Title

Molecular orbital studies of enzyme activity. 4. Hydrolysis of Peptides by Carboxypeptidase A

Document Type

Article

Journal/Book Title

Journal of the American Chemical Society

Publication Date

5-1977

Publisher

American Chemical Society

Volume

99

Abstract

An approximate molecular orbital method is used to study the catalytic activity of carboxypeptidase A. A proton donor is positioned near the nitrogen atom of the scissile bond of a model substrate. Nucleophilic attack on the carbonyl carbon leads to hydrolysis of the peptide. An electrophile positioned proximate to the carbonyl oxygen is seen to greatly facilitate this hydrolysis. The electrophile first polarizes the carbonyl bond of the substrate, making the carbon more susceptible to nucleophilic attack. The tetrahedral adduct formed as a result of this attack is stabilized by the electrophile in several ways. Bonding between the electrophile and the carbonyl oxygen reduces the negative charge on the oxygen. The electrophile also acts to strengthen the bonding between the central carbon and its four substituents in the adduct. The metal electrophiles which model Zn2+ and its ligands are more effective at catalyzing the hydrolysis than are various hydrogen-bonding species. The effects of strain on the peptide bond as a result of binding to the enzyme are examined for each of the electrophiles. Finally, a comparison is made between several proposed modes of nucleophilic attack.

Comments

Originally published in the Journal of the American Chemical Society by the American Chemical Society . Publisher’s PDF available through remote link. DOI: 10.1021/ja00452a046

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