ArticleInternational journal of molecular sciences2015
Acetic acid can catalyze succinimide formation from aspartic acid residues by a concerted bond reorganization mechanism: a computational study.
Article in International journal of molecular sciences, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 18 citations in OpenAlex.
- The Multi-Attribute Method (MAM), An Advanced LC-MS Approach for Protein A Resin Performance and Lifecycle Evaluation.Antibodies (Basel, Switzerland) · 2026Article
- 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
- 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
- A Computational Study of the Mechanism of Succinimide Formation in the Asn-His Sequence: Intramolecular Catalysis by the His Side Chain.Molecules (Basel, Switzerland) · 2016Article
- Acetic acid-catalyzed formation of N-phenylphthalimide from phthalanilic acid: a computational study of the mechanism.International journal of molecular sciences · 2015Article
- Glycolic acid-catalyzed deamidation of asparagine residues in degrading PLGA matrices: 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
Succinimide formation from aspartic acid (Asp) residues is a concern in the formulation of protein drugs. Based on density functional theory calculations using Ace-Asp-Nme (Ace = acetyl, Nme = NHMe) as a model compound, we propose the possibility that acetic acid (AA), which is often used in protein drug formulation for mildly acidic buffer solutions, catalyzes the succinimide formation from Asp residues by acting as a proton-transfer mediator. The proposed mechanism comprises two steps: cyclization (intramolecular addition) to form a gem-diol tetrahedral intermediate and dehydration of the intermediate. Both steps are catalyzed by an AA molecule, and the first step was predicted to be rate-determining. The cyclization results from a bond formation between the amide nitrogen on the C-terminal side and the side-chain carboxyl carbon, which is part of an extensive bond reorganization (formation and breaking of single bonds and the interchange of single and double bonds) occurring concertedly in a cyclic structure formed by the amide NH bond, the AA molecule and the side-chain C=O group and involving a double proton transfer. The second step also involves an AA-mediated bond reorganization. Carboxylic acids other than AA are also expected to catalyze the succinimide formation by a similar mechanism.
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