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Allosteric control of human cystathionine β-synthase activity by a redox active disulfide bond.

Cystathionine β-synthase (CBS) is the central enzyme in the trans-sulfuration pathway that converts homocysteine to cysteine. It is also one of the three major enzymes involved in the biogenesis of H2 S. CBS is a complex protein with a modular three-domain architecture, the central domain of which contains a 272 C XX C275 motif whose function has yet to be determined. In the present study, we demonstrated that the C XX C motif exists in oxidized and reduced states in the recombinant enzyme by mass spectroscopic analysis and a thiol labeling assay. The activity of reduced CBS is ∼2-3-fold greater than that of the oxidized enzyme, and substitution of either cysteine in C XX C motif leads to a loss of redox sensitivity. The Cys272 -Cys275 disulfide bond in CBS has a midpoint potential of -314 mV at pH 7.4. Additionally, the C XX C motif also exists in oxidized and reduced states in HEK293 cells under oxidative and reductive conditions, and stressing these cells with DTT results in more reduced enzyme and a concomitant increase in H2 S production in live HEK293 cells as determined using a H2 S fluorescent probe. By contrast, incubation of cells with aminooxyacetic acid, an inhibitor of CBS and cystathionine γ-lyase, eliminated the increase of H2 S production after the cells were exposed to DTT. These findings indicate that CBS is post-translationally regulated by a redox-active disulfide bond in the C XX C motif. The results also demonstrate that CBS-derived H2 S production is increased in cells under reductive stress conditions.

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