Carbonilic and redox stress associated with alpha-aminoketones and endogenous beta-ketoacids: mechanisms and biomarkers.

Abstract

Oxygen and nitric oxide are known to act normally as metabolic partners in biological events and any imbalance in this cooperative relationship results in oxidative and nitrosative damage to biomolecules and organelles, threatening the cell's life. Our research proposal focuses on the pro-oxidative and acylation properties of amino acid metabolites, particularly a-aminocarbonyls and B-ketoacids that accumulate in the tissues of individuals carrying metabolic errors. We aim to study: (i) 5-aminolevulinic acid (ALA), a heme precursor elevated in intermittent acute porphyria and lead poisoning; (ii) aminoacetone (AA), a threonine and glycine catabolite accumulated in diabetes, threoninemia, and cri-du-chat; (iv) succinylacetone, a B-diketone produced at high levels from tyrosine in tyrosinosis, where it leads indirectly to ALA overload; and (iv) 2- methylacetoacetate (MAA), an isoleucine catabolite abundant in isoleucinemia carriers. These metabolites undergo aerobic oxidation yielding cytotoxic and genotoxic species such as radicals, peroxides, triplet species and a-oxoaldehydes. The the latter compounds encompass 4,5-dioxovaleric acid (DOVA), linked to ALA and SA accumulation, and methylglyoxal (MG), derived from AA and SA. In the next four years we plan to continue investigating the chemical mechanisms of ALA, AA, SA, and MA oxidation in aerated medium, triggered by metals, peroxynitrite, hemeprotein/H2O2 or hypochloride, as well as the damaging effects of their intermediates and final products - DOVA, MG, and biacetyl - on cell cultures, rats and humans. In parallel, we will developed analytical methods by CE/MS/MS for detecting these metabolites in biological samples and other biomarkers of carbonyl stress. (AU)