍生的生物碱和丁酰辅酶A衍生的生物醇中，赖氨酸酰化机理相似。这些发现系统地揭示了蛋白质酰化对高浓度酰基辅酶A的积累与其在代谢途径中的利用效率之间相互作用的重要作用。