Modulation of Catalytic Promiscuity during Hydrogen Sulfide Oxidation.
Modulation of Catalytic Promiscuity during Hydrogen Sulfide Oxidation.
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DOI：
10.1021/acschembio.8b00258
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发表时间：
2018-06-15
影响因子：
4
通讯作者：
Banerjee R
中科院分区：
文献类型：
--
作者：
Landry AP;Ballou DP;Banerjee R
线粒体硫化物氧化途径防止硫化氢（H2S）的毒性积累，硫化氢是一种维持在低稳态浓度的信号分子。硫醌氧化还原酶（SQR）是一种线粒体内膜锚定蛋白，催化该途径中的第一步，将H2S氧化为过硫化物。该催化循环包括硫化物添加到SQR中的活性位点半胱氨酸二硫化物，然后硫转移到小分子受体，同时一对电子从硫化物移动到FAD，再移动到辅酶Q。虽然其氧化H2S的能力得到了很好的表征，但SQR在体外表现出显著程度的底物混杂性，这可能会破坏其典型的酶活性。为了评估其混杂性如何可能包含在体内，我们已经使用光谱和动力学分析来表征替代底物与嵌入纳米盘（ndSQR）与洗涤剂溶解酶（sSQR）的反应性。我们发现，ndSQR的膜环境抑制不必要的添加GSH，但提高亚硫酸盐添加，这可能会变得显着的病理条件下，其特征在于亚硫酸盐水平升高。我们证明，甲硫醇是一种由结肠和口腔微生物群大量产生的有毒硫化合物，可以添加到SQR半胱氨酸二硫化物中，也可以作为硫受体，当其浓度升高时可能会干扰硫化物氧化。这些研究表明，膜环境和底物的可用性联合收割机，以尽量减少混杂的反应，否则会破坏硫化物的稳态。
The mitochondrial sulfide oxidation pathway prevents the toxic accumulation of hydrogen sulfide (H2S), a signaling molecule that is maintained at low steady-state concentrations. Sulfide quinone oxidoreductase (SQR), an inner mitochondrial membrane-anchored protein, catalyzes the first and committing step in this pathway, oxidizing H2S to persulfide. The catalytic cycle comprises sulfide addition to the active site cysteine disulfide in SQR followed by sulfur transfer to a small molecule acceptor, while a pair of electrons moves from sulfide, to FAD, to coenzyme Q. While its ability to oxidize H2S is well characterized, SQR exhibits a remarkable degree of substrate promiscuity in vitro that could undermine its canonical enzyme activity. To assess how its promiscuity might be contained in vivo, we have used spectroscopic and kinetic analyses to characterize the reactivity of alternate substrates with SQR embedded in nanodiscs (ndSQR) versus detergent-solubilized enzyme (sSQR). We find that the membrane environment of ndSQR suppresses the unwanted addition of GSH but enhances sulfite addition, which might become significant under pathological conditions characterized by elevated sulfite levels. We demonstrate that methanethiol, a toxic sulfur compound produced in significant quantities by colonic and oral microbiota, can add to the SQR cysteine disulfide and also serve as a sulfur acceptor, potentially interfering with sulfide oxidation when its concentrations are elevated. These studies demonstrate that the membrane environment and substrate availability combine to minimize promiscuous reactions that would otherwise disrupt sulfide homeostasis.
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