Metabolism of sulfur compounds in homocystinurias

Abstract

Background and Purpose Homocystinurias are rare genetic defects characterized by altered fluxes of sulfur compounds including homocysteine and cysteine. We explored whether the severely perturbed sulfur amino acid metabolism in patients with homocystinurias affects the metabolism of hydrogen sulfide. Experimental Approach We studied 10 treated patients with a block in the conversion of homocysteine to cysteine due to cystathionine β‐synthase deficiency (CBSD) and six treated patients with remethylation defects (RMD) and an enhanced flux of sulfur metabolites via transsulfuration. Control groups for CBSD and RMD patients consisted of 22 patients with phenylketonuria on a low‐protein diet and of 12 healthy controls respectively. Plasma and urine concentrations of selected sulfur compounds were analysed by HPLC and LC–MS/MS. Key Results Patients with CBSD exhibited plasma concentrations of monobromobimane‐detected sulfide similar to appropriate controls. Urinary homolanthionine and thiosulfate in CBSD were increased significantly 1.9 and 3 times suggesting higher hydrogen sulfide synthesis by γ‐cystathionase and detoxification respectively. Surprisingly, patients with RMD had significantly lower plasma sulfide levels (53 and 64% of controls) with lower sulfite concentrations, and higher taurine and thiosulfate levels suggesting enhanced cysteine oxidation and hydrogen sulfide catabolism respectively. Conclusion and Implications The results from this study suggest that severe inherited defects in sulfur amino acid metabolism may be accompanied by only moderately perturbed hydrogen sulfide metabolism and lends support to the hypothesis that enzymes in the transsulfuration pathway may not be the major contributors to the endogenous hydrogen sulfide pool. Linked Articles This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc

Analysis of Total Thiols in the Urine of a Cystathionine β-Synthase-Deficient Mouse Model of Homocystinuria Using Hydrophilic Interaction Chromatography

“…However, in the present study, Cys and CysGly in urine samples did not differ significantly among CBS-WT, -Hetero, and -KO mice. Although it was not clear why different trends were observed for plasma and urine, similar results have been reported in a study with human patients [17]. No significant difference was observed in the total GSH in urine between CBS-WT, -Hetero, and -KO mice, which was also in agreement with the mouse plasma results.…”

Riboflavin metabolism: role in mitochondrial function

“…Biochemical abnormalities resulting from accumulation of hydrogen sulfide and its derivative thiosulfate in crucial tissues including liver, brain, and colonic mucosa leading to inhibition of both short-chain acyl-CoA dehydrogenase with consequent elevation of ethylmalonate, C4-and C5-acylcarnitines predominantly in muscle and brain, and cytochrome c oxidase deficiency, blocking mitochondrial respiration and increasing lactic acid [147,148] . Urinary thiosulfate is also markedly elevated [149] .…”

To the Editor:

“…383 μM. These H 2 S concentrations are about two orders of magnitude higher than those reported by others using this method for blood and/or tissue H 2 S quantification in mice, rats ( 3 ), swine ( 4 – 6 ), and humans (healthy volunteers and patients) ( 7 , 8 ). Administration of Na 2 S in rats (bolus injection of 4 mg/kg, continuous i.v.…”