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Information on EC 1.5.1.33 - pteridine reductase
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1.5.1.33 pteridine reductaseIUBMB Comments
The enzyme from Leishmania (both amastigote and promastigote forms) catalyses the reduction by NADPH of folate and a wide variety of unconjugated pterins, including biopterin, to their tetrahydro forms. It also catalyses the reduction of 7,8-dihydropterins and 7,8-dihydrofolate to their tetrahydro forms. In contrast to EC 1.5.1.3 (dihydrofolate reductase) and EC 1.5.1.34 (6,7-dihydropteridine reductase), pteridine reductase will not catalyse the reduction of the quinonoid form of dihydrobiopterin. The enzyme is specific for NADPH; no activity has been detected with NADH. It also differs from EC 1.5.1.3 (dihydrofolate reductase) in being specific for the Si-face of NADPH.
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Word Map
- 1.5.1.33
- leishmania
- dihydrofolate
- trypanosoma
-
antileishmanial
- antifolate
- promastigotes
- leishmaniasis
-
trypanosomatids
- pterins
- donovani
- amastigotes
- trypanosomiasis
-
dhfr-t
- trypanothione
-
reductase-thymidylate
- tarentolae
- dihydrobiopterin
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glucantime
- medicine
- drug development
- pharmacology
The enzyme appears in viruses and cellular organisms
Synonyms
pteridine reductase, pteridine reductase 1, tbptr1, lmptr1, ldptr1, tb-pr, nadph-dihydropteridine reductase, pteridine reductase i, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Atu1130
EC 1.1.1.253
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formerly
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H region methotrexate resistance protein
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LmPTR1
NADPH-dependent short-chain dehydrogenase/reductase pteridine reductase
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NADPH-dihydropteridine reductase
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PruA
pteridine reductase
pteridine reductase 1
pteridine reductase I
PTR1
reductase, dihydropteridine (reduced nicotinamide adenine dinucleotide phosphate)
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Tb-PR
TbPTR1
additional information
pteridine reductase 1
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pteridine reductase 1
broad-spectrum enzyme of pterin and folate metabolism
PTR1
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
5,6,7,8-tetrahydrobiopterin + 2 NADP+ = biopterin + 2 NADPH + 2 H+
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5,6,7,8-tetrahydrobiopterin + 2 NADP+ = biopterin + 2 NADPH + 2 H+
ordered sequential reaction mechanism
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5,6,7,8-tetrahydrobiopterin + 2 NADP+ = biopterin + 2 NADPH + 2 H+
ordered ternary complex mechanism with NADPH binding first and NADP+ dissociating after the reduced pteridine. The enzyme transfers the pro-S hydride of NADPH to carbon 6 on the si face of dihydrofolate
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5,6,7,8-tetrahydrobiopterin + 2 NADP+ = biopterin + 2 NADPH + 2 H+
conserved residue Tyr194 forms hydrogen bonds with the nucleophilic center of the substrate and stabilizes the transition state, conserved residue Lys198 lowers the pKa of the tyrosine, helps to stabilize the transition state, and may function as proton source for the tyrosine
5,6,7,8-tetrahydrobiopterin + 2 NADP+ = biopterin + 2 NADPH + 2 H+
the enzyme exhhibits a ping-pong mechanism
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
KEGG
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SYSTEMATIC NAME
IUBMB Comments
5,6,7,8-tetrahydrobiopterin:NADP+ oxidoreductase
The enzyme from Leishmania (both amastigote and promastigote forms) catalyses the reduction by NADPH of folate and a wide variety of unconjugated pterins, including biopterin, to their tetrahydro forms. It also catalyses the reduction of 7,8-dihydropterins and 7,8-dihydrofolate to their tetrahydro forms. In contrast to EC 1.5.1.3 (dihydrofolate reductase) and EC 1.5.1.34 (6,7-dihydropteridine reductase), pteridine reductase will not catalyse the reduction of the quinonoid form of dihydrobiopterin. The enzyme is specific for NADPH; no activity has been detected with NADH. It also differs from EC 1.5.1.3 (dihydrofolate reductase) in being specific for the Si-face of NADPH.
