{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:48:26Z","timestamp":1790722106369,"version":"4.1.0"},"reference-count":21,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2014,8,4]],"date-time":"2014-08-04T00:00:00Z","timestamp":1407110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Aspartic acid (Asp) residues in peptides and proteins are prone to isomerization to the \u03b2-form and racemization via a five-membered succinimide intermediate. These nonenzymatic reactions have relevance to aging and age-related diseases. In this paper, we report a three water molecule-assisted, six-step mechanism for the formation of succinimide from Asp residues found by density functional theory calculations. The first two steps constitute a stepwise iminolization of the C-terminal amide group. This iminolization involves a quintuple proton transfer along intramolecular and intermolecular hydrogen bonds formed by the C-terminal amide group, the side-chain carboxyl group, and the three water molecules. After a conformational change (which breaks the intramolecular hydrogen bond involving the iminol nitrogen) and a reorganization of water molecules, the iminol nitrogen nucleophilically attacks the carboxyl carbon of the Asp side chain to form a five-membered ring. This cyclization is accompanied by a triple proton transfer involving  two water molecules, so that a gem-diol tetrahedral intermediate is formed. The last step  is dehydration of the gem-diol group catalyzed by one water molecule, and this is the  rate-determining step. The calculated overall activation barrier (26.7 kcal mol\u22121) agrees well with an experimental activation energy.<\/jats:p>","DOI":"10.3390\/molecules190811440","type":"journal-article","created":{"date-parts":[[2014,8,4]],"date-time":"2014-08-04T08:06:18Z","timestamp":1407139578000},"page":"11440-11452","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Roles of Intramolecular and Intermolecular Hydrogen Bonding in a Three-Water-Assisted Mechanism of Succinimide Formation from Aspartic Acid Residues"],"prefix":"10.3390","volume":"19","author":[{"given":"Ohgi","family":"Takahashi","sequence":"first","affiliation":[{"name":"Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Kirikoshi","sequence":"additional","affiliation":[{"name":"Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyoshi","family":"Manabe","sequence":"additional","affiliation":[{"name":"Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,8,4]]},"reference":[{"key":"ref_1","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. 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Spartan\u201908, Wavefunction, Inc."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/19\/8\/11440\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:14:20Z","timestamp":1760217260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/19\/8\/11440"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,4]]},"references-count":21,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2014,8]]}},"alternative-id":["molecules190811440"],"URL":"https:\/\/doi.org\/10.3390\/molecules190811440","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,4]]}}}