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PDBsum entry 1h7w
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Electron transfer
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PDB id
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1h7w
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure of dihydropyrimidine dehydrogenase, A major determinant of the pharmacokinetics of the anti-Cancer drug 5-Fluorouracil.
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Authors
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D.Dobritzsch,
G.Schneider,
K.D.Schnackerz,
Y.Lindqvist.
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Ref.
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EMBO J, 2001,
20,
650-660.
[DOI no: ]
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PubMed id
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Abstract
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Dihydropyrimidine dehydrogenase catalyzes the first step in pyrimidine
degradation: the NADPH-dependent reduction of uracil and thymine to the
corresponding 5,6-dihydropyrimidines. Its controlled inhibition has become an
adjunct target for cancer therapy, since the enzyme is also responsible for the
rapid breakdown of the chemotherapeutic drug 5-fluorouracil. The crystal
structure of the homodimeric pig liver enzyme (2x 111 kDa) determined at 1.9 A
resolution reveals a highly modular subunit organization, consisting of five
domains with different folds. Dihydropyrimidine dehydrogenase contains two FAD,
clusters, arranged in two electron transfer chains
that pass the dimer interface twice. Two of the Fe-S clusters show a hitherto
unobserved coordination involving a glutamine residue. The ternary complex of an
inactive mutant of the enzyme with bound NADPH and 5-fluorouracil reveals the
architecture of the substrate-binding sites and residues responsible for
recognition and binding of the drug.
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Figure 1.
Figure 1 Structure of pig liver DPD. (A) Schematic view of the
subunit of DPD with the domains in different colors. The
cofactors are shown as ball-and-stick models, iron ions in
magenta and sulfur atoms in green. (B) The DPD dimer. The color
codes for the domains of the first subunit are the same as in
(A), the corresponding domains in the second subunit are shown
in light green, brown, cyan, pink and light blue.
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Figure 6.
Figure 6 Electron transfer pathways in DPD. Distances between
closest atoms of the cofactors are indicated. The nicotinamide
ring of NADPH is shown at its assumed position during electron
transfer.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2001,
20,
650-660)
copyright 2001.
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