Sulfheme formation during homocysteine S-oxygenation by catalase in cancers and neurodegenerative diseases

Dominique Padovani (), Assia Hessani, Francine T. Castillo, Géraldine Liot, Mireille Andriamihaja, Annaïg Lan, Camilla Pilati, François Blachier, Suvajit Sen, Erwan Galardon and Isabelle Artaud
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Dominique Padovani: UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité
Assia Hessani: UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité
Francine T. Castillo: David Geffen School of Medicine at University of California at Los Angeles
Géraldine Liot: Neurodegenerative Diseases Laboratory, UMR9199, CEA, CNRS, Paris-Sud University, Paris-Saclay University, MIRCen, I2BM, DRF
Mireille Andriamihaja: UMR 914 INRA-AgroParisTech, Nutrition Physiology and Ingestive Behavior
Annaïg Lan: UMR 914 INRA-AgroParisTech, Nutrition Physiology and Ingestive Behavior
Camilla Pilati: INSERM UMR-S1147, CNRS SNC 5014, Université Paris Descartes, Sorbonne Paris Cité
François Blachier: UMR 914 INRA-AgroParisTech, Nutrition Physiology and Ingestive Behavior
Suvajit Sen: David Geffen School of Medicine at University of California at Los Angeles
Erwan Galardon: UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité
Isabelle Artaud: UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13386

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