{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:10:27Z","timestamp":1790835027544,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T00:00:00Z","timestamp":1609891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15H01064"],"award-info":[{"award-number":["15H01064"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K08257"],"award-info":[{"award-number":["17K08257"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19J23595"],"award-info":[{"award-number":["19J23595"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019s 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\u22121. Some optimized geometries and reaction modes in the aqueous phase were observed that differed from those in the gas phase.<\/jats:p>","DOI":"10.3390\/ijms22020509","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T20:45:42Z","timestamp":1609965942000},"page":"509","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Molecular Mechanisms of Succinimide Formation from Aspartic Acid Residues Catalyzed by Two Water Molecules in the Aqueous Phase"],"prefix":"10.3390","volume":"22","author":[{"given":"Tomoki","family":"Nakayoshi","sequence":"first","affiliation":[{"name":"Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Aichi, Japan"},{"name":"Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Kato","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Aichi, Japan"},{"name":"Department of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Fukuyoshi","sequence":"additional","affiliation":[{"name":"Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ohgi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Kurimoto","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akifumi","family":"Oda","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Aichi, Japan"},{"name":"Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Ishikawa, Japan"},{"name":"Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2220\/biomedres.12.315","article-title":"Racemization of aspartic acids at specific sites in \u03b1A-crystallin from aged human lens","volume":"12","author":"Fujii","year":"1991","journal-title":"Biomed. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/tcr.20020","article-title":"Homochirality and life","volume":"4","author":"Fujii","year":"2004","journal-title":"Chem. Rec."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39992","DOI":"10.1074\/jbc.M112.399972","article-title":"A rapid, comprehensive liquid chromatography-mass spectrometry (LC-MS)-based survey of the Asp isomers in crystallins from human cataract lenses","volume":"287","author":"Fujii","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S0021-9258(19)75855-4","article-title":"Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation","volume":"262","author":"Geiger","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.mad.2013.01.002","article-title":"Interconversion of the peptide isoforms of aspartate: Stability of isoaspartates","volume":"134","author":"Hooi","year":"2013","journal-title":"Mech. Ageing Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1023\/A:1015807303766","article-title":"Chemical pathways of peptide degradation. II. Kinetics of deamidation of an asparaginyl residue in a model hexapeptide","volume":"7","author":"Patel","year":"1990","journal-title":"Pharm. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"22549","DOI":"10.1016\/S0021-9258(18)54607-X","article-title":"Effects of amino acid sequence, buffers, and ionic strength on the rate and mechanism of deamidation of asparagine residues in small peptides","volume":"266","author":"Schirch","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1093\/oxfordjournals.jbchem.a124577","article-title":"Simultaneous stereoinversion and isomerization at specific aspartic acid residues in \u03b1A-crystallin from human lens","volume":"116","author":"Fujii","year":"1994","journal-title":"J. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0167-4838(94)90003-5","article-title":"Simultaneous racemization and isomerization at specific aspartic acid residues in \u03b1B-crystallin from the aged human lens","volume":"1204","author":"Fujii","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1167\/iovs.06-1284","article-title":"Localization of d-\u03b2-aspartic acid-containing proteins in human eyes","volume":"48","author":"Kaji","year":"2007","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s11357-010-9171-7","article-title":"Racemisation and human cataract. d-Ser, d-Asp\/Asn and d-Thr are higher in the lifelong proteins of cataract lenses than in age-matched normal lenses","volume":"33","author":"Hooi","year":"2010","journal-title":"AGE"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/jnr.10350","article-title":"Isoaspartate formation at position 23 of amyloid beta peptide enhanced fibril formation and deposited onto senile plaques and vascular amyloids in Alzheimer\u2019s disease","volume":"70","author":"Shimizu","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1021\/ac403315h","article-title":"Simultaneous determination of post-translational racemization and isomerization of N-terminal amyloid-\u03b2 in Alzheimer\u2019s brain tissues by covalent chiral derivatized ultraperformance liquid chromatography tandem mass spectrometry","volume":"86","author":"Inoue","year":"2013","journal-title":"Anal. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1111\/j.1365-2133.2003.05618.x","article-title":"Aspartic acid racemization: Evidence for marked longevity of elastin in human skin","volume":"149","author":"Laumeier","year":"2003","journal-title":"Br. J. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s00414-002-0355-2","article-title":"Age estimation based on aspartic acid racemization in elastin from the yellow ligaments","volume":"117","author":"Laumeier","year":"2003","journal-title":"Int. J. Leg. