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 intermediate, T(±) which is in acid-base equilibrium with various forms characterized by the different grades of protonation, T0, T+ and T-. The Bronsted plot for the base-catalysis and the pH-rate profile give pK(a) ~ 7 and ~ 13 for the equilibria T- + H+ ⇆ T(±) + T(-) + H(+) ⇆ T0 respectively. The reaction is subjects to general base and general acid cataysis on different steps. Departure of the amino group from T0 and T- by two parallel routes gives the product. The bifunctional acid catalyst HCO3- strongly increase the reaction rate and at high concentrations cause a 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.

Mechanism of 2,5-Dioxopiperazine Formation

VERGARA, ALESSANDRO;
1998

Abstract

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 intermediate, T(±) which is in acid-base equilibrium with various forms characterized by the different grades of protonation, T0, T+ and T-. The Bronsted plot for the base-catalysis and the pH-rate profile give pK(a) ~ 7 and ~ 13 for the equilibria T- + H+ ⇆ T(±) + T(-) + H(+) ⇆ T0 respectively. The reaction is subjects to general base and general acid cataysis on different steps. Departure of the amino group from T0 and T- by two parallel routes gives the product. The bifunctional acid catalyst HCO3- strongly increase the reaction rate and at high concentrations cause a 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/168454
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