Transforming a Stable Amide into a Highly Reactive One: Capturing the Essence of Enzymatic Catalysis.

Aspartic proteinases, which include HIV-1 proteinase, function with two aspartate carboxy groups at the active site. This relationship has been modeled in a system possessing an otherwise unactivated amide positioned between two carboxy groups. The model amide is cleaved at an enzyme-like rate that renders the amide nonisolable at 35 °C and pH 4 owing to the joint presence of carboxy and carboxylate groups. A currently advanced theory attributing almost the entire catalytic power of enzymes to electrostatic reorganization is shown to be superfluous when suitable interatomic interactions are present. Our kinetic results are consistent with spatiotemporal concepts where embedding the amide group between two carboxylic moieties in proper geometries, at distances less than the diameter of water, leads to enzyme-like rate enhancements. Space and time are the essence of enzyme catalysis.

Mechanism of intramolecular catalysis in the hydrolysis of alkyl monoesters of 1,8-naphthalic acid.

Hydrolysis of alkyl 1,8-naphthalic acid monoesters 1a-d is subject to highly efficient intramolecular nucleophilic catalysis by the neighboring COOH group. The reactivity for the COOH reaction depends on the leaving group pK(a), with values of ß(LG) of -0.50, consistent with a mechanism involving rate determining breakdown of tetrahedral addition intermediates. The release of the steric strain of the peri-substitiuents in the highly reactive alkyl 1,8-naphthalic acid monoesters is fundamental to understand the observed special reactivity in this intramolecular reaction. DFT calculations show how the proton transfers involved in the cleavage of the neutral ester can be catalyzed by solvent water, thus facilitating the departure of poor alkoxide leaving groups.