1gth
From Proteopedia
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==Overview== | ==Overview== | ||
| - | 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, | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1GTH is a | + | 1GTH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with SF4, FMN, FAD, NDP, IDH, IUR and URA as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydropyrimidine_dehydrogenase_(NADP(+)) Dihydropyrimidine dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.2 1.3.1.2] Structure known Active Site: FA1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1GTH OCA]. |
==Reference== | ==Reference== | ||
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[[Category: pyrimidine catabolism]] | [[Category: pyrimidine catabolism]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 14:37:08 2007'' |
Revision as of 12:31, 5 November 2007
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DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, TERNARY COMPLEX WITH NADPH AND 5-IODOURACIL
Overview
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.
About this Structure
1GTH is a Single protein structure of sequence from Sus scrofa with SF4, FMN, FAD, NDP, IDH, IUR and URA as ligands. Active as Dihydropyrimidine dehydrogenase (NADP(+)), with EC number 1.3.1.2 Structure known Active Site: FA1. Full crystallographic information is available from OCA.
Reference
Crystal structure of the productive ternary complex of dihydropyrimidine dehydrogenase with NADPH and 5-iodouracil. Implications for mechanism of inhibition and electron transfer., Dobritzsch D, Ricagno S, Schneider G, Schnackerz KD, Lindqvist Y, J Biol Chem. 2002 Apr 12;277(15):13155-66. Epub 2002 Jan 16. PMID:11796730
Page seeded by OCA on Mon Nov 5 14:37:08 2007
Categories: Dihydropyrimidine dehydrogenase (NADP(+)) | Single protein | Sus scrofa | Dobritzsch, D. | Lindqvist, Y. | Ricagno, S. | Schnackerz, K.D. | Schneider, G. | FAD | FMN | IDH | IUR | NDP | SF4 | URA | 5-fluorouracil degradation | Electron transfer | Flavin | Iron-sulfur clusters | Oxidoreductase | Pyrimidine catabolism
