UMR 8601, LCBPT, CNRS-Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Sts Pères, Paris 75006, France.
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90095, USA.
Nat Commun. 2016 Nov 16;7:13386. doi: 10.1038/ncomms13386.
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.
越来越多的证据表明，同型半胱氨酸水平异常与血管功能障碍、癌细胞增殖和各种神经退行性疾病有关。就后者而言，已经报道了过渡金属稳态的扰动和过氧化氢酶生物活性的抑制。在此，我们报告了同型半胱氨酸细胞毒性的一些分子基础，并证明它在没有硫化氢干预的情况下诱导硫代过氧化氢酶的形成，即酶的不可逆失活状态。最初，同型半胱氨酸与天然过氧化氢酶和/或氧化还原活性过渡金属离子反应，生成介导化合物 II 形成的硫自由基，这是酶的暂时失活状态。然后，化合物 II 的铁氧还中心介入同型半胱氨酸的前所未有的 S-氧化作用，生成相应的亚磺酸物种，通过形成不寻常的 Fe(II) 亚砜进一步参与辅基血红素的修饰。此外，我们在癌症细胞、神经退行性疾病和溃疡性结肠炎的细胞外研究表明，这种情况很可能发生在一部分癌症细胞以及帕金森病的细胞模型中。我们的发现扩展了生物化合物促进的血红素修饰谱，并指出了同型半胱氨酸水平紊乱的另一个有害特征，它可能参与这些疾病的发病机制。
