Luisa Ronga - The Role of Selenoenzymes in the Toxic and Therapeutic Activity of Metallic Compounds
LP2i
Mammalian selenoproteins containing selenocysteine (Sec), the sulfur-to-selenium substituted variant of cysteine (Cys), at their active site, play critical roles in redox homeostasis, antioxidant defense, and cellular signaling. Due to the high nucleophilicity and reactivity of selenocysteine, these proteins represent potential target of toxic trace metal (Hg) and metallodugs (Au, Pt)1.
This presentation will elucidate the key role of Thioredoxin Reductases (TrxR) and Glutathione Peroxidases (Gpx), two main families of selenoenzymes, both in the toxicity of MeHg+, a potent neurotoxicant, and in the therapeutic activity of gold-based drugs.
The reactivity of TrxR and Gpx with MeHg+ or gold(III) cyclometallated compounds was evaluated by an integrated experimental, theoretical and cellular approach.
Our data offer a clear molecular explanation for the inhibition of the selenoenzymes TrxR1 and GPx1 by MeHg+, as well as for the associated toxic effects. This process involves MeHg+ preferentially reacting with SeCys, which is followed by the involvement of neighboring Cys residues2. We also provide mechanistic details and evidence supporting the use of selenopeptides for MeHg+ detoxification strategies3.
Moreover, the intrinsic preferences of cyclometallated gold(III) compounds for Sec- over Cys-arylation was demostrated in peptide models4 and translated to functional inhibition of selenoenzymes5. This activity can mediate the cytotoxicity of these metallodrugs, highlighting their potential in anticancer therapy.
References
1. Bernabeau de Maria M., Lamarche J., Ronga L. , Messori L., Szpunar J., Lobinski R. Coordination Chemistry Reviews (2023), 474, 214836.
2. Bernabeau de Maria M., Zangmo T., A. Gawor, E. Bulska, L. Messori, J. Szpunar, R. Lobinski, K. Miqueu, Ronga L. Inorganic Chemistry Frontiers (2026), 13, 32.
3. Bernabeu De Maria M., Tesauro D., Prencipe F., Saviano M., Messori L., Enjalbal C., Lobinski R., Ronga L., Inorganic Chemistry (2023), 62, 14980.
4. Nakahata D.H., Kanavos I., Zubiria-Ulacia M., Inague A., Salassa L., Lobinski R., Miyamoto S., Mattin Matxain J., Ronga L., de Paiva R.E.F, Chemistry a European J. (2024), 30, e202304050.
5. Kanavos I., Nakahata D., Barrett M., Dos Santos A.F., Zubiria-Ulacia M., Pieslinger G.E., Da Silva Teixeira A.B., Ribeiro Reily Rocha C., Eberle J., Lobinski R., Mattin Matxain J., Hall M.D., Friedmann Angeli J.P., Arnér E.S.J., Ronga L., R. De Paiva, Free Radical Biololgy and Medicine (2026), 247, 139.