| pubmed-article:11401542 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:11401542 | lifeskim:mentions | umls-concept:C0026383 | lld:lifeskim |
| pubmed-article:11401542 | lifeskim:mentions | umls-concept:C0012274 | lld:lifeskim |
| pubmed-article:11401542 | lifeskim:mentions | umls-concept:C0025552 | lld:lifeskim |
| pubmed-article:11401542 | lifeskim:mentions | umls-concept:C0681797 | lld:lifeskim |
| pubmed-article:11401542 | lifeskim:mentions | umls-concept:C0007382 | lld:lifeskim |
| pubmed-article:11401542 | lifeskim:mentions | umls-concept:C0205099 | lld:lifeskim |
| pubmed-article:11401542 | lifeskim:mentions | umls-concept:C1524063 | lld:lifeskim |
| pubmed-article:11401542 | pubmed:issue | 24 | lld:pubmed |
| pubmed-article:11401542 | pubmed:dateCreated | 2001-6-12 | lld:pubmed |
| pubmed-article:11401542 | pubmed:abstractText | Dihydroorotase plays a key role in pyrimidine biosynthesis by catalyzing the reversible interconversion of carbamoyl aspartate to dihydroorotate. Here we describe the three-dimensional structure of dihydroorotase from Escherichia coli determined and refined to 1.7 A resolution. Each subunit of the homodimeric enzyme folds into a "TIM" barrel motif with eight strands of parallel beta-sheet flanked on the outer surface by alpha-helices. Unexpectedly, each subunit contains a binuclear zinc center with the metal ions separated by approximately 3.6 A. Lys 102, which is carboxylated, serves as a bridging ligand between the two cations. The more buried or alpha-metal ion in subunit I is surrounded by His 16, His 18, Lys 102, Asp 250, and a solvent molecule (most likely a hydroxide ion) in a trigonal bipyramidal arrangement. The beta-metal ion, which is closer to the solvent, is tetrahedrally ligated by Lys 102, His 139, His 177, and the bridging hydroxide. L-Dihydroorotate is observed bound to subunit I, with its carbonyl oxygen, O4, lying 2.9 A from the beta-metal ion. Important interactions for positioning dihydroorotate into the active site include a salt bridge with the guanidinium group of Arg 20 and various additional electrostatic interactions with both protein backbone and side chain atoms. Strikingly, in subunit II, carbamoyl L-aspartate is observed binding near the binuclear metal center with its carboxylate side chain ligating the two metals and thus displacing the bridging hydroxide ion. From the three-dimensional structures of the enzyme-bound substrate and product, it has been possible to propose a unique catalytic mechanism for dihydroorotase. In the direction of dihydroorotate hydrolysis, the bridging hydroxide attacks the re-face of dihydroorotate with general base assistance by Asp 250. The carbonyl group is polarized for nucleophilic attack by the bridging hydroxide through a direct interaction with the beta-metal ion. During the cyclization of carbamoyl aspartate, Asp 250 initiates the reaction by abstracting a proton from N3 of the substrate. The side chain carboxylate of carbamoyl aspartate is polarized through a direct electrostatic interaction with the binuclear metal center. The ensuing tetrahedral intermediate collapses with C-O bond cleavage and expulsion of the hydroxide which then bridges the binuclear metal center. | lld:pubmed |
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| pubmed-article:11401542 | pubmed:grant | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11401542 | pubmed:language | eng | lld:pubmed |
| pubmed-article:11401542 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11401542 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:11401542 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:11401542 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:11401542 | pubmed:month | Jun | lld:pubmed |
| pubmed-article:11401542 | pubmed:issn | 0006-2960 | lld:pubmed |
| pubmed-article:11401542 | pubmed:author | pubmed-author:RaushelF MFM | lld:pubmed |
| pubmed-article:11401542 | pubmed:author | pubmed-author:PhillipsG... | lld:pubmed |
| pubmed-article:11401542 | pubmed:author | pubmed-author:HoldenH MHM | lld:pubmed |
| pubmed-article:11401542 | pubmed:author | pubmed-author:NealT MTM | lld:pubmed |
| pubmed-article:11401542 | pubmed:author | pubmed-author:ThodenJ BJB | lld:pubmed |
| pubmed-article:11401542 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:11401542 | pubmed:day | 19 | lld:pubmed |
| pubmed-article:11401542 | pubmed:volume | 40 | lld:pubmed |
| pubmed-article:11401542 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:11401542 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:11401542 | pubmed:pagination | 6989-97 | lld:pubmed |
| pubmed-article:11401542 | pubmed:dateRevised | 2007-11-14 | lld:pubmed |
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| pubmed-article:11401542 | pubmed:meshHeading | pubmed-meshheading:11401542... | lld:pubmed |
| pubmed-article:11401542 | pubmed:year | 2001 | lld:pubmed |
| pubmed-article:11401542 | pubmed:articleTitle | Molecular structure of dihydroorotase: a paradigm for catalysis through the use of a binuclear metal center. | lld:pubmed |
| pubmed-article:11401542 | pubmed:affiliation | Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, USA. | lld:pubmed |
| pubmed-article:11401542 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:11401542 | pubmed:publicationType | Comparative Study | lld:pubmed |
| pubmed-article:11401542 | pubmed:publicationType | Research Support, U.S. Gov't, P.H.S. | lld:pubmed |
| pubmed-article:11401542 | pubmed:publicationType | Research Support, U.S. Gov't, Non-P.H.S. | lld:pubmed |
| literatureCitation:2646_114... | literatureCitation:pubmed | pubmed-article:11401542 | lld:drugbank |
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