title: 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 β-synthase (CBS) and γ-cystathionase (CSE). These enzymes either commit sulfur metabolism to cysteine synthesis from homocysteine or utilize cysteine and/or homocysteine for synthesis of H2S, 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 H2S 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 H2S production. In contrast, genetic deficiency of CBS leads to chronic stimulation of H2S production. This metabolite switch from cystathionine to cysteine and/or homocysteine renders H2S synthesis by CSE responsive to the known modulators of CBS: S-adenosylmethionine, NO, and CO. Used acutely, it regulates H2S synthesis; used chronically, it might contribute to disease pathology.
authors.affiliation: From the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109 omerk@umich.edu.
authors.forename: Omer
authors.initials: O
authors.lastname: Kabil
authors.affiliation: From the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Vinita
authors.initials: V
authors.lastname: Yadav
authors.affiliation: From the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109 rbanerje@umich.edu.
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000096:biosynthesis / Q000235:genetics; D003542:Cystathionine gamma-Lyase / Q000096:biosynthesis / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D057809:HEK293 Cells; D006418:Heme / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006710:Homocysteine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D006710:Homocysteine; D006418:Heme; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: endoplasmic reticulum stress (ER stress); enzyme kinetics; homocysteine; hydrogen sulfide; metabolic regulation