1.5.1.33: pteridine reductase
This is an abbreviated version!
For detailed information about pteridine reductase, go to the full flat file.
Word Map on EC 1.5.1.33
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1.5.1.33
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leishmania
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dihydrofolate
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trypanosoma
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antileishmanial
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antifolate
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promastigotes
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leishmaniasis
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trypanosomatids
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pterins
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donovani
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amastigotes
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trypanosomiasis
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dhfr-t
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trypanothione
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reductase-thymidylate
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tarentolae
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dihydrobiopterin
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glucantime
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medicine
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drug development
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pharmacology
- 1.5.1.33
- leishmania
- dihydrofolate
- trypanosoma
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antileishmanial
- antifolate
- promastigotes
- leishmaniasis
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trypanosomatids
- pterins
- donovani
- amastigotes
- trypanosomiasis
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dhfr-t
- trypanothione
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reductase-thymidylate
- tarentolae
- dihydrobiopterin
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glucantime
- medicine
- drug development
- pharmacology
Reaction
Synonyms
Atu1130, EC 1.1.1.253, H region methotrexate resistance protein, LaPTR1, LbPTR1, LdPTR1, LmPTR1, LpPTR1, More, NADPH-dependent short-chain dehydrogenase/reductase pteridine reductase, NADPH-dihydropteridine reductase, PruA, pteridine reductase, pteridine reductase 1, pteridine reductase I, PTR1, reductase, dihydropteridine (reduced nicotinamide adenine dinucleotide phosphate), Tb-PR, TbPTR1, tcptr1
ECTree
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General Information
General Information on EC 1.5.1.33 - pteridine reductase
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evolution
malfunction
metabolism
physiological function
additional information
PTR1 is a NADPH-dependent enzyme belonging to the short-chain dehydrogenase/reductase (SDR) family
evolution
PTR1 is a short-chain dehydrogenase reductase family member. The trypanosomatid PTR1s are structurally very similar, sequence comparisons
evolution
PTR2 is a short-chain dehydrogenase reductase family member. In Trypanosoma cruzi, TcPTR1 and TcPTR2 are isoforms that show very high sequence homology but also display varied enzymatic activity. TcPTR1 in comparison to TcPTR2 shows higher activity with biopterin and folate than with H2F or H2B
evolution
the enzyme belong to the short-chain dehydrogenase/reductase (SDR) family of enzymes. Despite the overall low sequence identity among members of the SDR family (about 15-30%), a central catalytic YX3K motif is highly conserved, as is an N-terminal glycine motif (TGX3GXG), involved in cofactor binding and recognition. The pteridine reductases in the SDR family have an arginine in place of the glycine at position 6 in this motif (TGX3RXG)
evolution
the enzyme belong to the short-chain dehydrogenase/reductase (SDR) family of enzymes. Despite the overall low sequence identity among members of the SDR family (about 15-30%), a central catalytic YX3K motif is highly conserved, as is an N-terminal glycine motif (TGX3GXG), involved in cofactor binding and recognition. The pteridine reductases in the SDR family have an arginine in place of the glycine at position 6 in this motif (TGX3RXG)
evolution
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the enzyme belong to the short-chain dehydrogenase/reductase (SDR) family of enzymes. Despite the overall low sequence identity among members of the SDR family (about 15-30%), a central catalytic YX3K motif is highly conserved, as is an N-terminal glycine motif (TGX3GXG), involved in cofactor binding and recognition. The pteridine reductases in the SDR family have an arginine in place of the glycine at position 6 in this motif (TGX3RXG)
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evolution
