A computational investigation of the reactions of tyrosyl, tryptophanyl, and cysteinyl radicals with nitric oxide and molecular oxygen

Abstract

Proteins are main targets of oxidants in biological systems. This oxidation may occur in the protein backbone as well as in certain amino acid side chains, depending on the oxidant and amino acid intrinsic reactivity. Moreover, many enzymes are capable of generating stable amino acid radicals, such as tyrosyl, tryptophanyl and cysteinyl radicals. These species react very rapidly (many times as diffusion-controlled reactions) with relevant cellular open-shell species such as nitric oxide (·NO) or molecular oxygen (O₂). The exception to this apparent rule is tyrosyl radical, that reacts at diffusion rates with ·NO, but shows very slow reactivity towards O₂ (rate constant <10³ M⁻¹ s⁻¹). In this work, we provide a comparative molecular-level description of the reaction mechanisms involved in the reactions of tyrosyl, tryptophanyl and cysteinyl radicals towards ·NO and O₂, through quantum mechanics simulations which allow us to obtain relevant energetic and structural parameters, proposing a molecular explanation to this tyrosyl discrimination capability, namely, its marginal reactivity with O₂.

Keywords:

• Amino acid-derived radicals
• nitric oxide
• one-electron oxidation
• oxygen

Acknowledgements

This work was supported by the Universidad de Buenos Aires and CONICET (Argentina), Comisión Sectorial de Investigación Científica (CSIC), PEDECIBA, and Espacio Interdisciplinario, Universidad de la República (Uruguay). Further support was provided by Centro de Biología Estructural del Mercosur (CeBEM).

Disclosure statement

The authors report no conflict of interest.