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

Maršavelski, Aleksandra; Petrović, Dušan; Bauer, Paul; Vianello, Robert; Kamerlin, Shina Caroline Lynn (2018) Empirical Valence Bond Simulations Suggest a Direct Hydride Transfer Mechanism for Human Diamine Oxidase. ACS Omega, 3 (4). pp. 3665-3674. ISSN 2470-1343

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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 suggested. Rather, the electrostatic contributions of the most significant residues (including D373), together with the proximity of the Cu2+ cation to the reaction site, lower the activation barrier to drive the chemical reaction.

Item Type: Article
Uncontrolled Keywords: empirical valence bond ; hydride transfer mechanism ; diamine oxidase ; histamine metabolism
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Organic Chemistry and Biochemistry
Projects:
Project titleProject leaderProject codeProject type
Dizajn i sinteza novih dušikovih heterocikličkih fluorofora i fluorescentnih nanomaterijala kao kemijskih senzora za pH i metalne ione-iNFiNiTE–SENSRobert VianelloIP-2014-09-3386HRZZ
Depositing User: Robert Vianello
Date Deposited: 13 Dec 2018 12:38
Last Modified: 13 Dec 2018 12:41
URI: http://fulir.irb.hr/id/eprint/4380
DOI: 10.1021/acsomega.8b00346

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