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the enzyme belong to the short-chain dehydrogenase/reductase (SDR) family of enzymes. Despite the overall low sequence identity among members of the SDR family (about 15-30%), a central catalytic YX3K motif is highly conserved, as is an N-terminal glycine motif (TGX3GXG), involved in cofactor binding and recognition. The pteridine reductases in the SDR family have an arginine in place of the glycine at position 6 in this motif (TGX3RXG)
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comparisons of isogenic lines shows that ptr1-null mutants are 18fold more sensitive to H2O2 than PTR1-overproducing lines, and significant 3-5fold differences are seen with a broad panel of oxidant-inducing agents
malfunction
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impossible to generate PTR1 null mutants. RNA interference results in complete knockdown of endogenous protein after 48 h, followed by cell death after 4 days. Lethal phenotype is reversed by expression of PTR1 in RNAi lines or by addition of tetrahydrobiopterin to cultures. Loss of PTR1 is associated with gross morphological changes due to a defect in cytokinesis, resulting in cells with multiple nuclei and kinetoplasts, as well as multiple detached flagella. Electron microscopy also reveal increased numbers of glycosomes, while immunofluorescence microscopy show increased and more diffuse staining for glycosomal matrix enzymes, indicative of mis-localisation to the cytosol. RNAi cell lines are markedly less virulent than wild-type parasites in mice
malfunction
Leishmania can survive without copies of either DHFR-TS or PTR1 but not without both. Leishmania is pterin auxotroph but a PTR1 knockout cell will grow well if sufficient reduced pterins are available
malfunction
the mutant DELTApruA strain exhibits elevated biofilm formation and abundant polysaccharide production independent of surface contact. The plasmid-borne expression of wild-type PruA fully corrects this deficiency, while a plasmid-encoded PruA Y163A mutant variant expressed in the DELTApruA strain has no effect on these DELTApruA mutant phenotypes, with its phenotype appearing similar to the phenotype of the deletion strain alone
malfunction
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Leishmania can survive without copies of either DHFR-TS or PTR1 but not without both. Leishmania is pterin auxotroph but a PTR1 knockout cell will grow well if sufficient reduced pterins are available
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malfunction
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the mutant DELTApruA strain exhibits elevated biofilm formation and abundant polysaccharide production independent of surface contact. The plasmid-borne expression of wild-type PruA fully corrects this deficiency, while a plasmid-encoded PruA Y163A mutant variant expressed in the DELTApruA strain has no effect on these DELTApruA mutant phenotypes, with its phenotype appearing similar to the phenotype of the deletion strain alone
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malfunction
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the mutant DELTApruA strain exhibits elevated biofilm formation and abundant polysaccharide production independent of surface contact. The plasmid-borne expression of wild-type PruA fully corrects this deficiency, while a plasmid-encoded PruA Y163A mutant variant expressed in the DELTApruA strain has no effect on these DELTApruA mutant phenotypes, with its phenotype appearing similar to the phenotype of the deletion strain alone
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folates are reduced in Leishmania by the bifunctional dihydrofolate reductase thymidylate synthase (DHFR-TS) and by pteridine reductase (PTR1)
metabolism
key enzymes involved in trypanosome folate metabolism are dihydrofolate reductase (DHFR) and pteridine reductase (PTR1)
metabolism
key enzymes involved in trypanosome folate metabolism are dihydrofolate reductase (DHFR) and pteridine reductase (PTR1)
metabolism
traditional antifolates, such as methotrexate (MTX) inhibiting DHFR, are poorly effective towards trypanosome parasites because of the metabolic bypass provided by PTR1 also catalyzing folate reduction in addition to the conversion of biopterin to 7,8-dihydrobiopterin (DHB) and subsequently to 5,6,7,8-tetrahydrobiopterin (THB)
metabolism
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folates are reduced in Leishmania by the bifunctional dihydrofolate reductase thymidylate synthase (DHFR-TS) and by pteridine reductase (PTR1)
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using treatment with H2O2 as the selective pressure PTR1 is identified as a mediator of susceptibility to oxidative stress. Oxidant resistance depends upon reduced unconjugated pteridines and PTR1-derived pteridines can modulate oxidant susceptibility
physiological function
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the enzyme has an essential and dual role in pterin metabolism
physiological function
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the enzyme has an essential and dual role in pterin metabolism
physiological function
the enzyme is able to reduce both unconjugated and conjugated pterins and provides a metabolic bypass to alleviate a dihydrofolate reductase inhibition
