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

Cysteine homeostasis is dependent on the regulation of cysteine dioxygenase (CDO) in response to changes in sulfur amino acid intake. CDO oxidizes cysteine to cysteinesulfinate, which is further metabolized to either taurine or to pyruvate plus sulfate. To gain insight into the physiological function of CDO and the consequence of a loss of CDO activity, mice carrying a null CDO allele (CDO(+/-) mice) were crossed to generate CDO(-/-), CDO(+/-), and CDO(+/+) mice. CDO(-/-) mice exhibited postnatal mortality, growth deficit, and connective tissue pathology. CDO(-/-) mice had extremely low 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 desulfhydration pathways. Null mice had lower hepatic cytochrome c oxidase levels, suggesting impaired electron transport capacity. Supplementation of mice with taurine improved survival of male pups but otherwise had little effect on the phenotype of the CDO(-/-) mice. H(2)S has been identified as an important gaseous signaling molecule as well as a toxicant, and pathology may be due to dysregulation of H(2)S production. Control of cysteine levels by regulation of CDO may be necessary to maintain low H(2)S/sulfane sulfur levels and facilitate the use of H(2)S as a signaling molecule.

Hydrogen Sulfide as an Oxygen Sensor

“…Conversely, the H 2 S-forming trans-sulfuration pathway is not similarly regulated (154). In the absence of CDO, sulfur is redirected through the desulfuration pathway, which then increases thiosulfate and H 2 S production (142,173). Since O 2 is the only other substrate in CDO-mediated cysteine oxidation, it is likely that hypoxia will also impair cysteine oxidation and favor H 2 S production.…”

“…While this is not likely a rapid response, it could place a long-term bias on chronic O 2 sensing. The striking similarities between CDO and ETHE1 pathologies support sulfide/H 2 S as a common factor (173). Apart from this, the inability of CDO to handle a large transient cysteine load may partially explain how hypoxic responses are augmented by exogenous cysteine (see ''Physiological Evidence for H 2 S-Mediated O 2 Sensing'' section).…”

Identification and Characterization of the Anti-Methicillin-Resistant Staphylococcus aureus WAP-8294A2 Biosynthetic Gene Cluster from Lysobacter enzymogenes OH11

“…2). ORF4 is homologous to taurine catabolism dioxygenase, which is a nonheme iron, 2-ketoglutarate-dependent oxygenase (49). We subsequently disrupted this gene and found that the mutants (Fig.…”

Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury

“…A few studies conducted in genetic Cdo1-knockout mice revealed that whole-body complete CDO1 ablation caused more complex metabolic changes and subsequent pathological effects in mice. Global-Cdo1-knockout mice showed severe growth deficit, postnatal lethality, and toxicity in various organs include the liver, pancreas, and lung (48,49). Mice lacking CDO1 had decreased taurine production, and taurine supplement only improved survival but did not correct other adverse phenotypes.…”