Protein-bound 3,4-dihydroxy-phenylanine (DOPA), a redox-active product of protein oxidation, as a trigger for...

Protein hydroperoxides and protein-bound 3,4-dihydroxy-phenylanine are amongst the major long-lived redox-active products during free radical attack on proteins. Protein-bound 3,4-dihydroxy-phenylanine can redox cycle between catechol and quinone form, and bind transition metals, whereas hydroperoxides are converted to stable hydroxides. The free amino acid 3,4-dihydroxy-phenylanine is a normal metabolite, an oxidation product of tyrosine, involved in pathways of dopamine and melanin production, and we have shown that it may be incorporated into protein-by-protein synthesis. However, physiological levels of protein-bound 3,4-dihydroxy-phenylanine are very low; yet remarkably elevated levels occur in some pathologies. We propose that, unlike free 3,4-dihydroxy-phenylanine, protein-bound 3,4-dihydroxy-phenylanine is a signal for the activation of cellular defences both against the oxidative fluxes during oxidative stress and against the oxidative damage which sometimes ensues. Unlike free 3,4-dihydroxy-phenylanine, the levels of protein-bound 3,4-dihydroxy-phenylanine can change 5-10-fold during oxidative damage in vivo, an appropriate property for a signalling molecule. We suggest mechanisms by which protein-bound 3,4-dihydroxy-phenylanine might trigger oxidative defences, via NF-kappaB and other transcription factors. Little evidence yet bears directly on this, but we discuss some implications of observations on free 3,4-dihydroxy-phenylanine supply to cells in vitro, to Parkinson's patients, and to animal models of the disease. Several of the effects of 3,4-dihydroxy-phenylanine in these situations may be mediated by the production and actions of protein-bound 3,4-dihydroxy-phenylanine. Some experimental tests of the hypothesis are outlined and some possible therapeutic implications.