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Catalytic Site Atlas

CSA LITERATURE entry for 2c7v

E.C. namepteridine reductase
SpeciesTrypanosoma brucei brucei ()
E.C. Number (IntEnz) 1.5.1.33
CSA Homologues of 2c7v
CSA Entries With UniProtID O76290
CSA Entries With EC Number 1.5.1.33
PDBe Entry 2c7v
PDBSum Entry 2c7v
MACiE Entry M0237

Literature Report

IntroductionPteridine reductase (TbPTR1), isolated from Trypanosoma brucei, is an NADPH-dependent short-chain reductase. TbPTR1 has broad specificity and can catalyse the reduction of biopterin to 5,6,7,8-tetrahydrobiopterin (THB) and folate to tetrahydrofolate. Both these reactants can be reduced from the oxidised or dihydro-state since the mechanism is a two step reduction by two molecules of NADPH. These reactions are important for the salvage of pteridines from the host and so TbPTR1 is a potential drug target for the treatment of African trypanosomiasis.

MechansimNADPH binds first, followed by biopterin. NADPH transfers a hydride to C7 of biopterin. The N8 position is then protonated by Tyr174, which is part of a proton shuffling system also involving Asp161. The dihydrobiopterin intermediate dissociates, followed by NADP+. A second molecule of NADPH can then bind, followed by the intermediate. The 4-keto function of the intermediate enolises, with Arg14 stabilising the resulting hydroxyl and the phosphate of NADPH acting as a temporary proton acceptor for the N3 proton. NADPH then transfers a hydride to the C6 position and the N5 position is protonated by a water molecule. The latter is activated by interactions with the 4-hydroxyl group and is reprotonated by the 4-hydroxyl, leading to tautomerisation of THB to the keto-form.

Reaction

Catalytic Sites for 2c7v

Annotated By Reference To The Literature - Site 17 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrA174174macie:sideChainTyr174 is part of a proton shuffling system during the first reaction step. It transfers a proton from Asp161 to the N8 position of the pterin.
ArgA1414macie:sideChainArg14 stabilises the enol tautomer of the intermediate, which is better suited for water activation.
AspA161161macie:sideChainAsp161 is part of a proton shuffling system during the first reduction step. It transfers a proton from the solvent to Tyr194.

Annotated By Reference To The Literature - Site 18 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrB174174macie:sideChainTyr174 is part of a proton shuffling system during the first reaction step. It transfers a proton from Asp161 to the N8 position of the pterin.
ArgB1414macie:sideChainArg14 stabilises the enol tautomer of the intermediate, which is better suited for water activation.
AspB161161macie:sideChainAsp161 is part of a proton shuffling system during the first reduction step. It transfers a proton from the solvent to Tyr194.

Annotated By Reference To The Literature - Site 19 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrC174174macie:sideChainTyr174 is part of a proton shuffling system during the first reaction step. It transfers a proton from Asp161 to the N8 position of the pterin.
ArgC1414macie:sideChainArg14 stabilises the enol tautomer of the intermediate, which is better suited for water activation.
AspC161161macie:sideChainAsp161 is part of a proton shuffling system during the first reduction step. It transfers a proton from the solvent to Tyr194.

Annotated By Reference To The Literature - Site 20 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrD174174macie:sideChainTyr174 is part of a proton shuffling system during the first reaction step. It transfers a proton from Asp161 to the N8 position of the pterin.
ArgD1414macie:sideChainArg14 stabilises the enol tautomer of the intermediate, which is better suited for water activation.
AspD161161macie:sideChainAsp161 is part of a proton shuffling system during the first reduction step. It transfers a proton from the solvent to Tyr194.

Literature References

Notes:
Dawson A
Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate.
Mol Microbiol 2006 61 1457-1468
PubMed: 16968221
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