glutathione S-sulfinate(2-)

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: glutathione S-sulfinate(2-)
• 英文别名: (2S)-2-azaniumyl-5-[[(2R)-1-(carboxylatomethylamino)-1-oxo-3-sulfinatosulfanylpropan-2-yl]amino]-5-oxopentanoate
• 化学式: C10H15N3O8S2-2
• 分子量: 369.4
• InChiKey: QUBUTNSZZFICHL-WDSKDSINSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  -4.3
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  251
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  glutathione S-sulfinate(2-) 、 水 生成 (R)-2-((S)-4-Amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethanethiol anion 、 氢(+1)阳离子 、 三氧化硫
  参考文献：
  名称：

  Arabidopsis ETHE1 Encodes a Sulfur Dioxygenase That Is Essential for Embryo and Endosperm Development

  摘要：

  人类（智人）乙基丙二酸脑病蛋白1（ETHE1）的突变会导致复杂的代谢性疾病乙基丙二酸脑病，其部分特征是脑损伤、乳酸血症、乙基丙二酸排泄，最终导致死亡。ETHE1类似基因存在于多种生物中；然而，ETHE1的生化与生理作用尚未在乙基丙二酸脑病之外的环境下进行研究。在这项研究中，我们描述了拟南芥（Arabidopsis thaliana）ETHE1的特征，并确定了ETHE1功能丧失突变的影响，以研究ETHE1在植物中的作用。拟南芥ETHE1定位于线粒体，并表现出硫二氧酶活性。ETHE1中DNA插入的纯合种子表现出胚乳发育的改变，伴随着胚胎发育延迟，随后在早期心脏阶段停止发育。在细胞化之前，在野生型种子的外围和合点胚乳中观察到强烈的ETHE1标记。因此，ETHE1似乎在调节种子中的硫化物水平方面起着至关重要的作用。

  DOI：

  10.1104/pp.112.201855
• 作为产物：
  描述：

  氧气 、 S-sulfanylglutathionate(1-) 生成 glutathione S-sulfinate(2-) 、 氢(+1)阳离子
  参考文献：
  名称：

  过硫化物的硫磺是酸性嗜酸杆菌和酸性嗜酸杆菌属的硫氧化酶的实际底物。

  摘要：

  为了鉴定中酸性嗜酸性嗜酸硫硫杆菌硫氧化酶菌株DSM 504和K6的谷胱甘肽-依赖性硫双加氧酶（EC 1.13.11.18）元素硫氧化的实际底物，分析了酸性嗜氧硫杆菌铁氧体菌株R1和嗜酸性嗜酸杆菌DSM 700。在粗提取物中发现了高达460 nmol x min（-1）（mg蛋白）（-1）的高比硫双加氧酶活性。所有无细胞系统仅通过谷胱甘肽过硫化物（GSSH）来氧化元素硫，GSH是谷胱甘肽（GSH）和元素硫的非酶反应产物。因此，GSH在元素硫的活化中起催化作用，但在酶法硫烷硫氧化过程中不被消耗。亚硫酸盐是硫双加氧酶活性的第一个产物。它进一步非酶促地与硫酸盐反应，硫代硫酸盐或谷胱甘肽S-磺酸盐（GSSO（-3））。游离的硫化物未被硫双加氧酶氧化。过硫醚作为硫供体不能用其他含硫烷硫的化合物（硫代硫酸盐，多硫代酸盐，双有机基多硫烷或单芳基硫代磺酸盐）代替。通过双加氧酶氧化H（2）S需要GSSG，即G

  DOI：

  10.1099/mic.0.26212-0

文献信息

• Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy
  作者：Valeria Tiranti、Carlo Viscomi、Tatjana Hildebrandt、Ivano Di Meo、Rossana Mineri、Cecilia Tiveron、Michael D Levitt、Alessandro Prelle、Gigliola Fagiolari、Marco Rimoldi、Massimo Zeviani

