The cyclization of H-Ala-Pro-NH2 to the 2,5-dioxopiperazine (DKP) has been studied as a model for the spontaneous cleavage of the peptide bond with concomitant formation of 2,5-dioxopiperazine that can occur at the N-terminus of a polypeptide chain. The reaction involves pre-equilibrium attack of the N-terminal amino group on the carbonyl carbon of the second residue giving a zwitterionic cyclic intermediate, T+/-, which is in acid-base equilibrium with various forms characterized by different grades of protonation, T-0, T+ and T-. The Bronsted plot for the base-catalysis and the pH-rate profile give pK(a) similar to 7 and similar to 13 for the equilibria T- + H+ reversible arrow T+/- and T- + H+ reversible arrow T-0, respectively. The reaction is subject to general base and general acid catalysis, acting on different steps. Departure of the amino group from T-0 and T- by two parallel routes gives the product. The bifunctional acid catalyst HCO3-strongly increases the reaction rate and at high concentrations causes a change of the rate-limiting step. At high pH, the overall reaction rate is limited by the trans --> cis isomerization of the Ala-Pro peptide bond.