Computational Studies on Pyroglutamylation Mechanism of N-Terminal Glutamic Acid Residues in Aqueous Conditions
Tomoki Nakayoshi1,2, Koichi Kato1,3, Eiji Kurimoto1 , Akifumi Oda1,2,4
1Graduate School of Pharmacy, Meijo University, Nagoya, Aichi 468-8503
2Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192
3Department of Pharmacy, Kinjo Gakuin University, Nagoya, Aichi 463-8521
4Institute for Protein Research, Suita, Osaka 565-0871
Glutamic acid (Glu) residues located at N-termini in peptides and proteins are prone to spontaneous cyclization resulting in the formation of pyroglutamic acid (pGlu) residues. This post-translational modification is called “pyroglutamylation”. Pyroglutamylation of the N-terminal Glu residues is presumed to be involved in several neurodegenerative diseases, e.g., Alzheimer diseases (AD). One of the pathological hallmark of AD is the accumulation of amyloid β (Aβ). Since the formation of pGlu residues causes the loss of net two charged hydrophilic groups, pyroglutamylated Aβ is extremely hydrophobic and display an up to 250-fold accelerated initial rate of aggregation compared to unmodified Aβ. It was long believed that pyroglutamylation proceeds enzymatically, however, recently, it has been experimentally confirmed that pyroglutamylation can proceed nonenzymatically in aqueous buffer. Until now, the detailed nonenzymatic pyroglutamylation mechanism of N-terminal Glu residues has not been proposed nor investigated, and it is not even clear whether any catalysts are required for pyroglutamylation. Based on the fact that pyroglutamylation proceeds in aqueous conditions, we compared the pyroglutamylation mechanism without any catalysts, and in the presence of catalytic water molecules using quantum chemical calculations employing density functional methods.