Empirical Valence Bond Simulations Suggest a Direct Hydride Transfer Mechanism for Human Diamine Oxidase

ACS Omega
Aleksandra MaršavelskiShina C L Kamerlin

Abstract

Diamine oxidase (DAO) is an enzyme involved in the regulation of cell proliferation and the immune response. This enzyme performs oxidative deamination in the catabolism of biogenic amines, including, among others, histamine, putrescine, spermidine, and spermine. The mechanistic details underlying the reductive half-reaction of the DAO-catalyzed oxidative deamination which leads to the reduced enzyme cofactor and the aldehyde product are, however, still under debate. The catalytic mechanism was proposed to involve a prototropic shift from the substrate-Schiff base to the product-Schiff base, which includes the rate-limiting cleavage of the Cα-H bond by the conserved catalytic aspartate. Our detailed mechanistic study, performed using a combined quantum chemical cluster approach with empirical valence bond simulations, suggests that the rate-limiting cleavage of the Cα-H bond involves direct hydride transfer to the topaquinone cofactor-a mechanism that does not involve the formation of a Schiff base. Additional investigation of the D373E and D373N variants supported the hypothesis that the conserved catalytic aspartate is indeed essential for the reaction; however, it does not appear to serve as the catalytic base, as previously...Continue Reading

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Citations

Aug 23, 2020·Biomolecules·Oriol Comas-BastéMaría Del Carmen Vidal-Carou
Oct 8, 2019·Chemical Science·Ana Rita CalixtoPedro Alexandrino Fernandes

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Methods Mentioned

BETA
deamination

Software Mentioned

GROMACS
OPLS
ffld
Chimera
AA
EVB
VMD
Macromodel suite
Schrödinger
Gaussian

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