Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States.
J Am Chem Soc. 2023 Aug 30;145(34):18716-18721. doi: 10.1021/jacs.3c05750. Epub 2023 Aug 18.
The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic compounds and conjugated systems. Halogenated alkyne-containing molecules are known to occur in Nature; however, halogen atom installation on the terminus of an alkyne has not been demonstrated in enzyme catalysis. Herein, we report the discovery and characterization of an alkynyl halogenase in natural product biosynthesis. We show that the flavin-dependent halogenase from the jamaicamide biosynthetic pathway, JamD, is not only capable of terminal alkyne halogenation on a late-stage intermediate en route to the final natural product but also has broad substrate tolerance for simple to complex alkynes. Furthermore, JamD is specific for terminal alkynes over other electron-rich aromatic substrates and belongs to a newly identified family of halogenases from marine cyanobacteria, indicating its potential as a chemoselective biocatalyst for the formation of haloalkynes.
卤原子的生物合成装置主要由氧化卤化酶来完成，这些酶可以靶向多种富电子底物，包括芳香族化合物和共轭体系。卤代炔烃含有分子在自然界中是已知存在的；然而，在酶催化中，尚未证明在炔烃的末端上安装卤原子。在此，我们报告了在天然产物生物合成中发现和表征的炔基卤化酶。我们表明，来自 Jamaicamide 生物合成途径的黄素依赖性卤化酶 JamD 不仅能够对终产物途径中的晚期中间体进行末端炔烃卤化，而且对简单到复杂的炔烃具有广泛的底物耐受性。此外，JamD 对末端炔烃具有特异性，而不是其他富电子芳香族底物，并且属于海洋蓝细菌中新型卤化酶家族，表明其作为形成卤代炔烃的化学选择性生物催化剂的潜力。
