1gte: Difference between revisions

Revision as of 13:53, 21 February 2008

DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, BINARY COMPLEX WITH 5-IODOURACIL

OverviewOverview

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 StructureAbout this Structure

1GTE is a Single protein structure of sequence from Sus scrofa with , , and as ligands. Active as Dihydropyrimidine dehydrogenase (NADP(+)), with EC number 1.3.1.2 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

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

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 ==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.
+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==
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 [[Category: Lindqvist, Y.]]
 [[Category: Ricagno, S.]]
-[[Category: Schnackerz, K.D.]]
+[[Category: Schnackerz, K D.]]
 [[Category: Schneider, G.]]
 [[Category: FAD]]
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 [[Category: pyrimidine catabolism]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 09:42:28 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:53:46 2008''