Cleavage of the peptide bond of β-alanyl-l-histidine (carnosine) induced by a CoIII–amine complexes: reaction, structure and mechanism

Abstract

Cleavage of the peptide bond occurs when β-alanyl-L-histidine (carnosine) reacts with [Co(tren)Cl₂]⁺ (tren = tris(2-aminoethyl)amine) to give [Co(tren)(histidine)]²⁺1 and [Co(tren)(β-alanine)]²⁺2. [Co(tren)(histidine)]²⁺1 crystallizes in the enantiomorphic space group P2₁2₁2₁ and 2 crystallizes in the P2₁/c space group. The mechanism of the cleavage reactions were studied in detail for the precursor [Co(tren)Cl₂]⁺ and [Co(trien)Cl₂]⁺, which convert into [Co(tren)(OH)₂]⁺/[Co(tren)(OH)(OH₂)]²⁺ and [Co(trien)(OH)₂]⁺/[Co(trien)(OH)(OH₂)]²⁺ in water at basic pH (trien = 1,4,7,10-tetraazadecane). At a slightly basic pH, the initial coordination of the substrate (β-alanyl-L-histidine) is by the carboxylate group for the reaction with [Co(tren)Cl₂]⁺. This is followed by a rate-limiting nucleophilic attack of the hydroxide group at the β-alanyl-L-histidine carbonyl group. In a strongly basic reaction medium substrate, binding of the metal was through carboxylate and amine terminals. On the other hand, for the reaction between [cis-β-Co(trien)Cl₂]⁺ and β-alanyl-L-histidine, the initial coordination of the substrate takes place via an imidazole ring nitrogen, independently, and followed by a nucleophilic attack of the hydroxide group at the β-alanyl-L-histidine carbonyl group. The circular dichroism spectrum for 1 suggests that a very small extent of racemization of the amino acid (L-histidine) takes place during the cleavage reaction between [Co(tren)Cl₂]⁺ and β-alanyl-L-histidine. Reaction between [cis-β-Co(trien)Cl₂]⁺ and β-alanyl-L-histidine also causes cleavage of the peptide bond, producing a free β-alanyl molecule and a cationic fragment [cis-α-Co(trien)(histidine)]²⁺3 that crystallizes in the optically active space group P2₁2₁2₁. Unlike the previous case an appreciable degree of racemization of the L-histidine takes place during the reaction between [cis-β-Co(trien)Cl₂]⁺ and β-alanyl-L-histidine. Crystals containing L-histidine and D-histidine fragments in the [cis-α-Co(trien)(histidine)]²⁺ moiety were crystallographically documented by mounting a number of randomly selected crystals.