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  • Kimuda, M.P.; Laming, D.; Hoppe, H.C.; Tastan Bishop, Oe.
    Identification of novel potential inhibitors of pteridine reductase 1 in Trypanosoma brucei via computational structure-based approaches and in vitro inhibition assays (2019), Molecules, 24, 142 .
    View publication on PubMedView publication on EuropePMC

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.3 additional information successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR) and Trypanosoma brucei pteridine reductase 1 (TbPTR1, EC 1.5.1.33) has implications in the exploitation of anti-folates. Molecular docking of a ligand library of 5742 compounds against TbPTR1 and identification of compounds showing promising binding modes. The protein-ligand complexes are subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. Five compounds show low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Docking study with TbPTR1 and comparison with Trypanosoma cruzi PTR2, moleuclar dynamics, overview Trypanosoma brucei brucei
1.5.1.3 additional information successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR) and Trypanosoma brucei pteridine reductase 1 (TbPTR1, EC 1.5.1.33) has implications in the exploitation of anti-folates. Molecular docking of a ligand library of 5742 compounds against TbPTR1 and identification of compounds showing promising binding modes. The protein-ligand complexes are subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. Five compounds show low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Docking study with TbPTR1 and comparison with Trypanosoma cruzi PTR2, moleuclar dynamics, overview Trypanosoma cruzi
1.5.1.3 SANC00368
-
 Trypanosoma brucei brucei
1.5.1.3 SANC00368
-
 Trypanosoma cruzi
1.5.1.3 SANC00470
-
 Trypanosoma brucei brucei
1.5.1.3 SANC00470
-
 Trypanosoma cruzi
1.5.1.3 WR99210 a known TbDHFR inhibitor Trypanosoma brucei brucei
1.5.1.3 WR99210 a known TbDHFR inhibitor Trypanosoma cruzi
1.5.1.3 ZINC00057846
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC00057846
-
 Trypanosoma cruzi
1.5.1.3 ZINC00359797
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC00359797
-
 Trypanosoma cruzi
1.5.1.3 ZINC0058117
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC0058117
-
 Trypanosoma cruzi
1.5.1.3 ZINC00612219
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC00612219
-
 Trypanosoma cruzi
1.5.1.3 ZINC00630525
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC00630525
-
 Trypanosoma cruzi
1.5.1.3 ZINC00677623
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC00677623
-
 Trypanosoma cruzi
1.5.1.3 ZINC00809143
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC00809143
-
 Trypanosoma cruzi
1.5.1.3 ZINC01003765
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC01003765
-
 Trypanosoma cruzi
1.5.1.3 ZINC02177983
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC02177983
-
 Trypanosoma cruzi
1.5.1.3 ZINC02184332
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC02184332
-
 Trypanosoma cruzi
1.5.1.3 ZINC02690799
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC02690799
-
 Trypanosoma cruzi
1.5.1.3 ZINC04313814
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC04313814
-
 Trypanosoma cruzi
1.5.1.3 ZINC04523829
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC04523829
-
 Trypanosoma cruzi
1.5.1.3 ZINC04671320
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC04671320
-
 Trypanosoma cruzi
1.5.1.3 ZINC06556964
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC06556964
-
 Trypanosoma cruzi
1.5.1.3 ZINC08992677
-
 Trypanosoma brucei brucei
1.5.1.3 ZINC08992677
-
 Trypanosoma cruzi
1.5.1.33 additional information successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR, EC 1.5.1.3) and Trypanosoma brucei pteridine reductase 1 (TbPTR1) has implications in the exploitation of anti-folates. Molecular docking of a ligand library of 5742 compounds against TbPTR1 and identification of compounds showing promising binding modes. The protein-ligand complexes are subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. Five compounds show low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Docking study with TbPTR1 and comparison with Trypanosoma cruzi PTR2, molecular dynamics, overview Trypanosoma brucei brucei