physiological function
the enzyme is able to reduce both unconjugated and conjugated pterins and provides a metabolic bypass to alleviate a dihydrofolate reductase inhibition
physiological function
the enzyme participates in the salvage of pteridines, which are essential to maintain growth of Leishmania
physiological function
the enzyme participates in the salvage of pteridines, which are essential to maintain growth of Leishmania
physiological function
the enzyme participates in the salvage of pteridines, which are essential to maintain growth of Leishmania
physiological function
the enzyme participates in the salvage of pteridines, which are essential to maintain growth of Leishmania
physiological function
biofilms are complex multicellular communities that are formed by diverse bacteria. In the plant pathogen Agrobacterium tumefaciens, the transition from a free-living motile state to a nonmotile biofilm state is governed by a novel signaling pathway involving small molecules called pterins. Involvement of pterins in biofilm formation. PruA pteridine reductase is involved in the signaling pathway. The enzymatic activity of PruA is essential for the proposed pterin-dependent regulatory pathway. Wild-type Agrobacterium tumefaciens exhibits basal levels of biofilm formation in laboratory culture and forms pale orange or white colonies when grown on solid growth medium supplemented with Congo red. PruA is an important factor in controlling the motile-to-sessile transition in Agrobacterium tumefaciens
physiological function
in addition to folate reduction, PTR1 also catalyzes the conversion of biopterin to 7,8-dihydrobiopterin (DHB) and subsequently to 5,6,7,8-tetrahydrobiopterin (THB). Under dihydrofolate reductase (DHFR, EC 1.5.1.3) inhibition, PTR1 is upregulated providing reduced folates necessary for parasite survival
physiological function
pteridine reductase 1 (PTR1) has the ability to catalyze the NADPH-dependent two-stage reduction of biopterins to their 7,8-dihydro and 5,6,7,8-tetrahydro forms as well as folates to their H2F and H4F forms. PTR1 is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of dihydrofolate reductase (DHFR, EC 1.5.1.3) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo
physiological function
pteridine reductase 1 (PTR1, EC 1.5.1.33) has the ability to catalyze the NADPH-dependent two-stage reduction of biopterins to their 7,8-dihydro and 5,6,7,8-tetrahydro forms as well as folates to their H2F and H4F forms. PTR1 is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of dihydrofolate reductase (DHFR) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo. In Trypanosoma cruzi, TcPTR1 and TcPTR2 are isoforms that show very high sequence homology but also display varied enzymatic activity. TcPTR1 in comparison to TcPTR2 shows higher activity with biopterin and folate than with dihydrofolate or dihydrobiopterin
physiological function
PTR1 is essential in the absence of an intact bifunctional dihydrofolate reductase thymidylate synthase (DHFR-TS) even in the presence of flavin-dependent bacterial TS gene ThyX or thymidine supplementation, indicating the essential role of reduced pterins or folate beyond thymidine synthesis
physiological function
PTR1 produces tetrahydrobiopterin (H4BPt) from dihydrobiopterin (H2BPt) or from fully oxidized biopterin (BPt) scavenged from host cells
physiological function
the enzyme plays a critical role in the pterin metabolic pathway that is absolutely essential for the parasite's survival in the human host
physiological function
the enzyme plays a critical role in the pterin metabolic pathway that is absolutely essential for the parasite's survival in the human host
physiological function
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PTR1 is essential in the absence of an intact bifunctional dihydrofolate reductase thymidylate synthase (DHFR-TS) even in the presence of flavin-dependent bacterial TS gene ThyX or thymidine supplementation, indicating the essential role of reduced pterins or folate beyond thymidine synthesis
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physiological function
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biofilms are complex multicellular communities that are formed by diverse bacteria. In the plant pathogen Agrobacterium tumefaciens, the transition from a free-living motile state to a nonmotile biofilm state is governed by a novel signaling pathway involving small molecules called pterins. Involvement of pterins in biofilm formation. PruA pteridine reductase is involved in the signaling pathway. The enzymatic activity of PruA is essential for the proposed pterin-dependent regulatory pathway. Wild-type Agrobacterium tumefaciens exhibits basal levels of biofilm formation in laboratory culture and forms pale orange or white colonies when grown on solid growth medium supplemented with Congo red. PruA is an important factor in controlling the motile-to-sessile transition in Agrobacterium tumefaciens
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physiological function
