Abstract
Spontaneous deamidation in the Asn-Gly-Arg (NGR) motif that yields an isoAsp-Gly-Arg (isoDGR) sequence has recently attracted considerable attention because of the possibility of application to dual tumor targeting. It is well known that Asn deamidation reactions in peptide chains occur via the five-membered ring succinimide intermediate. Recently, we computationally showed by the B3LYP density functional theory method, that inorganic phosphate and the Arg side chain can catalyze the NGR deamidation using a cyclic peptide, c[CH2CO–NGRC]–NH2. In this previous study, the tetrahedral intermediate of the succinimide formation was assumed to be readily protonated at the nitrogen originating from the Asn side chain by the solvent water before the release of an NH3 molecule. In the present study, we found a new mechanism for the decomposition of the tetrahedral intermediate that does not require the protonation by an external proton source. The computational method is the same as in the previous study. In the new mechanism, the release of an NH3 molecule occurs after a proton exchange between the peptide and the phosphate and conformational changes. The rate-determining step of the overall reaction course is the previously reported first step, i.e., the cyclization to form the tetrahedral intermediate.
Highlights
It is well known that Asn residues in peptides and proteins undergo spontaneous, non-enzymatic deamidation via the five-membered ring succinimide intermediate (Scheme 1) [38,39,40,41,42,43,44,45,46,47,48]
In the previous paper [67], we reported a phosphate-catalyzed mechanism of the succinimide formation from CP15 found by a density functional theory (DFT) computational study
We found a new pathway for the deammoniation process where the initially tetrahedral intermediate, which we denote as IC1 in the present paper, formed tetrahedral intermediate, which we denote as IC1 in the present decomposes without an external proton source
Summary
Since Ruoslahti and co-workers discovered the tumor-homing property of the asparagine-glycinearginine (Asn-Gly-Arg, NGR) motif by in vivo phage display in tumor-bearing mice [1], peptides containing this motif, especially cyclic ones, have been attracting considerable attention for application to tumor diagnosis and therapy [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. It is well known that Asn residues in peptides and proteins undergo spontaneous, non-enzymatic deamidation via the five-membered ring succinimide intermediate (Scheme 1) [38,39,40,41,42,43,44,45,46,47,48]. This intermediate is formed by the nucleophilic attack of the main-chain nitrogen atom of the C-terminal adjacent residue on the Asn side-chain amide carbon (Cγ ) with the release of an ammonia (NH3 ). An NH3 molecule is released from the tetrahedral intermediate to give
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