Molecular Mechanisms of Succinimide Formation from Aspartic Acid Residues Catalyzed by Two Water Molecules in the Aqueous Phase.

Tomoki Nakayoshi,Koichi Kato,Akifumi Oda,Eiji Kurimoto,Ohgi Takahashi,Shuichi Fukuyoshi

doi:10.3390/ijms22020509

Abstract

Aspartic acid (Asp) residues are prone to nonenzymatic isomerization via a succinimide (Suc) intermediate. The formation of isomerized Asp residues is considered to be associated with various age-related diseases, such as cataracts and Alzheimer’s disease. In the present paper, we describe the reaction pathway of Suc residue formation from Asp residues catalyzed by two water molecules using the B3LYP/6-31+G(d,p) level of theory. Single-point energies were calculated using the MP2/6-311+G(d,p) level of theory. For these calculations, we used a model compound in which an Asp residue was capped with acetyl and methylamino groups on the N- and C-termini, respectively. In the aqueous phase, Suc residue formation from an Asp residue was roughly divided into three steps, namely, iminolization, cyclization, and dehydration, with the activation energy estimated to be 109 kJ mol−1. Some optimized geometries and reaction modes in the aqueous phase were observed that differed from those in the gas phase.

Highlights

Of the proteinogenic amino acids, aspartic acid (Asp) is relatively reactive, and Asp residues in peptides and proteins can be site- isomerized [1,2,3,4], with nonenzymatic isomerization proceeding via a five-membered-ring succinimide (Suc) intermediate (Scheme 1) [1,2,3,4,5]
We propose a by which Suc is formed from Asp residues in the aqueous phase using a polarization molecular mechanism by which Suc is formed from Asp residues in the aqueous phase continuum model (PCM)
Asp residue catalyzed by two water molecules in the aqueous phase

Summary

Introduction

Of the proteinogenic amino acids, aspartic acid (Asp) is relatively reactive, and Asp residues in peptides and proteins can be site- isomerized [1,2,3,4], with nonenzymatic isomerization proceeding via a five-membered-ring succinimide (Suc) intermediate (Scheme 1) [1,2,3,4,5]. Subsequent hydrolysis of L-Suc residues forms L-Asp and L-isoAsp, and hydrolysis of D-Suc residues forms D-Asp and D-isoAsp. Typically, the hydrolysis of Suc residue produces Asp and isoAsp residues at a molar ratio of approximately 1:3 [4,6,7]. The hydrolysis of Suc residue produces Asp and isoAsp residues at a molar ratio of approximately 1:3 [4,6,7] These isomerized Asp residues (i.e., L-isoAsp, D-Asp, and D-isoAsp) have been detected in various aging tissues, such as eye lenses [1,8,9,10,11], brains [12,13], skin [14], ligaments [15], aortas [16], teeth [17,18], and bones [19]. The formation of isomerized Asp residues disrupts the three-dimensional structures of peptides and proteins and is considered to be associated with various age-related diseases, such

Methods

Discussion

Conclusion