Amino Acid Nitrosation Products as Alkylating Agents

Abstract

Nitrosation reactions of alpha-, beta-, and gamma-amino acids whose reaction products can act as alkylating agents of DNA were investigated. To approach in vivo conditions for the two-step mechanism (nitrosation and alkylation), nitrosation reactions were carried out in aqueous acid conditions (mimicking the conditions of the stomach lumen) while the alkylating potential of the nitrosation products was investigated at neutral pH, as in the stomach lining cells into which such products can diffuse. These conclusions were drawn: (i) The alkylating species resulting from the nitrosation of amino acids with an -NH(2) group are the corresponding lactones; (ii) the sequence of alkylating power is: alpha-lactones > beta-lactones > gamma-lactones, coming respectively from the nitrosation of alpha-, beta-, and gamma-amino acids; and (iii) the results obtained may be useful in predicting the mutagenic effectiveness of the nitrosation products of amino acids.

O6‐alkylguanine‐DNA alkyltransferase: Role in carcinogenesis and chemotherapy

“…More recent work, however, suggests that the most-likely candidates for endogenous alkylators are nitrosated amino-acids or possibly other amino-compounds. (59) Whilst these can be generated by bacterial nitrosation processes, occurring for example in the gastrointestinal tract, it is becoming increasingly clear that endogenously formed nitric oxide can nitrosate primary and secondary amino groups in amino acids and peptides (60) . It seems likely that this is the principal source of endogenous alkylation damage in DNA.…”

Structures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations

“…Nitrosation derives from reaction at neutral or alkaline pH with dinitrogen trioxide (N 2 O 3 ), which in turn is generated by the oxidation of NO (4), from dietary nitrite or after exposure to ionizing radiation (5). N -Nitrosoglycine is converted into diazoacetate or α-lactone (6,7), potent mutagens that can alkylate guanine in DNA to form O 6 -CMG and O 6 -MeG (8). In humans, O 6 -methylguanine-DNA methyltransferase (MGMT) repairs DNA containing a wide variety of different O 6 -alkylguanine lesions by transferring the alkyl group to the thiolate side chain of the active site Cys (9).…”

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].…”