Reactivity of Amino Acids in Nitrosation Reactions and Its Relation to the Alkylating Potential of Their Products

Abstract

Nitrosation reactions of amino acids with an -NH(2) group [namely, six alpha-amino acids (glycine, alanine, alpha-aminobutyric acid, alpha-aminoisobutyric acid, valine, and norvaline); two beta-amino acids (beta-alanine and beta-aminobutyric acid), and one gamma-amino acid (gamma-aminobutyric acid)] were studied. Nitrosation was carried out in aqueous acid media, mimicking the conditions of the stomach lumen. The rate equation was r = k(3)(exp)[amino acid][nitrite](2), with a maximum k(3)(exp) value in the 2.3-2.7 pH range. The existence of an isokinetic relationship supports the argument that all the reactions share a common mechanism. A nitrosation mechanism is proposed, and the following conclusions are drawn: (i) Nitrosation reactions of amino acids with a primary amino group in acid media occur with dinitrogen trioxide as the main nitrosating agent. The finding that the nitrosation rate is proportional to the square of the nitrite concentration suggests that the yield of nitrosation products in the stomach would increase sharply with higher nitrate/nitrite intakes. (ii) Stomach hypochlorhydria could be a potential enhancer of in vivo amino acid nitrosation. (iii) The reactivity (k(3)()(exp)) [alpha-amino acids > beta-amino acids > gamma-amino acids] is the same as that found in a previous work for the alkylating potential of lactones formed from nitrosation products of the same amino acids. This implies that the nitrosation reactions of the most common natural amino acids are the most efficient precursors of the most powerful alkylating agents. (iv) The order of magnitude (10(7)-10(8) M(-1) s(-1)) of the bimolecular rate constants of nitrosation shows that such reactions occur through an encounter process.

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

“…Finally, SNO can also be achieved by direct reaction between thiyl radicals and NO with the latter being formed by reactions between cysteine and aromatic amino acid radicals in a highly hydrophobic environment [19,20]. However, this mechanism is likely confined to proteins or membranes in close proximity to a NO source [50]. SNO of a specific cysteine protein is dependent on a range of environmental factors including levels of NO and O 2 , neucleophilicity of the thiol group, local hydrophobicity, and redox state of proximate amino acids [19,20,50].…”

“…However, this mechanism is likely confined to proteins or membranes in close proximity to a NO source [50]. SNO of a specific cysteine protein is dependent on a range of environmental factors including levels of NO and O 2 , neucleophilicity of the thiol group, local hydrophobicity, and redox state of proximate amino acids [19,20,50].…”

Regiospecific Nitrosation of N-terminal-blocked Tryptophan Derivatives by N2O3 at Physiological pH

“…The main nitrosating species in this reaction is postulated to be dinitrogen trioxide (N 2 O 3 ) formed from HNO 2 dehydration (7,29). Provided that this is indeed the case, N 2 O 3 formed from ⅐ NO in the presence of oxygen at pH 7.4 should also nitrosate N-terminal-blocked tryptophan derivatives, like N-acetyltryptophan and peptide-associated tryptophan (lysine-tryptophan-lysine).…”

The reactivity of vinyl compounds as alkylating agents

“…In previous work we studied the in vitro reactivity of several alkylating compounds capable of forming DNA adducts: sorbic acid [4] and sorbates [5], nitrosoureas [6,7], p-nitrostyrene oxide [8], and lactones [9][10][11][12]. The results revealed a correlation between the carcinogenicity of the substances and their reactivity with 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilicity similar to that of DNA [13,14].…”