  DOI：10.1038/nm.1907

  日期：2009.2

  Ethylmalonic encephalopathy is an autosomal recessive developmental disorder that is characterized by chronic diarrhea and multiple neurological deficits. It is associated with loss-of-function mutations in the ETHE1 gene. Now, Massimo Zeviani and his colleagues report that ETHE1 is a dioxygenase that is responsible for breaking down toxic sulfide in a variety of organs. Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine. ETHE1, a gene encoding a β-lactamase–like, iron-coordinating metalloprotein, is mutated in ethylmalonic encephalopathy. In bacteria, ETHE1-like sequences are in the same operon of, or fused with, orthologs of TST, the gene encoding rhodanese, a sulfurtransferase. In eukaryotes, both ETHE1 and rhodanese are located within the mitochondrial matrix. We created a Ethe1−/− mouse that showed the cardinal features of ethylmalonic encephalopathy. We found that thiosulfate was excreted in massive amounts in urine of both Ethe1−/− mice and humans with ethylmalonic encephalopathy. High thiosulfate and sulfide concentrations were present in Ethe1−/− mouse tissues. Sulfide is a powerful inhibitor of COX and short-chain fatty acid oxidation, with vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1−/− mice, whereas it was markedly increased by ETHE1 overexpression in HeLa cells and Escherichia coli. Therefore, ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.

  氧酶，负责分解多种器官中的有毒硫化物。乙基丙二酸脑病是一种常染色体隐性遗传的致命疾病，其特征为早发性脑病、微血管病变、慢性腹泻、肌肉和大脑中细胞色素c氧化酶（COX）缺陷、血液中C4和C5酰基肉碱浓度过高以及尿液中乙基丙二酸排泄过多。ETHE1是一种编码β-内酰胺酶样铁配位金属蛋白的基因，在乙基丙二酸脑病中发生突变。在细菌中，ETHE1样序列位于TST同源基因的同一操作子中，或与其融合，TST是硫转移酶rhodanese的编码基因。在真核生物中，ETHE1和rhodanese都位于线粒体基质内。我们创建了Ethe1△/△小鼠，它表现出乙基丙二酸脑病的主要特征。我们发现，硫代硫酸盐在Ethe1△/△小鼠和乙基丙二酸脑病患者的尿液中大量排泄。Ethe1△/△小鼠组织中存在高浓度的硫代硫酸盐和硫化物。硫化物是COX和短链脂肪酸氧化的强效抑制剂，具有血管活性作用和血管毒性作用，这解释了乙基丙二酸脑病患者出现微血管病变的原因
• Characterization of Patient Mutations in Human Persulfide Dioxygenase (ETHE1) Involved in H2S Catabolism
  作者：Omer Kabil、Ruma Banerjee

  DOI：10.1074/jbc.m112.407411

  日期：2012.12

  enzymes, cystathionine beta-synthase and gamma-cystathionase, whereas its catabolism occurs in the mitochondrion and couples to the energy-yielding electron transfer chain. Low steady-state levels of H(2)S appear to be controlled primarily by efficient oxygen-dependent catabolism via sulfide quinone oxidoreductase, persulfide dioxygenase (ETHE1), rhodanese, and sulfite oxidase. Mutations in the persulfide

  硫化氢 (H(2)S) 是最近描述的内源性气体信号分子，它影响中枢神经系统、心血管系统和胃肠道中的各种细胞过程。H(2)S 的生物发生涉及细胞质转硫酶、胱硫醚β-合酶和γ-胱硫醚酶，而其分解代谢发生在线粒体中并与产生能量的电子传递链结合。H(2)S 的低稳态水平似乎主要由有效的氧依赖分解代谢通过硫化醌氧化还原酶、过硫化物双加氧酶 (ETHE1)、硫氰酸盐和亚硫酸盐氧化酶控制。过硫化物双加氧酶（即 ETHE1）中的突变会导致乙基丙二酸脑病，这是一种先天性代谢缺陷。在这项研究中，我们报告了人类过硫化物双加氧酶的生化特征和动力学特性，并描述了与两个患者突变 T152I 和 D196N 相关的生化惩罚。稳态动力学分析表明，与野生型酶相比，T152I 突变导致活性降低 3 倍，这与铁含量降低 3 倍相关。D196N 突变导致底物谷胱甘肽过硫化物的 K(m) 高 2 倍。
• Distribution, Diversity, and Activities of Sulfur Dioxygenases in Heterotrophic Bacteria
  作者：Honglei Liu、Yufeng Xin、Luying Xun

