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Empirical Valence Bond Simulations Suggest a Direct Hydride Transfer Mechanism for Human Diamine Oxidase
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Rudjer Boskovic Inst, Div Organ Chem & Biochem, Computat Organ Chem & Biochem Grp, Bijenicka Cesta 54, Zagreb 10000, Croatia;Univ Zagreb, Fac Sci, Dept Chem, Horvatovac 102a, Zagreb 10000, Croatia.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Biology.ORCID iD: 0000-0002-1834-7358
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. KTH Royal Inst Technol, Dept Biophys, SciLifeLab, S-10691 Stockholm, Sweden.
Rudjer Boskovic Inst, Div Organ Chem & Biochem, Computat Organ Chem & Biochem Grp, Bijenicka Cesta 54, Zagreb 10000, Croatia.
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2018 (English)In: ACS Omega, ISSN 2470-1343, Vol. 3, no 4, p. 3665-3674Article in journal (Refereed) Published
Abstract [en]

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 substrateSchiff base to the product-Schiff base, which includes the ratelimiting cleavage of the C alpha-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 C alpha-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.

Place, publisher, year, edition, pages
2018. Vol. 3, no 4, p. 3665-3674
National Category
Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-353209DOI: 10.1021/acsomega.8b00346ISI: 000430200300005OAI: oai:DiVA.org:uu-353209DiVA, id: diva2:1217357
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Swedish Research Council, 2015-04928Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-12-03Bibliographically approved

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Petrovic, DusanBauer, PaulKamerlin, Shina Caroline Lynn

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