title: Sulfheme formation during homocysteine S-oxygenation by catalase in cancers and neurodegenerative diseases.
abstract: Accumulating evidence suggests that abnormal levels of homocysteine are associated with vascular dysfunctions, cancer cell proliferation and various neurodegenerative diseases. With respect to the latter, a perturbation of transition metal homeostasis and an inhibition of catalase bioactivity have been reported. Herein, we report on some of the molecular bases for the cellular toxicity of homocysteine and demonstrate that it induces the formation of sulfcatalase, an irreversible inactive state of the enzyme, without the intervention of hydrogen sulfide. Initially, homocysteine reacts with native catalase and/or redox-active transition metal ions to generate thiyl radicals that mediate compound II formation, a temporarily inactive state of the enzyme. Then, the ferryl centre of compound II intervenes into the unprecedented S-oxygenation of homocysteine to engender the corresponding sulfenic acid species that further participates into the prosthetic heme modification through the formation of an unusual Fe(II) sulfonium. In addition, our ex cellulo studies performed on cancer cells, models of neurodegenerative diseases and ulcerative colitis suggest the likelihood of this scenario in a subset of cancer cells, as well as in a cellular model of Parkinson's disease. Our findings expand the repertoire of heme modifications promoted by biological compounds and point out another deleterious trait of disturbed homocysteine levels that could participate in the aetiology of these diseases.
authors.affiliation: UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Sts Pères, Paris 75006, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Padovani
authors.affiliation: UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Sts Pères, Paris 75006, France.
authors.forename: Assia
authors.initials: A
authors.lastname: Hessani
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Francine T
authors.initials: FT
authors.lastname: Castillo
authors.affiliation: Neurodegenerative Diseases Laboratory, UMR9199, CEA, CNRS, Paris-Sud University, Paris-Saclay University, MIRCen, I2BM, DRF, 18 route du Panorama, B.P. 6, Fontenay-aux-Roses 92265, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Liot
authors.affiliation: UMR 914 INRA-AgroParisTech, Nutrition Physiology and Ingestive Behavior, 16 Rue Claude Bernard, Paris 75005, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Andriamihaja
authors.affiliation: UMR 914 INRA-AgroParisTech, Nutrition Physiology and Ingestive Behavior, 16 Rue Claude Bernard, Paris 75005, France.
authors.forename: Annaïg
authors.initials: A
authors.lastname: Lan
authors.affiliation: INSERM UMR-S1147, CNRS SNC 5014, Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Sts Pères, Paris 75006, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.affiliation: UMR 914 INRA-AgroParisTech, Nutrition Physiology and Ingestive Behavior, 16 Rue Claude Bernard, Paris 75005, France.
authors.forename: François
authors.initials: F
authors.lastname: Blachier
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Suvajit
authors.initials: S
authors.lastname: Sen
authors.affiliation: UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Sts Pères, Paris 75006, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Galardon
authors.affiliation: UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Sts Pères, Paris 75006, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Artaud
mesh_terms: D000818:Animals; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004789:Enzyme Activation / Q000187:drug effects; D006418:Heme / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism*; D006862:Hydrogen Sulfide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000494:pharmacology
chemical_list: D013438:Sulfhydryl Compounds; D006710:Homocysteine; C052173:sulfheme; D006418:Heme; D007501:Iron; D002374:Catalase; D010100:Oxygen; D006862:Hydrogen Sulfide