  DOI：10.1128/aem.03281-13

  日期：2014.3

  Sulfur oxidation by chemolithotrophic bacteria is well known; however, sulfur oxidation by heterotrophic bacteria is often ignored. Sulfur dioxygenases (SDOs) (EC 1.13.11.18) were originally found in the cell extracts of some chemolithotrophic bacteria as glutathione (GSH)-dependent sulfur dioxygenases. GSH spontaneously reacts with elemental sulfur to generate glutathione persulfide (GSSH), and SDOs oxidize GSSH to sulfite and GSH. However, SDOs have not been characterized for bacteria, including chemolithotrophs. The gene coding for human SDO (human ETHE1 [hETHE1]) in mitochondria was discovered because its mutations lead to a hereditary human disease, ethylmalonic encephalopathy. Using sequence analysis and activity assays, we discovered three subgroups of bacterial SDOs in the proteobacteria and cyanobacteria. Ten selected SDO genes were cloned and expressed in Escherichia coli , and the recombinant proteins were purified. The SDOs used Fe ²⁺ for catalysis and displayed considerable variations in specific activities. The wide distribution of SDO genes reveals the likely source of the hETHE1 gene and highlights the potential of sulfur oxidation by heterotrophic bacteria.

  摘要 化石营养细菌的硫氧化作用已广为人知，但异养细菌的硫氧化作用却常常被忽视。硫二氧化酶（SDOs）（EC 1.13.11.18）最初是作为谷胱甘肽（GSH）依赖性硫二氧化酶存在于一些化石营养细菌的细胞提取物中。GSH 自发地与元素硫反应生成过硫化谷胱甘肽（GSSH），而 SDO 将 GSSH 氧化为亚硫酸盐和 GSH。然而，细菌（包括化石营养体）的 SDOs 还没有定性。线粒体中编码人类 SDO 的基因（人类 ETHE1 [hETHE1]）之所以被发现，是因为它的突变会导致一种遗传性人类疾病--乙基丙二酸脑病。通过序列分析和活性测定，我们在蛋白细菌和蓝藻中发现了三个细菌 SDO 亚群。我们克隆了十个选定的 SDO 基因，并在 大肠杆菌 中表达，并纯化了重组蛋白。这些 SDO 利用 Fe 2+ 进行催化，并在特异性活性方面表现出相当大的差异。SDO 基因的广泛分布揭示了 hETHE1 基因的可能来源，并凸显了异养菌氧化硫的潜力。
• Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy
  作者：I. Pettinati、J. Brem、M. A. McDonough、C. J. Schofield

