O. Kabil, R. Banerjee
Nov 9, 2012
Citations
10
Influential Citations
111
Citations
Quality indicators
Journal
The Journal of Biological Chemistry
Abstract
Background: ETHE1 converts persulfides to sulfite in the mitochondrial sulfide oxidation pathway. Results: The kinetics of human ETHE1 and two mutants described in patients have been characterized. Conclusion: Both glutathione and coenzyme A serve as persulfide carriers for ETHE1, albeit with different efficacies. Significance: Low steady-state H2S levels are maintained by its efficient oxidation, and patient mutations in ETHE1 impair this activity. Hydrogen sulfide (H2S) is a recently described endogenously produced gaseous signaling molecule that influences various cellular processes in the central nervous system, cardiovascular system, and gastrointestinal tract. The biogenesis of H2S involves the cytoplasmic transsulfuration enzymes, cystathionine β-synthase and γ-cystathionase, whereas its catabolism occurs in the mitochondrion and couples to the energy-yielding electron transfer chain. Low steady-state levels of H2S appear to be controlled primarily by efficient oxygen-dependent catabolism via sulfide quinone oxidoreductase, persulfide dioxygenase (ETHE1), rhodanese, and sulfite oxidase. Mutations in the persulfide dioxgenase, i.e. ETHE1, result in ethylmalonic encephalopathy, an inborn error of metabolism. In this study, we report the biochemical characterization and kinetic properties of human persulfide dioxygenase and describe the biochemical penalties associated with two patient mutations, T152I and D196N. Steady-state kinetic analysis reveals that the T152I mutation results in a 3-fold lower activity, which is correlated with a 3-fold lower iron content compared with the wild-type enzyme. The D196N mutation results in a 2-fold higher Km for the substrate, glutathione persulfide.