ArticleMolecules (Basel, Switzerland)2014
Roles of intramolecular and intermolecular hydrogen bonding in a three-water-assisted mechanism of succinimide formation from aspartic acid residues.
Article in Molecules (Basel, Switzerland), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 31 citations in OpenAlex.
- Predicting Reaction Mechanisms for the Threonine-Residue Stereoinversion Catalyzed by a Dihydrogen Phosphate Ion.ACS omega · 2022Article
- Molecular Mechanisms of Succinimide Formation from Aspartic Acid Residues Catalyzed by Two Water Molecules in the Aqueous Phase.International journal of molecular sciences · 2021Article
- Computational Studies on Water-Catalyzed Mechanisms for Stereoinversion of Glutarimide Intermediates Formed from Glutamic Acid Residues in Aqueous Phase.International journal of molecular sciences · 2019Article
- Phosphate-Catalyzed Succinimide Formation from Asp Residues: A Computational Study of the Mechanism.International journal of molecular sciences · 2018Article
- Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion.International journal of molecular sciences · 2016Article
- Acetic acid-catalyzed formation of N-phenylphthalimide from phthalanilic acid: a computational study of the mechanism.International journal of molecular sciences · 2015Article
- Acetic acid can catalyze succinimide formation from aspartic acid residues by a concerted bond reorganization mechanism: a computational study.International journal of molecular sciences · 2015Article
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3 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Aspartic acid (Asp) residues in peptides and proteins are prone to isomerization to the β-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(-1)) agrees well with an experimental activation energy.
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