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0021-9150(92)90132-Z","article-title":"On the accumulation of d-aspartate in elastin and other proteins of the ageing aorta","volume":"97","author":"Powell","year":"1992","journal-title":"Atherosclerosis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1111\/j.1556-4029.2010.01472.x","article-title":"Age estimation by amino acid racemization in human teeth","volume":"55","author":"Ohtani","year":"2010","journal-title":"J. Forensic Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s12024-018-9984-8","article-title":"Aspartic acid racemization of root dentin used for dental age estimation in a Polish population sample","volume":"14","author":"Wochna","year":"2018","journal-title":"Forensic Sci. Med. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0379-0738(95)01834-4","article-title":"Identification of osteocalcin as a permanent aging constituent of the bone matrix: Basis for an accurate age at death determination","volume":"77","author":"Ritz","year":"1996","journal-title":"Forensic Sci. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1021\/acs.analchem.5b03891","article-title":"Amyloid plaque in the human brain can decompose from A\u03b2(1-40\/1-42) by spontaneous nonenzymatic processes","volume":"88","author":"Lyons","year":"2016","journal-title":"Anal. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/j.1399-3011.1996.tb00821.x","article-title":"Kinetic study of racemization of aspartyl residues in model peptides of \u03b1A-crystallin","volume":"48","author":"Fujii","year":"2009","journal-title":"Int. J. Pept. Protein Res."},{"key":"ref_22","unstructured":"Jones, J.E., and Morano, D.M. (2012). Amide-iminol tautomerization of the C-terminal peptide groups of aspartic acid residues: Two-water-assisted mechanism, cyclization from the iminol tautomer leading to the tetrahedral intermediate of succinimide formation, and im-plication to peptide group hydrogen exchange. Tyrosine and Aspartic Acid: Properties, Source and Health Benefits, Nova Science Publishers."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"140459","DOI":"10.1016\/j.bbapap.2020.140459","article-title":"Computational studies on nonenzymatic succinimide-formation mechanisms of the aspartic acid residues catalyzed by two water molecules","volume":"1868","author":"Nakayoshi","year":"2020","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1002\/cbdv.200900296","article-title":"Modeling the enolization of succinimide derivatives, a key step of racemization of aspartic acid residues: Importance of a two-H2O mechanism","volume":"7","author":"Takahashi","year":"2010","journal-title":"Chem. Biodivers."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.4236\/health.2013.512273","article-title":"Two-water-assisted racemization of the succinimide intermediate formed in proteins. A computational model study","volume":"5","author":"Takahashi","year":"2013","journal-title":"Health"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Takahashi, O., and Kirikoshi, R. (2014). Intramolecular cyclization of aspartic acid residues assisted by three water molecules: A density functional theory study. Comput. Sci. Discov., 7.","DOI":"10.1088\/1749-4699\/7\/1\/015005"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11440","DOI":"10.3390\/molecules190811440","article-title":"Roles of intramolecular and intermolecular hydrogen bonding in a three-water-assisted mechanism of succinimide formation from aspartic acid residues","volume":"19","author":"Takahashi","year":"2014","journal-title":"Molecules"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.3390\/ijms16011613","article-title":"Acetic acid can catalyze succinimide formation from aspartic acid residues by a concerted bond reorganization mechanism: A computational study","volume":"16","author":"Takahashi","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.bbapap.2017.12.011","article-title":"Comparison of the activation energy barrier for succinimide formation from \u03b1- and \u03b2-aspartic acid residues obtained from density functional theory calculations","volume":"1866","author":"Nakayoshi","year":"2018","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kirikoshi, R., Manabe, N., and Takahashi, O. (2018). Phosphate-catalyzed succinimide formation from Asp residues: A computational study of the mechanism. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020637"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1021\/jp808597v","article-title":"Deamidation of asparagine residues: Direct hydrolysis versus succin-imide-mediated deamidation mechanisms","volume":"113","author":"Catak","year":"2009","journal-title":"J. Phys. Chem. A"},{"key":"ref_32","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16, Rev. A.03, Gaussian, Inc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.bbapap.2018.01.006","article-title":"Influences of conformations of peptides on stereoinversions and\/or isomerizations of aspartic acid residues","volume":"1866","author":"Oda","year":"2018","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Nakayoshi, T., Kato, K., Kurimoto, E., and Oda, A. (2020). Influence of the conformations of \u03b1A-crystallin peptides on the isomerization rates of aspartic acid residues. Biochim. Biophys. Acta, 140480.","DOI":"10.1016\/j.bbapap.2020.140480"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/509\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:07:48Z","timestamp":1760159268000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/509"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,6]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22020509"],"URL":"https:\/\/doi.org\/10.3390\/ijms22020509","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,6]]}}}