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| {{STRUCTURE_1gte| PDB=1gte | SCENE= }} | | {{STRUCTURE_1gte| PDB=1gte | SCENE= }} |
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| '''DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, BINARY COMPLEX WITH 5-IODOURACIL'''
| | ===DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, BINARY COMPLEX WITH 5-IODOURACIL=== |
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| ==Overview==
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| Dihydroprymidine dehydrogenase catalyzes the first and rate-limiting step in pyrimidine degradation by converting pyrimidines to the corresponding 5,6- dihydro compounds. The three-dimensional structures of a binary complex with the inhibitor 5-iodouracil and two ternary complexes with NADPH and the inhibitors 5-iodouracil and uracil-4-acetic acid were determined by x-ray crystallography. In the ternary complexes, NADPH is bound in a catalytically competent fashion, with the nicotinamide ring in a position suitable for hydride transfer to FAD. The structures provide a complete picture of the electron transfer chain from NADPH to the substrate, 5-iodouracil, spanning a distance of 56 A and involving FAD, four [Fe-S] clusters, and FMN as cofactors. The crystallographic analysis further reveals that pyrimidine binding triggers a conformational change of a flexible active-site loop in the alpha/beta-barrel domain, resulting in placement of a catalytically crucial cysteine close to the bound substrate. Loop closure requires physiological pH, which is also necessary for correct binding of NADPH. Binding of the voluminous competitive inhibitor uracil-4-acetic acid prevents loop closure due to steric hindrance. The three-dimensional structure of the ternary complex enzyme-NADPH-5-iodouracil supports the proposal that this compound acts as a mechanism-based inhibitor, covalently modifying the active-site residue Cys-671, resulting in S-(hexahydro-2,4-dioxo-5-pyrimidinyl)cysteine.
| | The line below this paragraph, {{ABSTRACT_PUBMED_11796730}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 11796730 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_11796730}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Oxidoreductase]] | | [[Category: Oxidoreductase]] |
| [[Category: Pyrimidine catabolism]] | | [[Category: Pyrimidine catabolism]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 17:59:05 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 06:02:48 2008'' |