Cargando…
Computational Studies on the Mechanisms of Nonenzymatic Intramolecular Cyclization of the Glutamine Residues Located at N-Termini Catalyzed by Inorganic Phosphate Species
[Image: see text] Glutamine (Gln) residues located at N-termini undergo spontaneous intramolecular cyclization, causing the formation of pyroglutamic acid (pGlu) residues. pGlu residues have been detected at the N-termini in various peptides and proteins. The formation of pGlu residues during the fe...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2020
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191561/ https://www.ncbi.nlm.nih.gov/pubmed/32363268 http://dx.doi.org/10.1021/acsomega.9b04384 |
_version_ | 1783527873905164288 |
---|---|
author | Nakayoshi, Tomoki Kato, Koichi Kurimoto, Eiji Oda, Akifumi |
author_facet | Nakayoshi, Tomoki Kato, Koichi Kurimoto, Eiji Oda, Akifumi |
author_sort | Nakayoshi, Tomoki |
collection | PubMed |
description | [Image: see text] Glutamine (Gln) residues located at N-termini undergo spontaneous intramolecular cyclization, causing the formation of pyroglutamic acid (pGlu) residues. pGlu residues have been detected at the N-termini in various peptides and proteins. The formation of pGlu residues during the fermentation and purification processes of antibody drugs is one of the concerns in the design and formulation of these drugs and has been reported to proceed rapidly in a phosphate buffer. In this study, we have examined the phosphate-catalyzed mechanisms of the pGlu residue formation from N-terminal Gln residues via quantum chemical calculations using B3LYP density functional methods. Single-point energies were calculated using the second-order Møller–Plesset perturbation theory. We performed the calculations for the model compound in which an uncharged N-terminal Gln residue is capped with a methyl amino group on the C-terminal. The activation energy of the formation of pGlu residues was calculated as 83.8 kJ mol(–1), which was lower than that of the typical nonenzymatic reaction of amino acid residues. In addition, the computational results indicate that the flexibility of the main and side chains in N-terminal Gln residues was necessary for the formation of pGlu residues to proceed. In the obtained pathway, inorganic phosphate species act as the catalyst by mediating the proton transfer. |
format | Online Article Text |
id | pubmed-7191561 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-71915612020-05-01 Computational Studies on the Mechanisms of Nonenzymatic Intramolecular Cyclization of the Glutamine Residues Located at N-Termini Catalyzed by Inorganic Phosphate Species Nakayoshi, Tomoki Kato, Koichi Kurimoto, Eiji Oda, Akifumi ACS Omega [Image: see text] Glutamine (Gln) residues located at N-termini undergo spontaneous intramolecular cyclization, causing the formation of pyroglutamic acid (pGlu) residues. pGlu residues have been detected at the N-termini in various peptides and proteins. The formation of pGlu residues during the fermentation and purification processes of antibody drugs is one of the concerns in the design and formulation of these drugs and has been reported to proceed rapidly in a phosphate buffer. In this study, we have examined the phosphate-catalyzed mechanisms of the pGlu residue formation from N-terminal Gln residues via quantum chemical calculations using B3LYP density functional methods. Single-point energies were calculated using the second-order Møller–Plesset perturbation theory. We performed the calculations for the model compound in which an uncharged N-terminal Gln residue is capped with a methyl amino group on the C-terminal. The activation energy of the formation of pGlu residues was calculated as 83.8 kJ mol(–1), which was lower than that of the typical nonenzymatic reaction of amino acid residues. In addition, the computational results indicate that the flexibility of the main and side chains in N-terminal Gln residues was necessary for the formation of pGlu residues to proceed. In the obtained pathway, inorganic phosphate species act as the catalyst by mediating the proton transfer. American Chemical Society 2020-04-13 /pmc/articles/PMC7191561/ /pubmed/32363268 http://dx.doi.org/10.1021/acsomega.9b04384 Text en Copyright © 2020 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Nakayoshi, Tomoki Kato, Koichi Kurimoto, Eiji Oda, Akifumi Computational Studies on the Mechanisms of Nonenzymatic Intramolecular Cyclization of the Glutamine Residues Located at N-Termini Catalyzed by Inorganic Phosphate Species |
title | Computational Studies on the Mechanisms of Nonenzymatic
Intramolecular Cyclization of the Glutamine Residues Located at N-Termini
Catalyzed by Inorganic Phosphate Species |
title_full | Computational Studies on the Mechanisms of Nonenzymatic
Intramolecular Cyclization of the Glutamine Residues Located at N-Termini
Catalyzed by Inorganic Phosphate Species |
title_fullStr | Computational Studies on the Mechanisms of Nonenzymatic
Intramolecular Cyclization of the Glutamine Residues Located at N-Termini
Catalyzed by Inorganic Phosphate Species |
title_full_unstemmed | Computational Studies on the Mechanisms of Nonenzymatic
Intramolecular Cyclization of the Glutamine Residues Located at N-Termini
Catalyzed by Inorganic Phosphate Species |
title_short | Computational Studies on the Mechanisms of Nonenzymatic
Intramolecular Cyclization of the Glutamine Residues Located at N-Termini
Catalyzed by Inorganic Phosphate Species |
title_sort | computational studies on the mechanisms of nonenzymatic
intramolecular cyclization of the glutamine residues located at n-termini
catalyzed by inorganic phosphate species |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191561/ https://www.ncbi.nlm.nih.gov/pubmed/32363268 http://dx.doi.org/10.1021/acsomega.9b04384 |
work_keys_str_mv | AT nakayoshitomoki computationalstudiesonthemechanismsofnonenzymaticintramolecularcyclizationoftheglutamineresidueslocatedatnterminicatalyzedbyinorganicphosphatespecies AT katokoichi computationalstudiesonthemechanismsofnonenzymaticintramolecularcyclizationoftheglutamineresidueslocatedatnterminicatalyzedbyinorganicphosphatespecies AT kurimotoeiji computationalstudiesonthemechanismsofnonenzymaticintramolecularcyclizationoftheglutamineresidueslocatedatnterminicatalyzedbyinorganicphosphatespecies AT odaakifumi computationalstudiesonthemechanismsofnonenzymaticintramolecularcyclizationoftheglutamineresidueslocatedatnterminicatalyzedbyinorganicphosphatespecies |