文章基本信息

标题：The structural basis of an NADP+-independent dithiol oxidase in FK228 biosynthesis
本地全文：下载
作者：Jie Li ; Cheng Wang ; Zhi-Min Zhang 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2015
卷号：4
期号：1
DOI：10.1038/srep04145
语种：English
出版社：Springer Nature
摘要：The disulfide bond is unusual in natural products and critical for thermal stability, cell permeability and bioactivity. DepH from Chromobacterium violaceum No. 968 is an FAD-dependent enzyme responsible for catalyzing the disulfide bond formation of FK228, an anticancer prodrug approved for the treatment of cutaneous T-cell lymphoma. Here we report the crystal structures of DepH and DepH complexed with a substrate analogue S,S'-dimethyl FK228 at 1.82 Å and 2.00 Å, respectively. Structural and biochemical analyses revealed that DepH, in contrast to the well characterized low molecular weight thioredoxin reductases (LMW TrxRs), is an NADP⁺-independent dithiol oxidase. DepH not only lacks a conserved GGGDXAXE motif necessary for NADP⁺ binding in the canonical LMW TrxRs, but also contains a 11-residue sequence which physically impedes the binding of NADP⁺. These observations explain the difference between NADP⁺-independent small molecule dithiol oxidases and NADP⁺-dependent thioredoxin reductases and provide insights for understanding the catalytic mechanism of dithiol oxidases involved in natural product biosynthesis.