近日，美国加州大学伯克利分校Chang, Michelle C. Y.团队报道了tRNA-脱乙酰酶导向的生物合成途径的发现。该研究于2026年4月13日发表在《自然-化学》杂志上。

氨基酸是自然界中最具优势的构建模块之一，能够在从小分子到蛋白质的尺度上产生分子多样性。虽然某些特定类型生物合成途径产生的氨基酸产物可以通过已有的生物信息学策略发现，但那些不属于这些类型的产物仍然难以鉴定。

为了应对这一挑战，研究组开发了一种方法来寻找利用和修饰氨基酸单体、且不依赖于生物合成类型的生物合成基因簇。他们证明，针对宿主合成的非天然氨基酸的tRNA脱酰酶可作为非天然氨基酸代谢的通用基因组标记。利用这种方法，他们能够识别出数千个隐秘的BGC，并展示了对几种不同非天然氨基酸BGC以及一个含酰肼的三肽BGC的发现。研究组预计，该方法将在发现含有非天然氨基酸及其他成分的天然产物方面具有广泛的应用前景。

附：英文原文

Title: tRNA-deacylase-directed discovery of biosynthetic pathways

Author: Millar, Douglas C., Zhou, Yu, Marchand, Jorge A., Roberts-Mataric, Helena, Chen, Tavis, Hu, Calvin X., Fang, Jason, Millar, Shannon, Stone, Elizabeth A., Pelton, Jeffrey G., Sosa, Max B., Chang, Michelle C. Y.

Issue&Volume: 2026-04-13

Abstract: Amino acids are one of nature’s most privileged building blocks for generating molecular diversity on length scales ranging from small molecules to proteins. While amino acid products arising from certain class-defined biosynthetic pathways can be found with established bioinformatic strategies, those that fall outside of these types remain difficult to identify. Here, to address this challenge, we have developed an approach to find biosynthetic gene clusters (BGCs) that utilize and modify amino acid monomers while remaining agnostic to biosynthetic class. We demonstrate that tRNA deacylases specific for host-synthesized non-canonical amino acids (ncAAs) serve as a common genomic marker of ncAA metabolism. Using this approach, we show that thousands of cryptic BGCs can be identified and demonstrate the discovery of BGCs for several distinct ncAAs as well as a hydrazide-containing tripeptide. We anticipate this approach will have broad applications for discovering natural products with ncAAs and beyond.

DOI: 10.1038/s41557-026-02126-5

Source: https://www.nature.com/articles/s41557-026-02126-5