The role of glutamate oxaloacetate transaminases in sulfite biosynthesis and H2S metabolism

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, H 2 S and persulfidated cysteine and glutathione, which is consistent with an increase of SQR protein levels. Surprisingly, none of the known H 2 S-producing pathways were found to be upregulated under conditions of sulfite toxicity suggesting an alternative route of sulfite-induced shift from oxidative to H 2 S dependent cysteine catabolism.

Emerging Role of TCA Cycle-Related Enzymes in Human Diseases

“…Two isoforms of glutamate-oxaloacetate transaminase (GOT), GOT1 and GOT2, are known to be important regulators of glutamate levels [ 43 ]. GOT1 and GOT2 are localized in the cytosol and mitochondria, respectively.…”

Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation

“…This is consistent with the fact that the persulfide-catabolizing enzyme ETHE1 was down-regulated in shCBS Cal51 xenografts compared to controls and in human BLBC tumors compared to other PAM50 subtypes. In addition, despite being key enzymes of the CDO pathway, the levels of GOT1 and GOT2 were not significantly lower in basal-like tumors, which may be due to the fact that they also play important roles in persulfide production as we demonstrated in our recent publication (56), most likely via contribution to H 2 S production along with MPST (SI Appendix, Fig. S8).…”

Is There a Connection between the Metabolism of Copper, Sulfur, and Molybdenum in Alzheimer’s Disease? New Insights on Disease Etiology

“…The reaction catalyzed by SUOX is the terminal step in the excretory metabolism of S-containing amino acids such as Met and Cys, by which sulfite produced from Met and Cys metabolism is detoxified [ 90 ]. Additionally, via the H 2 S pathways, obtained during metabolism of Hcy in Cys, significant quantities of sulfite are formed that require oxidation by SUOX [ 91 ]. In the nervous system, H 2 S acts as a neuromodulator influencing synaptic activity under regulation of steroid hormones and neurotransmitters; it may be involved in associative learning [ 92 ].…”