The Cysteine Dioxgenase Knockout Mouse: Altered Cysteine Metabolism in Nonhepatic Tissues Leads to Excess H₂S/HS⁻Production and Evidence of Pancreatic and Lung Toxicity

Abstract

The CDO(-/-) mouse clearly demonstrates that H2S/HS(-) production in tissues can exceed the capacity of the animal to oxidize sulfide to sulfate and demonstrates that pancreas and lung are more susceptible to toxicity from endogenous H2S/HS(-)production than are liver and kidney.

Organization of the Human Mitochondrial Hydrogen Sulfide Oxidation Pathway

“…The mitochondrial availability of sulfite derived from this pathway is uncertain because cysteine sulfinate, the product of the cytoplasmic cysteine dioxygenase, is either partitioned to taurine or to sulfite via the activities of cysteine sulfinate decarboxylase and a transaminase, respectively, which have widely differing K M values (0.2 mM for the decarboxylase and 20 and 3 mM for the cytoplasmic and mitochondrial transaminases, respectively) (20). Despite the high efficiency of sulfite as an acceptor (k cat /K M ϭ 1.7 ϫ 10 6 mM Ϫ1 s Ϫ1 ) in the SQR reaction, its provision by the cysteine oxidation pathway is not supported by the occurrence of elevated thiosulfate levels in cysteine dioxygenase knock-out mice (21). Furthermore, sulfite entering the mitochondrion would presumably be consumed by sulfite oxidase, present in the intermitochondrial space (Fig.…”

Enzyme replacement with PEGylated cystathionine β-synthase ameliorates homocystinuria in murine model

“…Plasma metabolites were determined by stable-isotope dilution gas chromatography/mass spectrometry as previously described (40). Measurements of tHcy and nonprotein-bound homocysteine and other aminothiols as well as of amino acids in tissue were performed as described previously (21,41). The analysis was performed in a blinded fashion, without knowledge of the animal treatment regimen.…”

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.…”