Exploring oxidative modifications of tyrosine: An update on mechanisms of formation, advances in analysis and biological consequences

Abstract

Protein oxidation is increasingly recognised as an important modulator of biochemical pathways controlling both physiological and pathological processes. While much attention has focused on cysteine modifications in reversible redox signalling, there is increasing evidence that other protein residues are oxidised in vivo with impact on cellular homeostasis and redox signalling pathways. A notable example is tyrosine, which can undergo a number of oxidative post-translational modifications to form 3-hydroxy-tyrosine, tyrosine crosslinks, 3-nitrotyrosine and halogenated tyrosine, with different effects on cellular functions. Tyrosine oxidation has been studied extensively in vitro, and this has generated detailed information about the molecular mechanisms that may occur in vivo. An important aspect of studying tyrosine oxidation both in vitro and in biological systems is the ability to monitor the formation of oxidised derivatives, which depends on a variety of analytical techniques. While antibody-dependent techniques such as ELISAs are commonly used, these have limitations, and more specific assays based on spectroscopic or spectrometric techniques are required to provide information on the exact residues modified and the nature of the modification. These approaches have helped understanding of the consequences of tyrosine oxidation in biological systems, especially its effects on cell signalling and cell dysfunction, linking to roles in disease. There is mounting evidence that tyrosine oxidation processes are important in vivo and can contribute to cellular pathology.

Chemical biology approaches for studying posttranslational modifications

“…Protein oxidation is an important modulator of redox-dependent signaling and related biological processes. 102 In particular, protein tyrosine nitration (PTN) is known to be involved in aging and various pathological processes, including autoimmune disorders, cancers, and neurodegenerative diseases. Unlike other PTMs, which are mediated by specific enzymes, PTN is caused by various reactive nitrogen species (RNS), especially secondary radical species (¢NO 2 , CO 3 ¢ ¡ ) generated from peroxynitrite (ONOO-).…”

Exposure of tropoelastin to peroxynitrous acid gives high yields of nitrated tyrosine residues, di-tyrosine cross-links and altered protein structure and function

“…significant consumption of Tyr residues and the known formation of cross-linked species from this amino acid (e.g. di-tyrosine, and cross-links involving quinones derived from Tyr[76]) prompted an examination of the nature of the cross-links formed in ONOOH-treated TE. The presence of cross-links was investigated by making use of the addition mass differences present in cross-linked peptides containing two carboxyl termini after protein digestion by trypsin in H2 77]).…”

NADPH oxidase-derived H 2 O 2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA

“…Reaction 2 would proceed via a 2-hydroxy-3,5-cyclohexadienone intermediate, whereas reaction 3 would predict generation of a tyrosinyl radical intermediate (Fig. S7, red box) (22,23). The addition of free tyrosine to the oxidation reaction will discriminate between these two possibilities, because only a tyrosinyl radical intermediate will permit dityrosine formation.…”