title: Roles of intramolecular and intermolecular hydrogen bonding in a three-water-assisted mechanism of succinimide formation from aspartic acid residues.
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.
authors.affiliation: Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. ohgi@tohoku-pharm.ac.jp.
authors.forename: Ohgi
authors.initials: O
authors.lastname: Takahashi
authors.affiliation: Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. kirikoshi@tohoku-pharm.ac.jp.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kirikoshi
authors.affiliation: Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. manabe@tohoku-pharm.ac.jp.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Manabe
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D013388:Succinimides / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D013388:Succinimides; D014867:Water; C032620:succinimide; D001224:Aspartic Acid
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