The role of glutamate oxaloacetate transaminases in sulfite biosynthesis and H(2)S metabolism.
The role of glutamate oxaloacetate transaminases in sulfite biosynthesis and H(2)S metabolism.
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DOI：
10.1016/j.redox.2020.101800
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Schwarz G
中科院分区：
文献类型：
--
作者：
Mellis AT;Misko AL;Arjune S;Liang Y;Erdélyi K;Ditrói T;Kaczmarek AT;Nagy P;Schwarz G
钼辅因子缺乏症和孤立性亚硫酸盐氧化酶缺乏症是两种罕见的遗传性疾病，是由线粒体酶亚硫酸盐氧化酶受损引起的。亚硫酸盐氧化酶催化细胞半胱氨酸催化剂的末端反应，即亚硫酸盐氧化成硫酸盐。缺乏亚硫酸盐氧化酶导致亚硫酸盐的积累，亚硫酸盐已被鉴定为细胞毒素。然而，导致亚硫酸盐产生的分子途径仍然没有完全了解。为了确定这两种疾病的新治疗方案，了解细胞半胱氨酸催化剂-及其在亚硫酸盐氧化酶丧失后的变化-是至关重要的。在这里，我们应用了一种新的检测方法，亚硫酸盐在细胞提取物中的半胱氨酸亚磺酸的亚硫酸盐和丙酮酸盐的转化中的细胞溶质和线粒体谷氨酸草酰乙酸转氨酶（GOT）的贡献进行解剖。我们发现，胞质异构体GOT1是主要负责生产亚硫酸盐。此外，亚硫酸盐氧化酶活性的丧失导致亚硫酸盐、H2S和过硫化半胱氨酸和谷胱甘肽的积累，这与SQR蛋白水平的增加一致。令人惊讶的是，没有发现已知的H2S产生途径在亚硫酸盐毒性的条件下上调，这表明亚硫酸盐诱导的从氧化性转变为H2S依赖性半胱氨酸催化剂的替代途径。亚硫酸盐氧化酶（SO）缺乏后半胱氨酸催化剂的变化。野生型和SO缺陷细胞中的半胱氨酸催化剂。定位于线粒体的步骤和酶由淡蓝色背景描绘。外面的区域是指细胞质。细胞溶质谷氨酸草酰乙酸转氨酶1（GOT 1）负责细胞亚硫酸盐的产生，而线粒体GOT（GOT 2）在SO缺乏时的H2S产生中起重要作用。在没有SO的情况下，亚硫酸盐（SO32 −）和硫化氢（H2S）会积累。SO缺乏进一步影响细胞半胱氨酸催化剂，导致细胞内半胱氨酸水平降低和许多相关酶的下调（以灰色字母描绘）。GOT2的适度增加和硫化物：醌氧化还原酶（SQR）的强烈诱导表明通过GOT2-MPST-SQR轴的硫通量增加。缩略语：CBS，胱硫醚β-合酶; CSE，胱硫醚γ-裂解酶; CDO，半胱氨酸双加氧酶; GOT，谷氨酸草酰乙酸转氨酶; MPST，巯基丙酮酸硫转移酶; SQR，硫化物：醌氧化还原酶; ETHE1，过硫化物双加氧酶; TST，硫代硫酸盐硫转移酶。细胞亚硫酸盐检测使得能够研究细胞提取物中的半胱氨酸催化剂。细胞质谷氨酸草酰乙酸转氨酶1是细胞亚硫酸盐的主要来源。亚硫酸盐氧化酶的缺乏导致H2S和过硫化小分子的积累。亚硫酸盐氧化酶缺乏导致H2S合成下调和SQR表达增加。
Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are two rare genetic disorders that are caused by impairment of the mitochondrial enzyme sulfite oxidase. Sulfite oxidase is catalyzing the terminal reaction of cellular cysteine catabolism, the oxidation of sulfite to sulfate. Absence of sulfite oxidase leads to the accumulation of sulfite, which has been identified as a cellular toxin. However, the molecular pathways leading to the production of sulfite are still not completely understood. In order to identify novel treatment options for both disorders, the understanding of cellular cysteine catabolism – and its alterations upon loss of sulfite oxidase – is of utmost importance. Here we applied a new detection method of sulfite in cellular extracts to dissect the contribution of cytosolic and mitochondrial glutamate oxaloacetate transaminase (GOT) in the transformation of cysteine sulfinic acid to sulfite and pyruvate. We found that the cytosolic isoform GOT1 is primarily responsible for the production of sulfite. Moreover, loss of sulfite oxidase activity results in the accumulation of sulfite, H2S and persulfidated cysteine and glutathione, which is consistent with an increase of SQR protein levels. Surprisingly, none of the known H2S-producing pathways were found to be upregulated under conditions of sulfite toxicity suggesting an alternative route of sulfite-induced shift from oxidative to H2S dependent cysteine catabolism. Alterations in cysteine catabolism following sulfite oxidase (SO) deficiency. Cysteine catabolism in wildtype and SO-deficient cells. Steps and enzymes that localize to mitochondria are depicted by the light blue background. The area outside refers to the cytosol. Cytosolic glutamate oxaloacetate transaminase 1 (GOT1) is responsible for cellular sulfite production, whereas mitochondrial GOT (GOT2), plays an important role in H2S production in SO deficiency. In absence of SO, sulfite (SO32−) and hydrogen sulfide (H2S) accumulate. SO deficiency furthermore further impacts cellular cysteine catabolism resulting in lower intracellular cysteine levels and downregulation of many involved enzymes (depicted in gray letters). Moderate increase in GOT2 and strong induction of sulfide:quinone oxidoreductase (SQR) suggest an increased flux of sulfur via the GOT2-MPST-SQR axis. Abbreviations: CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; CDO, cysteine dioxygenase; GOT, glutamate oxaloacetate transaminase; MPST, mercaptopyruvate sulfurtransferase; SQR, sulfide:quinone oxidoreductase; ETHE1, persulfide dioxygenase; TST, thiosulfate sulfurtransferase. Cellular sulfite detection enables investigation of cysteine catabolism in cell extracts. Cytosolic glutamate oxaloacetate transaminase 1 is the primary source for cellular sulfite. Deficiency of sulfite oxidase leads to accumulation of H2S and persulfidated small molecules. Sulfite oxidase deficiency results in a downregulation of H2S synthesis and increased SQR expression.
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影响因子：
4.6
作者：
Kimura Y;Toyofuku Y;Koike S;Shibuya N;Nagahara N;Lefer D;Ogasawara Y;Kimura H
通讯作者：
Kimura H
影响因子：
2.9
作者：
Jackson, Michael R.;Melideo, Scott L.;Jorns, Marilyn Schuman
通讯作者：
Jorns, Marilyn Schuman
影响因子：
6.6
作者：
Kabil, Omer;Vitvitsky, Victor;Banerjee, Ruma
通讯作者：
Banerjee, Ruma
DOI：
10.1007/8904_2011_89
发表时间：
2012-01-01
期刊：
JIMD REPORTS - CASE AND RESEARCH REPORTS, 2012/2
影响因子：
--
作者：
Belaidi, Abdel Ali;Arjune, Sita;Schwarz, Guenter
通讯作者：
Schwarz, Guenter
影响因子：
3.6
作者：
FAFFMICHALAK, L;ALBRECHT, J
通讯作者：
ALBRECHT, J