Heme-dependent Metabolite Switching Regulates H2S Synthesis in Response to Endoplasmic Reticulum (ER) Stress

Abstract

Substrate ambiguity and relaxed reaction specificity underlie the diversity of reactions catalyzed by the transsulfuration pathway enzymes, cystathionine ␤-synthase (CBS) and ␥-cystathionase (CSE). These enzymes either commit sulfur metabolism to cysteine synthesis from homocysteine or utilize cysteine and/or homocysteine for synthesis of H 2 S, a signaling molecule. We demonstrate that a kinetically controlled heme-dependent metabolite switch in CBS regulates these competing reactions where by cystathionine, the product of CBS, inhibits H 2 S synthesis by the second enzyme, CSE. Under endoplasmic reticulum stress conditions, induction of CSE and up-regulation of the CBS inhibitor, CO, a product of heme oxygenase-1, flip the operating preference of CSE from cystathionine to cysteine, transiently stimulating H 2 S production. In contrast, genetic deficiency of CBS leads to chronic stimulation of H 2 S production. This metabolite switch from cystathionine to cysteine and/or homocysteine renders H 2 S synthesis by CSE responsive to the known modulators of CBS: S-adenosylmethionine, NO, and CO. Used acutely, it regulates H 2 S synthesis; used chronically, it might contribute to disease pathology.

Regulators of the transsulfuration pathway

“…One of the less studied aspects of the transsulfuration pathway is the elucidation of conditions leading to cysteine synthesis by CSE as opposed to the production of H 2 S, GSH or taurine. The haem in CBS plays a key role in switching the transsulfuration pathway from cysteine production to H 2 S generation (Kabil et al ., ). When haem is bound by endogenous ligands, the production of cystathionine occurs due to the higher intracellular levels of serine and its greater affinity for CBS as compared to cysteine.…”

Hydrogen sulfide in physiology and pathogenesis of bacteria and viruses

“…In addition to PLP, human CBS also contains heme which acts as a redox dependent gas sensor . Apart from this the heme moiety also functions as a “metabolic switch” committing the pathway toward H 2 S production . Under ER stress, heme oxygenase is induced, which catabolises heme in presence of molecular oxygen to produce biliverdin and CO, the later one binds to heme cofactor of CBS and inhibits its activity.…”

Catalytic promiscuity and heme-dependent redox regulation of H 2 S synthesis

“…The heme in CBS is a key operator that can switch the transsulfuration pathway between the cysteine and H 2 S production tracks [54]. When the heme is coordinated by endogenous ligands, synthesis of cystathionine via the canonical reaction is favored due to the higher intracellular concentration of serine and its higher affinity for CBS versus cysteine.…”