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CAS REGISTRY NUMBER
COMMENTARY
131384-61-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 biopterin + 3 NADPH + 3 H+
dihydrobiopterin + tetrahydrobiopterin + 3 NADP+
essential enzyme of pterin and folate metabolism
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-
?
2 biopterin + 3 NADPH + 3 H+
dihydrobiopterin + tetrahydrobiopterin + 3 NADP+
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salvage of pterins, enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, PTR1 contributes about 10% of the reduction of folates in wild-type cells while the remaining 90% is due to the activity of dihydrofolate reductase-thymidylate synthase (EC 1.5.1.3)
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-
?
6-biopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
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?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
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-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
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-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
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-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
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-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
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-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
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-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
low activity
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?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
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?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
low activity
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?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
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?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
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?
7,8-dihydromonapterin + NADPH + H+
5,6,7,8-tetrahydromonapterin + NADP+
cf. EC 1.5.1.50, moderate activity
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?
7,8-dihydromonapterin + NADPH + H+
5,6,7,8-tetrahydromonapterin + NADP+
cf. EC 1.5.1.50, moderate activity
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?
7,8-dihydromonapterin + NADPH + H+
5,6,7,8-tetrahydromonapterin + NADP+
cf. EC 1.5.1.50, moderate activity
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?
7,8-dihydroneopterin + NADPH + H+
5,6,7,8-tetrahydroneopterin + NADP+
stereoisomer of biopterin, moderate activity
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?
7,8-dihydroneopterin + NADPH + H+
5,6,7,8-tetrahydroneopterin + NADP+
stereoisomer of biopterin, moderate activity
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?
7,8-dihydroneopterin + NADPH + H+
5,6,7,8-tetrahydroneopterin + NADP+
stereoisomer of biopterin, moderate activity
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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?
biopterin + 2 NADPH + 2 H+
5,6,7,8-tetrahydrobiopterin + 2 NADP+
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substrate binding structure
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?
Biopterin + NADPH
5,6,7,8-Tetrahydrobiopterin + NADP+
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?
Biopterin + NADPH
5,6,7,8-Tetrahydrobiopterin + NADP+
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activity with NADH is less than 5% of the activity with NADPH
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?
Biopterin + NADPH
5,6,7,8-Tetrahydrobiopterin + NADP+
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?
Biopterin + NADPH
5,6,7,8-Tetrahydrobiopterin + NADP+
2-step reaction via intermediate 7,8-dihydrobiopterin
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?
Biopterin + NADPH
5,6,7,8-Tetrahydrobiopterin + NADP+
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no activity with NADH and NADP+
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?
Biopterin + NADPH
5,6,7,8-Tetrahydrobiopterin + NADP+
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no activity with NADH and NADP+
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?
biopterin + NADPH + H+
7,8-dihydrobiopterin + NADP+
best substrate
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?
biopterin + NADPH + H+
7,8-dihydrobiopterin + NADP+
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?
dihydrobiopterin + NADPH
5,6,7,8-tetrahydrobiopterin + NADP+
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r
dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
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?
dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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-
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?
dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
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?
Dihydrofolate + NADPH
5,6,7,8-Tetrahydrofolate + NADP+
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?
folate + NADPH + H+
7,8-dihydrofolate + NADP+
high activity, see also EC 1.5.1.3
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?
folate + NADPH + H+
7,8-dihydrofolate + NADP+
reaction of EC 1.5.1.3
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?
folate + NADPH + H+
7,8-dihydrofolate + tetrahydrofolate + NADP+
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?
folate + NADPH + H+
7,8-dihydrofolate + tetrahydrofolate + NADP+
essential enzyme of pterin and folate metabolism
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?
quinonoid dihydrobiopterin + NADPH + H+
tetrahydrobiopterin + NADP+
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?
quinonoid dihydrobiopterin + NADPH + H+
tetrahydrobiopterin + NADP+
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?
additional information
?
