Department of Chemistry , University of Basel , Mattenstrasse 24a , Basel 4002 , Switzerland.
Focal Area Structural Biology and Biophysics, Biozentrum , University of Basel , Basel 4056 , Switzerland.
J Am Chem Soc. 2019 Apr 3;141(13):5275-5285. doi: 10.1021/jacs.8b13023. Epub 2019 Mar 18.
Sulfoxide synthases are nonheme iron enzymes that catalyze oxidative carbon-sulfur bond formation between cysteine derivatives and N-α-trimethylhistidine as a key step in the biosynthesis of thiohistidines. The complex catalytic mechanism of this enzyme reaction has emerged as the controversial subject of several biochemical and computational studies. These studies all used the structure of the γ-glutamyl cysteine utilizing sulfoxide synthase, MthEgtB from Mycobacterium thermophilum (EC 1.14.99.50), as a structural basis. To provide an alternative model system, we have solved the crystal structure of CthEgtB from Chloracidobacterium thermophilum (EC 1.14.99.51) that utilizes cysteine as a sulfur donor. This structure reveals a completely different configuration of active site residues that are involved in oxygen binding and activation. Furthermore, comparison of the two EgtB structures enables a classification of all ergothioneine biosynthetic EgtBs into five subtypes, each characterized by unique active-site features. This active site diversity provides an excellent platform to examine the catalytic mechanism of sulfoxide synthases by comparative enzymology, but also raises the question as to why so many different solutions to the same biosynthetic problem have emerged.
亚砜合酶是一类非血红素铁酶，能够催化半胱氨酸衍生物与 N-α-三甲基组氨酸之间的氧化碳-硫键形成，这是硫组氨酸生物合成中的关键步骤。该酶反应的复杂催化机制是几个生化和计算研究的争议主题。这些研究都使用了来自嗜热分枝杆菌（Mycobacterium thermophilum）的γ-谷氨酰半胱氨酸利用亚砜合酶（γ-glutamyl cysteine utilizing sulfoxide synthase，MthEgtB，EC 1.14.99.50）的结构作为结构基础。为了提供替代的模型系统，我们已经解决了来自嗜热嗜酸杆菌（Chloracidobacterium thermophilum）的 CthEgtB 的晶体结构（EC 1.14.99.51），该酶利用半胱氨酸作为硫供体。该结构揭示了参与氧结合和激活的活性位点残基的完全不同的构象。此外，对两种 EgtB 结构的比较能够将所有的麦角硫因生物合成 EgtB 分为五个亚型，每个亚型都具有独特的活性位点特征。这种活性位点多样性为通过比较酶学来研究亚砜合酶的催化机制提供了一个极好的平台，但也提出了一个问题，即为什么会出现如此多针对同一生物合成问题的不同解决方案。
