Knockout of the murine cysteine dioxygenase gene results in severe impairment in ability to synthesize taurine and an increased catabolism of cysteine to hydrogen sulfide

Abstract

Regulation of body cysteine levels is dependent on the regulation of cysteine dioxygenase (CDO), the first enzyme in the pathway for cysteine oxidation to taurine or pyruvate + sulfate. To gain insight into the physiological function of CDO, we generated CDO+/− mice and crossed them to generate CDO−/−, CDO+/−, and CDO+/+ mice. CDO null mice exhibited increased postnatal mortality, a marked growth deficit, and connective tissue pathology. CDO−/− mice had extremely low plasma and tissue taurine levels and somewhat elevated cysteine levels, consistent with the lack of flux through CDO‐dependent catabolic pathways. However, plasma sulfate levels were slightly higher in CDO−/− mice than in CDO+/− or CDO+/+ mice and tissue levels of acid‐labile sulfide were elevated, indicating an increase in cysteine catabolism by cysteine desulfuration pathways in the null mice. Supplementation of mice with taurine improved survival of male pups but otherwise had little effect on the phenotype of the CDO−/− mice. Because H2S has been identified as an important gaseous signaling molecule, pathology may be due to dysregulation of H2S production. Control of cysteine levels by regulation of CDO may be necessary to maintain low H2S levels and facilitate the use of H2S as a signaling molecule. Supported by NIH grant DK056649..