Peptide Deamination

Carman, Neill Hugh (1992). Peptide Deamination. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00010174

Abstract

The nitrosation of the terminal amino group of peptides and amino acids, the synthesis and properties of diazoamino adds and diazopeptides and their decomposition products, particularly products resulting from intramolecular cyclisations are reviewed and discussed in relation to human cancer. The reactivity of N-(1'-methoxycarbonyl-2'-phenyl)ethyloxetan-2-one-4-carboxamide (1) formed from the deamination of L-aspartyl-L-phenylalanine methyl ester (aspartame) is examined from a mechanistic stand-point to determine its potential as an alkylating agent in-vivo. The stability of (1) in aqueous solution is investigated. Three hydrolysis mechanisms are observed for the β-lactone ring at differing pH values. Below pH2 the A_AC2 mechanism dominates and above pH7 the B_AC2 mechanisin is observed. In the physiological pH range (2-7) hydrolysis is independent of pH occuring via the B_A12 mechanism and (1) has a half life of 13.5h at 37°C.

The reactivity of (1) to nucleophiles other than water is studied Alkylation and acylation are both observed depending upon the nucleophile used Attempts to rationalise this dual reactivity which is also observed for β-butyrolactone and β-propiolactone, two known carcinogens, are made. The implications of the nitrosation of aspartame in vivo are discussed briefly.

The formation of cyclic products from the nitrosation of asparagine and glutamine derivatives is described. In aqueous solution intra-molecular cyclisation is observed, occurring on the carboxamide O-atom. The synthesis of new diazocompounds derived from glutamine, asparagine and glutaminyl and asparaginyl dipeptides are described. The stabilities of these compounds in aqueous media are examined and they are found to decompose via an A-S_E2 pathway. Further, they are decomposed thermally in an organic solvent and the formation of a variety of cyclic products is observed. Mechanisms are proposed. Intramolecular cyclisation on the carboxamide side chain N-atom is not observed. The possible implications of the nitrosation of asparaginyl and glutaminyl compounds are briefly discussed.