Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog.
Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog.
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DOI：
10.1021/bi500650h
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发表时间：
2014-07-22
期刊：
影响因子：
2.9
通讯作者：
Jorns, Marilyn Schuman
中科院分区：
文献类型：
--
作者：
Melideo, Scott L.;Jackson, Michael R.;Jorns, Marilyn Schuman
人类硫化物：醌氧化还原酶（SQOR）催化H2S转化为硫代硫酸盐，这是哺乳动物H2S代谢的第一步。SQOR不能产生硫双加氧酶（SDO）的谷胱甘肽过硫化物（GSS-）底物，这表明需要硫代硫酸盐：谷胱甘肽硫转移酶（TST）来提供SQOR和SDO反应之间缺失的环节。虽然TST可以从酵母中纯化，但分离哺乳动物酶的尝试并不成功。我们使用生物信息学方法来鉴定可能编码人类TST（TSTD 1）及其酵母直系同源物（RDL 1）的基因。重组TSTD 1和RDL 1催化谷胱甘肽向GSS-的预测硫代硫酸盐依赖性转化。这两种酶都含有一个罗丹酸同源结构域和一个催化必需的半胱氨酸，它在与硫代硫酸盐反应时转化为半胱氨酸过硫化物。GSS-是TSTD 1和RDL 1的强效抑制剂，通过在SDO存在下观察到的谷胱甘肽初始速率加速和Km值降低≥25倍来判断。GSS-和SDO的联合作用可能调节活性代谢物的生物合成。SDO驱动完成由TSTD 1和RDL 1催化的对甲苯硫代磺酸：谷胱甘肽硫转移酶反应。不可逆的SDO和可逆的TST反应的热力学耦合提供了一个模型，与硫代硫酸盐作为硫烷供体的生理相关的反应。包含SDO和TSTD 1融合体的细菌Rosetta Stone蛋白的发现提供了这些酶相关性的系统发育证据。编码SDO-TSTD 1融合蛋白和类人SQOR的相邻细菌基因的存在表明这些原核生物和哺乳动物表现出惊人相似的H2S代谢途径。
Human sulfide:quinone oxidoreductase (SQOR) catalyzes the conversion of H2S to thiosulfate, the first step in mammalian H2S metabolism. SQOR’s inability to produce the glutathione persulfide (GSS–) substrate for sulfur dioxygenase (SDO) suggested that a thiosulfate:glutathione sulfurtransferase (TST) was required to provide the missing link between the SQOR and SDO reactions. Although TST could be purified from yeast, attempts to isolate the mammalian enzyme were not successful. We used bioinformatic approaches to identify genes likely to encode human TST (TSTD1) and its yeast ortholog (RDL1). Recombinant TSTD1 and RDL1 catalyze a predicted thiosulfate-dependent conversion of glutathione to GSS–. Both enzymes contain a rhodanese homology domain and a single catalytically essential cysteine, which is converted to cysteine persulfide upon reaction with thiosulfate. GSS– is a potent inhibitor of TSTD1 and RDL1, as judged by initial rate accelerations and ≥25-fold lower Km values for glutathione observed in the presence of SDO. The combined action of GSS– and SDO is likely to regulate the biosynthesis of the reactive metabolite. SDO drives to completion p-toluenethiosulfonate:glutathione sulfurtransferase reactions catalyzed by TSTD1 and RDL1. The thermodynamic coupling of the irreversible SDO and reversible TST reactions provides a model for the physiologically relevant reaction with thiosulfate as the sulfane donor. The discovery of bacterial Rosetta Stone proteins that comprise fusions of SDO and TSTD1 provides phylogenetic evidence of the association of these enzymes. The presence of adjacent bacterial genes encoding SDO–TSTD1 fusion proteins and human-like SQORs suggests these prokaryotes and mammals exhibit strikingly similar pathways for H2S metabolism.
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