Presentation Information
[U17-P03]Quantum Chemical Calculations on Metal-Catalyzed Deamidation of Asparagine Residues as Proteinogenic Amino Acids
*Ayato Mizuno1, Tomoki Nakayoshi1,2, Yuhki Ishimaru3, Mitsutaka Okumura3, Koichi Kato1,4, Akifumi Oda1 (1.Grad. Sch. Pharm., Meijo Univ., 2.Inst. Adv. Res., Nagoya Univ., 3.Grad. Sch. Sci., UOsaka, 4.Shonan Univ. Med. Sci.)
Introduction
Deamidation of asparagine (Asn) residues is a post-translational modification observed in variety of proteins. It is known to proceed spontaneously and non-enzymatically under physiological conditions. This reaction involves the formation of a succinimide intermediate, which is subsequently hydrolyzed to yield aspartic acid or isoaspartic acid residue. In our previous study, we demonstrated that the activation barrier for Asn deamidation catalyzed by dihydrogen phosphate ion is 67.9 kJ mol-1. This value is low for a non-enzymatic reaction, indicating that Asn residues are highly susceptible to deamidation. Asn is one of the approximately 20 standard amino acids that constitute proteins; however, it may be unstable in proteins. In this study, the instability of Asn residues was investigated by analyzing the deamidation of Asn using quantum chemical calculations.
We have previously investigated the reaction mechanisms and activation barriers of Asn deamidation catalyzed by dihydrogen phosphate and bicarbonate ions using quantum chemical calculations. However, in the deamidation of Asn residues, the involvement of metal ions thought to be abundant on the primitive Earth as catalyst has received little attention. In this study, we aim to elucidate the role of metal ions in the deamidation of Asn residues through quantum chemical calculations.
Method
Ac–Asn–NMe (Ac = acetyl, NMe = methylamino) was employed as a model compound. The reaction was presumed to proceed via two steps: (1) a cyclization process forming a gem-hydroxylamine intermediate, and (2) formation of a succinimide intermediate via ammonia elimination from the gem-hydroxylamine intermediate. Iron(III) hydroxide was placed in the vicinity of the model compound as a catalytic species, and reaction pathways were explored using quantum chemical calculations.
Results
The reaction pathway of Asn deamidation can be obtained by density functional theory calculations of model compound, and energy profiles were calculated. It was confirmed that Fe(III) hydroxide catalyzes proton relay at the transition state.
Deamidation of asparagine (Asn) residues is a post-translational modification observed in variety of proteins. It is known to proceed spontaneously and non-enzymatically under physiological conditions. This reaction involves the formation of a succinimide intermediate, which is subsequently hydrolyzed to yield aspartic acid or isoaspartic acid residue. In our previous study, we demonstrated that the activation barrier for Asn deamidation catalyzed by dihydrogen phosphate ion is 67.9 kJ mol-1. This value is low for a non-enzymatic reaction, indicating that Asn residues are highly susceptible to deamidation. Asn is one of the approximately 20 standard amino acids that constitute proteins; however, it may be unstable in proteins. In this study, the instability of Asn residues was investigated by analyzing the deamidation of Asn using quantum chemical calculations.
We have previously investigated the reaction mechanisms and activation barriers of Asn deamidation catalyzed by dihydrogen phosphate and bicarbonate ions using quantum chemical calculations. However, in the deamidation of Asn residues, the involvement of metal ions thought to be abundant on the primitive Earth as catalyst has received little attention. In this study, we aim to elucidate the role of metal ions in the deamidation of Asn residues through quantum chemical calculations.
Method
Ac–Asn–NMe (Ac = acetyl, NMe = methylamino) was employed as a model compound. The reaction was presumed to proceed via two steps: (1) a cyclization process forming a gem-hydroxylamine intermediate, and (2) formation of a succinimide intermediate via ammonia elimination from the gem-hydroxylamine intermediate. Iron(III) hydroxide was placed in the vicinity of the model compound as a catalytic species, and reaction pathways were explored using quantum chemical calculations.
Results
The reaction pathway of Asn deamidation can be obtained by density functional theory calculations of model compound, and energy profiles were calculated. It was confirmed that Fe(III) hydroxide catalyzes proton relay at the transition state.