Acetylation-Deacetylation-Driven Natural Product Biosynthesis

Huibin Wang, Ikuro Abe
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Abstract

Acetylation introduces acetyl groups to substrates, thus altering their chemical reactivity and stability, and plays a crucial role in natural product biosynthesis by driving structural diversification and functional optimization. Emerging evidence now highlights cryptic acetylations as transient modifications that guide sequential reactions, enabling the efficient assembly of bioactive molecules. Here, we systematically examine the multifaceted roles of acetylation-deacetylation dynamics in natural product biosynthesis, with particular emphasis on four key mechanistic paradigms. First, we explore the strategy of acetylation followed by deacetylation after several biosynthetic steps, which serves as a protective and directing mechanism. Second, we investigate acetylation-mediated rearrangement, where the introduction of an acetyl group triggers structural rearrangement to generate novel molecular architectures. Third, we analyze acetylation-triggered elimination, a process that facilitates the formation of crucial double bonds in molecular scaffolds. Finally, we discuss the acetylation cycle as a regulatory mechanism, highlighting its role in controlling biosynthetic flux and intermediate stability. We also examine the challenges of identifying and characterizing cryptic acetylations, while highlighting future opportunities to harness these modifications for synthetic biology. By elucidating the hidden roles of acetylation-deacetylation dynamics, this not only deepens our understanding of natural product biosynthesis but also provides innovative strategies for future drug discovery.

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乙酰化-去乙酰化驱动的天然产物生物合成
乙酰化将乙酰基引入到底物中,从而改变其化学反应性和稳定性,并通过推动结构多样化和功能优化在天然产物生物合成中起着至关重要的作用。新出现的证据表明,隐乙酰化是一种引导连续反应的瞬时修饰,使生物活性分子能够有效地组装。在这里,我们系统地研究了乙酰化-去乙酰化动力学在天然产物生物合成中的多方面作用,特别强调了四个关键的机制范式。首先,我们探索了在几个生物合成步骤后乙酰化和去乙酰化的策略,这是一种保护和指导机制。其次,我们研究了乙酰化介导的重排,其中乙酰基的引入触发结构重排以产生新的分子结构。第三,我们分析了乙酰化引发的消除,这一过程促进了分子支架中关键双键的形成。最后,我们讨论了乙酰化循环作为一种调控机制,强调了其在控制生物合成通量和中间稳定性方面的作用。我们还研究了识别和表征隐乙酰化的挑战,同时强调了利用这些修饰进行合成生物学的未来机会。通过阐明乙酰化-去乙酰化动力学的隐藏作用,这不仅加深了我们对天然产物生物合成的理解,而且为未来的药物发现提供了创新策略。
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