Abstract
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.
Highlights
Sulfite is a highly reactive molecule which is produced by the catabolism of the sulfur-containing amino acid cysteine, a semi-essential amino acid [1]
In this study we investigated the role of cytosolic and mitochondrial glutamate oxaloacetate transaminase (GOT) enzymes in oxidative and H2S-dependent cysteine catabolism
Based on the structural similarity of cysteine sulfinic acid (CSA) to the primary GOT substrate aspartate, the enzyme has been suggested to catalyze the deamination of CSA resulting in the formation of β-sulfinyl pyruvate and glutamate [27,28]
Summary
Sulfite is a highly reactive molecule which is produced by the catabolism of the sulfur-containing amino acid cysteine, a semi-essential amino acid [1]. Cysteine plays a pivotal role in protein structure due to its high reactivity and ability to form disulfides in an oxidative environ ment [3]. Cysteine serves as a sulfur source for various types of cofactors, such as coenzyme A, biotin, Fe–S clusters and the molybdenum cofactor. Non-protein bound cysteine is catabolized via two distinct processes, 1) the oxidative pathway and 2) various H2S-generating pathways. Both branches of cysteine catabolism converge in the production of sulfite and its detoxification by the mitochondrial molybdenum cofactorcontaining enzyme sulfite oxidase (SO) [5]. H2S is an important signaling molecule in mammals that has gained increasing attention in recent years due to its versatile functions in cardio-vascular systems, neuronal tissues and in the gastrointestinal tract [6,7]
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