The Unexpected and Exceptionally Facile Chemical Modification of the Phenolic Hydroxyl Group of Tyrosine by Polyhalogenated Quinones under Physiological Conditions

Abstract

ABSTRACT:The phenolic hydroxyl group of tyrosine residue plays a crucial role in the structure and function of many proteins. However, little study has been reported about its modification by chemical agents under physiological conditions. In this study, we found, unexpectedly, that the phenolic hydroxyl group of tyrosine can be rapidly and efficiently modified by tetrafluoro-1,4-benzoquinone and other polyhalogenated quinones, which are the major genotoxic and carcinogenic quinoid metabolites of polyhalogenated aromatic compounds. The modification was found to be mainly due to the formation of a variety of fluoroquinone−O-tyrosine conjugates and their hydroxylated derivatives via nucleophilic substitution pathway. Analogous modifications were observed for tyrosine-containing peptides. Further studies showed that the blockade of the reactive phenolic hydroxyl group of tyrosine in the substrate peptide, even by very low concentration of tetrafluoro-1,4-benzoquinone, can prevent the kinase catalyzed tyrosine phosphorylation. This is the first report showing the exceptionally facile chemical modification of the phenolic hydroxyl group of tyrosine by polyhalogenated quinones under normal physiological conditions, which may have potential biological and toxicological implications.

Mass Spectrometry-Based Protein Footprinting for Higher-Order Structure Analysis: Fundamentals and Applications

“…Apart from the three major reagents introduced above, some other reagents for Tyr footprinting are acid anhydrides and acyl chlorides (target phenolic hydroxyl groups), , cyanuric fluoride (targets phenolic hydroxyl groups), , various diazonium salts (target phenolic C–H bonds), , polyhalogenated quinones (target phenolic hydroxyl groups), p -nitrobenzenesulfonyl fluoride (NBSF, targets phenolic hydroxyl group), , diisopropylphosphorofluoridate (targets phenolic hydroxyl groups), , p -nitrophenyl acetate (targets phenolic hydroxyl groups), and hemin-activated luminol derivatives (target phenolic C–H bonds) . Although this wide variety of reactive reagents demonstrates the opportunities of footprinting a given functional group, most await establishment in MS-based protein HOS elucidation.…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“…To date, 518 protein kinases have been identified and verified. 42 The 518 protein kinases are mainly divided into the following three categories according to the type of amino acids on which protein phosphorylation occurs, including serine/threonine protein kinases (STKs), 46 protein tyrosine kinases (PTKs), 47 dual‐specificity kinases (DSKs), 42 and histidine protein kinases (HPKs) (Figure 3 ). 48 The STKs are enzymes that phosphorylate serine or threonine and are activated by different events such as DNA damage and chemical signals.…”

Mechanistic Study on Oxidative DNA Damage and Modifications by Haloquinoid Carcinogenic Intermediates and Disinfection Byproducts

“…During our systematic studies on synergism of biochemical and toxicological interactions between organic environmetal pollutants (especially chlorophenols and their quinoid metabolites) and inorganic compounds (especially redox-active transition metals such as copper and iron, and H 2 O 2 ), − we found that reactive hydroxyl/alkoxyl radicals can be produced by XQs and hydroperoxides through the novel pathway independent of transition-metal ions, which was proposed through a new-type nucleophilic substitution followed by homolytical decomposition reaction mechanism ,− (Scheme ). Intriguingly, except for the traditional hydroxyl/alkoxyl radicals, several unprecedented carbon-centered quinone ketoxy radicals and oxygen-centered quinone-enoxy radicals were also measured and identified from the XQs/hydropeoxide system. , …”