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Dihydropyrimidine dehydrogenase: a flavoprotein with four iron-sulfur clusters
Karolinska Institutet. (Molecular Structural Biology)
2004 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1701, no 1-2, 61-74 p.Article in journal (Refereed) Published
Abstract [en]

Dihydropyrimidine dehydrogenase (DPD) is the first and rate-limiting enzyme in the pathway for degradation of pyrimidines, responsible for the reduction of the 5,6-double bond to give the dihydropyrimidine using NADPH as the reductant. The enzyme is a dimer of 220 kDa, and each monomer contains one FAD, one FMN, and four FeS clusters. The FAD is situated at one end of the protein, the FMN is at the other, and four FeS clusters form a conduit for electron transfer between the two sites comprised of two FeS clusters from each monomer. The enzyme has a two-site ping-pong mechanism with NADPH reducing FAD and reduced FMN responsible for reducing the pyrimidine. Solvent deuterium kinetic isotope effects indicate a rate-limiting reduction of FAD accompanied by pH-dependent structural rearrangement for proper orientation of the nicotinamide ring. Transfer of electrons from site 1 to site 2 is downhill with FMN rapidly reduced by FADH(2) via the FeS conduit. The reduction of the pyrimidine at site 2 proceeds using general acid catalysis with protonation at N5 of FMN carried out by K574 as FMN is reduced and protonation at C5 of the pyrimidine by C671 as it is reduced. Kinetic isotope effects indicate a stepwise reaction for reduction of the pyrimidine with hydride transfer at C6 preceding proton transfer at C5, with a late transition state for the proton transfer step.

Place, publisher, year, edition, pages
2004. Vol. 1701, no 1-2, 61-74 p.
National Category
Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-214439DOI: 10.1016/j.bbapap.2004.06.009PubMedID: 15450176OAI: oai:DiVA.org:uu-214439DiVA: diva2:684981
Available from: 2014-01-08 Created: 2014-01-08 Last updated: 2017-12-06Bibliographically approved

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Dobritzsch, Doreen

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