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Catalytic Site Atlas

CSA LITERATURE entry for 1ylu

E.C. name6,7-dihydropteridine reductase
SpeciesEscherichia coli (Bacteria)
E.C. Number (IntEnz) 1.5.1.34
CSA Homologues of 1ylu
CSA Entries With UniProtID P38489
CSA Entries With EC Number 1.5.1.34
PDBe Entry 1ylu
PDBSum Entry 1ylu
MACiE Entry M0211

Literature Report

IntroductionNitroreductase (NTR) isolated from Escherichia coli catalyses the reduction of nitroaromatics, such as nitrofurazone and nitrofurantoin, to hydroxylamines and quinones, such as menadione, to quinols. Unusually, it can use either NADPH or NADH as the reducing agent. The enzyme is oxygen-insensitive in that it does not transfers electrons to oxygen to produce superoxide. NTR is part of a family of FMN-containing oxidoreductases that have broadly similar substrate specificities. These enzymes are dimeric and contain two active sites, catalysing nitroaromatic reduction via a ping-pong bi bi mechanism.
NTR is of interest in suicide gene therapy, where NTR is used as an activating enzyme for nitroaromatic prodrugs. The hydroxylamines produced can target proteins and DNA, causing strand cleavage in the latter. They can also be further activated to produce DNA cross-linking agents.
MechansimNADH transfers a hydride to N5 of FMN, causing a negative charge to build up on N1. This can be stabilised by Lys14 and Lys74. The carbonyl is reformed and the hydride then acts as a nucleophile for attacking the nitro group of the substrate. This produces a dihydroxylamine and FMN. The dihydroxylamine spontaneously rearranges to eliminate water and produce a nitrosyl group. A second molecule of NADH transfers a hydride to FMN with subsequent nucleophilic attack by the hydride on the nitrosyl group to produce a hydroxylamine group.
Reaction

Catalytic Sites for 1ylu

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysA7474macie:sideChainLys74 is thought to stabilise the negative charge on N1 of FMN during its transient reduction. It is also thought to modulate the redox potential of FMN.
LysA1414macie:sideChainLys14 is thought to stabilise the negative charge on N1 of FMN during its transient reduction. It is also thought to modulate the redox potential of FMN.
GluA165165macie:mainChainAmideGlu165 forms a hydrogen bond to N5 of FMN and is thought to increase its oxidative power.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysB7474macie:sideChainLys74 is thought to stabilise the negative charge on N1 of FMN during its transient reduction. It is also thought to modulate the redox potential of FMN.
LysB1414macie:sideChainLys14 is thought to stabilise the negative charge on N1 of FMN during its transient reduction. It is also thought to modulate the redox potential of FMN.
GluB165165macie:mainChainAmideGlu165 forms a hydrogen bond to N5 of FMN and is thought to increase its oxidative power.

Literature References

Notes:
Race PR
Structural and mechanistic studies of Escherichia coli nitroreductase with the antibiotic nitrofurazone. Reversed binding orientations in different redox states of the enzyme.
J Biol Chem 2005 280 13256-13264
PubMed: 15684426
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