Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Collaborative Research Institute for Innovative Microbiology (CRIIM), The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Biosci Biotechnol Biochem. 2021 Jan 7;85(1):42-52. doi: 10.1093/bbb/zbaa052.
Phosphonates are organophosphorus compounds possessing a characteristic C-P bond in which phosphorus is directly bonded to carbon. As phosphonates mimic the phosphates and carboxylates of biological molecules to potentially inhibit metabolic enzymes, they could be lead compounds for the development of a variety of drugs. Fosfomycin (FM) is a representative phosphonate natural product that is widely used as an antibacterial drug. Here, we review the biosynthesis of FM, which includes a recent breakthrough to find a missing link in the biosynthetic pathway that had been a mystery for a quarter-century. In addition, we describe the genome mining of phosphonate natural products using the biosynthetic gene encoding an enzyme that catalyzes C-P bond formation. We also introduce the chemoenzymatic synthesis of phosphonate derivatives. These studies expand the repertoires of phosphonates and the related biosynthetic machinery. This review mainly covers the years 2012-2020.
膦酸酯是一类具有特征性 C-P 键的有机磷化合物，其中磷原子直接与碳键合。由于膦酸酯可以模拟生物分子的磷酸盐和羧酸盐，从而潜在地抑制代谢酶，因此它们可能成为开发各种药物的先导化合物。磷霉素 (FM) 是一种具有代表性的膦酸酯天然产物，被广泛用作抗菌药物。在这里，我们综述了 FM 的生物合成，其中包括最近在生物合成途径中发现了一个缺失环节的突破，该环节在过去四分之一个世纪一直是个谜。此外，我们还描述了利用催化 C-P 键形成的酶的生物合成基因对膦酸酯天然产物进行基因组挖掘。我们还介绍了膦酸酯衍生物的化学酶合成。这些研究扩展了膦酸酯及其相关生物合成机制的应用范围。本综述主要涵盖了 2012 年至 2020 年的研究进展。