  DOI：10.1093/hmg/ddv007

  日期：2015.5.1

  The ethylmalonic encephalopathy protein 1 (ETHE1) catalyses the oxygen-dependent oxidation of glutathione persulfide (GSSH) to give persulfite and glutathione. Mutations to the hETHE1 gene compromise sulfide metabolism leading to the genetic disease ethylmalonic encephalopathy. hETHE1 is a mono-iron binding member of the metallo-β-lactamase (MBL) fold superfamily. We report crystallographic analysis of hETHE1 in complex with iron to 2.6 Å resolution. hETHE1 contains an αββα MBL-fold, which supports metal-binding by the side chains of an aspartate and two histidine residues; three water molecules complete octahedral coordination of the iron. The iron binding hETHE1 enzyme is related to the ‘classical’ di-zinc binding MBL hydrolases involved in antibiotic resistance, but has distinctive features. The histidine and aspartate residues involved in iron-binding in ETHE1, occupy similar positions to those observed across both the zinc 1 and zinc 2 binding sites in classical MBLs. The active site of hETHE1 is very similar to an ETHE1-like enzyme from Arabidopsis thaliana (60% sequence identity). A channel leading to the active site is sufficiently large to accommodate a GSSH substrate. Some of the observed hETHE1 clinical mutations cluster in the active site region. The structure will serve as a basis for detailed functional and mechanistic studies on ETHE1 and will be useful in the development of selective MBL inhibitors.

  乙基丙二酸脑病蛋白1（ETHE1）催化谷胱甘肽过硫酸盐（GSSH）的氧依赖性氧化反应，生成过硫酸盐和谷胱甘肽。hETHE1基因突变会破坏硫代谢，导致遗传性疾病乙基丙二酸脑病。hETHE1是金属β-内酰胺酶（MBL）折叠超家族中的一种单铁结合成员。我们报告了hETHE1与铁结合的晶体分析，分辨率为2.6 Å。hETHE1包含一个αββα MBL折叠，通过天冬氨酸和两个组氨酸残基的侧链支持金属结合；三个水分子完成铁的八面体配位。铁结合hETHE1酶与涉及抗生素抗性的“经典”二锌结合MBL水解酶有关，但具有独特的特征。参与ETHE1中铁结合的组氨酸和天冬氨酸残基与经典MBL中锌1和锌2结合位点中的残基占据相似的位置。hETHE1的活性位点与拟南芥（Arabidopsis thaliana）中的ETHE1样酶非常相似（60%的序列同源性）。通向活性位点的通道足够大，可以容纳GSSH底物。一些观察到的hETHE1临床突变聚集在活性位点区域。该结构将
• The sulfane sulfur of persulfides is the actual substrate of the sulfur-oxidizing enzymes from Acidithiobacillus and Acidiphilium spp.
  作者：Thore Rohwerder、Wolfgang Sand

  DOI：10.1099/mic.0.26212-0

  日期：2003.7.1

  found in crude extracts. All cell-free systems oxidized elemental sulfur only via glutathione persulfide (GSSH), a non-enzymic reaction product from glutathione (GSH) and elemental sulfur. Thus, GSH plays a catalytic role in elemental sulfur activation, but is not consumed during enzymic sulfane sulfur oxidation. Sulfite is the first product of sulfur dioxygenase activity; it further reacted non-enzymically

  为了鉴定中酸性嗜酸性嗜酸硫硫杆菌硫氧化酶菌株DSM 504和K6的谷胱甘肽-依赖性硫双加氧酶（EC 1.13.11.18）元素硫氧化的实际底物，分析了酸性嗜氧硫杆菌铁氧体菌株R1和嗜酸性嗜酸杆菌DSM 700。在粗提取物中发现了高达460 nmol x min（-1）（mg蛋白）（-1）的高比硫双加氧酶活性。所有无细胞系统仅通过谷胱甘肽过硫化物（GSSH）来氧化元素硫，GSH是谷胱甘肽（GSH）和元素硫的非酶反应产物。因此，GSH在元素硫的活化中起催化作用，但在酶法硫烷硫氧化过程中不被消耗。亚硫酸盐是硫双加氧酶活性的第一个产物。它进一步非酶促地与硫酸盐反应，硫代硫酸盐或谷胱甘肽S-磺酸盐（GSSO（-3））。游离的硫化物未被硫双加氧酶氧化。过硫醚作为硫供体不能用其他含硫烷硫的化合物（硫代硫酸盐，多硫代酸盐，双有机基多硫烷或单芳基硫代磺酸盐）代替。通过双加氧酶氧化H（2）S需要GSSG，即G