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enzyme PruA does not exhibit pteridine reductase activity with 7,8-dihydrofolate or fully oxidized pterins. PruA exhibits maximal catalytic efficiency with H2BPt, while both H2MPt and 7,8-dihydroneopterin (H2NPt) also serve as competent substrates. Substrate specificity, overview. No activity with 7,8-dihydrofolate, biopterin, and folate
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additional information
?
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enzyme PruA does not exhibit pteridine reductase activity with 7,8-dihydrofolate or fully oxidized pterins. PruA exhibits maximal catalytic efficiency with H2BPt, while both H2MPt and 7,8-dihydroneopterin (H2NPt) also serve as competent substrates. Substrate specificity, overview. No activity with 7,8-dihydrofolate, biopterin, and folate
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additional information
?
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enzyme PruA does not exhibit pteridine reductase activity with 7,8-dihydrofolate or fully oxidized pterins. PruA exhibits maximal catalytic efficiency with H2BPt, while both H2MPt and 7,8-dihydroneopterin (H2NPt) also serve as competent substrates. Substrate specificity, overview. No activity with 7,8-dihydrofolate, biopterin, and folate
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additional information
?
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enzyme is associated with folate metabolism, responsible for salvage of pterins and reduction of folates
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?
additional information
?
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enzyme is associated with folate metabolism, responsible for salvage of pterins and reduction of folates
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?
additional information
?
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NADPH binds first, the enzyme-NADPH complex binds the substrate
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?
additional information
?
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NADPH binds first, the enzyme-NADPH complex binds the substrate
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?
additional information
?
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no activity with quinoid dihydrobiopterin
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?
additional information
?
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primary enzyme mediating pteridine salvage
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?
additional information
?
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the enzyme mediates the synthesis of tetrahydropteridines
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?
additional information
?
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essential for the salvage of pterins
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?
additional information
?
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enzyme PTR1 synthesizes the formation of tetrahydrobiopterin from biopterin via dihydrobiopterin or from the quinoide form dihydrobiopterin, pathway overview
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additional information
?
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enzyme PTR1 synthesizes the formation of tetrahydrobiopterin from biopterin via dihydrobiopterin or from the quinoide form dihydrobiopterin, pathway overview
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additional information
?
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7,8-dihydro-L-biopterin and pyrimethamine (PMA) interact with enzyme residues S112, Y194, L226, and S227, molecular dynamics and docking study, overview
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additional information
?
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7,8-dihydro-L-biopterin and pyrimethamine (PMA) interact with enzyme residues S112, Y194, L226, and S227, molecular dynamics and docking study, overview
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additional information
?
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the enzyme mediates the synthesis of tetrahydropteridines
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?
additional information
?
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enzyme is used by the organism to bypass antifolate inhibition, catalytic pathway
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?
additional information
?
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enzyme is used by the organism to bypass antifolate inhibition, catalytic pathway
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?
additional information
?
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enzyme PTR1 synthesizes the formation of tetrahydrobiopterin from biopterin via dihydrobiopterin or from the quinoide form dihydrobiopterin, pathway overview
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additional information
?
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the enzyme is involved in the resistance to the methotrexate, aminopterin and trimethoprim antifolates
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?
additional information
?
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the enzyme is involved in the resistance to the methotrexate, aminopterin and trimethoprim antifolates
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?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 biopterin + 3 NADPH + 3 H+
dihydrobiopterin + tetrahydrobiopterin + 3 NADP+
essential enzyme of pterin and folate metabolism
-
-
?
2 biopterin + 3 NADPH + 3 H+
dihydrobiopterin + tetrahydrobiopterin + 3 NADP+
-
salvage of pterins, enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, PTR1 contributes about 10% of the reduction of folates in wild-type cells while the remaining 90% is due to the activity of dihydrofolate reductase-thymidylate synthase (EC 1.5.1.3)
-
-
?
6-biopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
best substrate
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+