Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism

Abstract

Cysteine is one of the two key sulfur-containing amino acids with important functions in redox homeostasis, protein functionality and metabolism. Cysteine is taken up by mammals via their diet and can also be derived from methionine via the transsulfuration pathway. The cellular concentration of cysteine is kept within a narrow range by controlling its synthesis and degradation. There are two pathways for the catabolism of cysteine leading to sulfate, taurine and thiosulfate as terminal products. The oxidative pathway produces taurine and sulfate, while the H S pathway involves different enzymatic reactions leading to the formation and clearance of H S, an important signalling molecule in mammals, resulting in thiosulfate and sulfate. Sulfite is a common intermediate in both catabolic pathways. Sulfite is considered as cytotoxic and produces neurotoxic S-sulfonates. As a result, a deficiency in the terminal steps of cysteine or H S catabolism leads to severe forms of encephalopathy with the accumulation of sulfite and H S in the body. This review links the homeostatic regulation of both cysteine catabolic pathways to sulfite and H S.

Metabolism of sulfur compounds in homocystinurias

“…The increased thiosulfate with simultaneously unchanged or decreased plasma sulfide and/or sulfite is intriguing. Sulfite may be formed by SDO from GSH persulfide or by the activity of aspartate aminotransferase from Cys sulfinate, which is synthesized by CDO from Cys (Kohl et al ., ). Since Cys sulfinate is further converted to Tau, assessment of Tau levels in homocystinurias may help dissecting the changes in the CDO‐related formation of sulfite as discussed below.…”

“…The increased Cys production in RMD is indirectly supported also by higher concentrations of Tau and Hyp, originating from Cys oxidation by the likely up‐regulated CDO expression (Kohl et al ., ). Despite this increased production of Hcy and Cys, we did not detect any significant changes in Lanth and Hlanth concentrations as by‐products of H 2 S synthesis in plasma, but we observed marginally elevated concentration in urine.…”

“…The most surprising finding was the significantly lower detected plasma H 2 S concentration in patients with RMD compared to healthy controls; the model for these observations is proposed in Figure B. In RMD patients, the provision of Cys and Hcy for H 2 S synthesis is increased and the activity of both CBS and CSE is preserved, suggesting that deficient synthesis of H 2 S by these two enzymes is quite unlikely reason for low plasma H 2 S. It is perceivable that increased thiosulfate in plasma and urine may result from enhanced conversion of GSH persulfide and sulfite into thiosulfate via the actions of TST in cellular mitochondria (Kohl et al ., ), which would entail decreased sulfide levels due to a drop in GSH‐persulfide (a proposed major contributor of the bound sulfide pools). Consistent with this hypothesis, we observed significantly decreased plasma sulfite levels.…”

“…Degradation of H 2 S is located mostly in the mitochondria (see Figure ) and starts by persulfidation of sulfide : quinone oxidoreductase (SQOR). Two alternative pathways for further oxidation of persulfidated SQR were proposed involving sulfur dioxygenase (SDO), thiosulfate transferase (TST) and sulfite oxidase (SO) with formation of intermediate metabolites sulfite, thiosulfate and thiocyanate, and of the final H 2 S oxidation product sulfate (Augustyn et al ., ; Olson, ; Kohl et al ., ).…”

Highlighted mechanistic aspects in the chemical biology of reactive sulfur species

“…provide a comprehensive overview on the catalytic pathways of cysteine catabolism leading to sulfite and thiosulfate as terminal products. They discuss different homeostatic effects of sulfite and H 2 S on cysteine metabolism as well as the potential clinical impacts of their malfunctioning (Kohl et al ., ). Related to this, Kimura et al .…”