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biofilms are complex multicellular communities that are formed by diverse bacteria. In the plant pathogen Agrobacterium tumefaciens, the transition from a free-living motile state to a nonmotile biofilm state is governed by a novel signaling pathway involving small molecules called pterins. Involvement of pterins in biofilm formation. PruA pteridine reductase is involved in the signaling pathway. The enzymatic activity of PruA is essential for the proposed pterin-dependent regulatory pathway. Wild-type Agrobacterium tumefaciens exhibits basal levels of biofilm formation in laboratory culture and forms pale orange or white colonies when grown on solid growth medium supplemented with Congo red. PruA is an important factor in controlling the motile-to-sessile transition in Agrobacterium tumefaciens
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additional information
active site structure of TbPTR1, overview
additional information
active-site structure analysis using computational docking and virtual screening techniques. Active site structure comparisons of Tb-PR (PDB ID 3JQ9) with Leishmania major pteridine reductase (Lm-PR). The size of substrate binding cleft is reduced in TbPTR1 due to differences in specific amino acids, the presence of Trp221, adjustment of the beta6-alpha6 loop. Formation of the triad is due to the presence of Cys168, C-terminal carboxyl group and His267 in TbPTR1, detailed overview
additional information
active-site structure analysis using computational docking and virtual screening techniques. Active site structure comparisons of Trypanosoma brucei pteridine reductase Tb-PR (PDB ID 3JQ9) with Lm-PR. The size of substrate binding cleft is reduced in TbPTR1 due to differences in specific amino acids, the presence of Trp221, adjustment of the beta6-alpha6 loop. Formation of the triad is due to the presence of Cys168, C-terminal carboxyl group and His267 in TbPTR1, detailed overview
additional information
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active-site structure analysis using computational docking and virtual screening techniques. Active site structure comparisons of Trypanosoma brucei pteridine reductase Tb-PR (PDB ID 3JQ9) with Lm-PR. The size of substrate binding cleft is reduced in TbPTR1 due to differences in specific amino acids, the presence of Trp221, adjustment of the beta6-alpha6 loop. Formation of the triad is due to the presence of Cys168, C-terminal carboxyl group and His267 in TbPTR1, detailed overview
additional information
enzyme structure modelling, residue Y163 is involved in catalysis
additional information
isozyme TcPTR1 has no crystal structure, so for this study a structure is calculated using homology modeling with TcPTR2 as a template
additional information
pterin and folate substrates, along with inhibitors, interact with PTR1 complexes quite similarly, often via binding in a Pi-sandwich between the NADPH nicotinamide ring and residue Phe97. The NADPH cofactor is known to be essential in creating both the substrate binding site as well as the catalytic center. Arg14, Ser95, Phe97, Asp161, and Tyr174 are important residues that interact with the folate and pterin substrates
additional information
the critical proton donor in the reaction is a tyrosine residue which is part of a highly conserved YX3K motif, Tyr 194 and Lys 198 in Leishmania major PTR1
additional information
the substrate-binding domain of LmPTR1 is characterized by a considerable degree of lipophilicity, especially in a part mainly made up by hydrophobic amino acids like Tyr, Phe, Leu, or Val. The NADPH/NADP+-binding part of the catalytic site, on the other hand, is characterized by more hydrophilic amino acids and more polar properties overall. Due to the close vicinity of the co-substrate and substrate binding sites, the co-substrate NADPH/NADP+ may also contribute to the properties of the substrate cavity, introducing the possibility of polar interactions with a ligand bound in the folic acid binding site
additional information
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the substrate-binding domain of LmPTR1 is characterized by a considerable degree of lipophilicity, especially in a part mainly made up by hydrophobic amino acids like Tyr, Phe, Leu, or Val. The NADPH/NADP+-binding part of the catalytic site, on the other hand, is characterized by more hydrophilic amino acids and more polar properties overall. Due to the close vicinity of the co-substrate and substrate binding sites, the co-substrate NADPH/NADP+ may also contribute to the properties of the substrate cavity, introducing the possibility of polar interactions with a ligand bound in the folic acid binding site
additional information
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enzyme structure modelling, residue Y163 is involved in catalysis
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additional information
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enzyme structure modelling, residue Y163 is involved in catalysis
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