Department of Chemical and Biomolecular Engineering, University of California, Los Angeles , 420 Westwood Plaza, Los Angeles, California 90095, United States.
ACS Chem Biol. 2013 Oct 18;8(10):2322-30. doi: 10.1021/cb400541z. Epub 2013 Sep 9.
Griseofulvin (1) is a spirocyclic fungal natural product used in treatment of fungal dermatophytes. Formation of the spirocycle, or the grisan scaffold, from a benzophenone precursor is critical for the activity of 1. In this study, we have systematically characterized each of the biosynthetic enzymes related to the biogenesis of 1, including the characterization of a new polyketide synthase GsfA that synthesizes the benzophenone precursor and a cytochrome P450 GsfF that performs oxidative coupling between the orcinol and the phloroglucinol rings to yield the grisan structure. Notably, the finding of GsfF is in sharp contrast to the copper-dependent dihydrogeodin oxidase that performs a similar reaction in the geodin biosynthetic pathway. The biosynthetic knowledge enabled the in vitro total biosynthesis of 1 from malonyl-CoA using all purified enzyme components. This work therefore completely maps out the previously unresolved enzymology of the biosynthesis of a therapeutically relevant natural product.
灰黄霉素（1）是一种用于治疗真菌性皮肤癣菌的螺旋环真菌天然产物。从苯甲酮前体形成螺旋环或灰黄霉素支架对于 1 的活性至关重要。在这项研究中，我们系统地描述了与 1 的生物合成相关的每一种生物合成酶，包括表征了一种新的聚酮合酶 GsfA，它合成苯甲酮前体，以及一种细胞色素 P450 GsfF，它在间苯三酚和邻苯二酚环之间进行氧化偶联，生成灰黄霉素结构。值得注意的是，GsfF 的发现与铜依赖性二氢革二酮氧化酶形成鲜明对比，后者在革二酮生物合成途径中执行类似的反应。生物合成知识使我们能够使用所有纯化的酶成分，从丙二酰辅酶 A 体外全合成 1。因此，这项工作完全阐明了以前未解决的治疗相关天然产物生物合成的酶学。