1.5.1.33 additional information successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR, EC 1.5.1.3) and Trypanosoma brucei pteridine reductase 1 (TbPTR1) has implications in the exploitation of anti-folates. Molecular docking of a ligand library of 5742 compounds against TbPTR1 and identification of compounds showing promising binding modes. The protein-ligand complexes are subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. Five compounds show low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Docking study with TbPTR1 and comparison with Trypanosoma cruzi PTR2, molecular dynamics, overview Trypanosoma cruzi
1.5.1.33 SANC00368
-
 Trypanosoma brucei brucei
1.5.1.33 SANC00368
-
 Trypanosoma cruzi
1.5.1.33 SANC00470
-
 Trypanosoma brucei brucei
1.5.1.33 SANC00470
-
 Trypanosoma cruzi
1.5.1.33 ZINC00057846
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC00057846
-
 Trypanosoma cruzi
1.5.1.33 ZINC00359797
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC00359797
-
 Trypanosoma cruzi
1.5.1.33 ZINC0058117 i.e. SANC00320, eriodictyol Trypanosoma brucei brucei
1.5.1.33 ZINC0058117 i.e. SANC00320, eriodictyol Trypanosoma cruzi
1.5.1.33 ZINC00612219
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC00612219
-
 Trypanosoma cruzi
1.5.1.33 ZINC00630525
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC00630525
-
 Trypanosoma cruzi
1.5.1.33 ZINC00677623
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC00677623
-
 Trypanosoma cruzi
1.5.1.33 ZINC00809143
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC00809143
-
 Trypanosoma cruzi
1.5.1.33 ZINC01003765
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC01003765
-
 Trypanosoma cruzi
1.5.1.33 ZINC02177983
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC02177983
-
 Trypanosoma cruzi
1.5.1.33 ZINC02184332
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC02184332
-
 Trypanosoma cruzi
1.5.1.33 ZINC02690799
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC02690799
-
 Trypanosoma cruzi
1.5.1.33 ZINC04313814
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC04313814
-
 Trypanosoma cruzi
1.5.1.33 ZINC04523829
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC04523829
-
 Trypanosoma cruzi
1.5.1.33 ZINC04671320
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC04671320
-
 Trypanosoma cruzi
1.5.1.33 ZINC06556964
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC06556964
-
 Trypanosoma cruzi
1.5.1.33 ZINC08992677
-
 Trypanosoma brucei brucei
1.5.1.33 ZINC08992677
-
 Trypanosoma cruzi

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.5.1.3 7,8-dihydrofolate + NADPH + H+ Trypanosoma cruzi
-
 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
1.5.1.3 7,8-dihydrofolate + NADPH + H+ Trypanosoma brucei brucei
-
 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
1.5.1.3 folate + NADPH + H+ Trypanosoma cruzi
-
 7,8-dihydrofolate + NADP+
-
 ?
1.5.1.3 folate + NADPH + H+ Trypanosoma brucei brucei
-
 7,8-dihydrofolate + NADP+
-
 ?
1.5.1.33 7,8-dihydrobiopterin + NADPH + H+ Trypanosoma brucei brucei
-
 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?
1.5.1.33 7,8-dihydrofolate + NADPH + H+ Trypanosoma cruzi
-
 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
1.5.1.33 biopterin + NADPH + H+ Trypanosoma brucei brucei
-
 7,8-dihydrobiopterin + NADP+
-
 ?
1.5.1.33 folate + NADPH + H+ Trypanosoma cruzi
-
 7,8-dihydrofolate + NADP+
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.3 Trypanosoma brucei brucei Q27783
-
-
1.5.1.3 Trypanosoma cruzi O44029
-
-
1.5.1.33 Trypanosoma brucei brucei O76290
-
-
1.5.1.33 Trypanosoma cruzi O44029
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.3 7,8-dihydrofolate + NADPH + H+
-
 Trypanosoma cruzi 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
1.5.1.3 7,8-dihydrofolate + NADPH + H+
-
 Trypanosoma brucei brucei 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
1.5.1.3 folate + NADPH + H+
-
 Trypanosoma cruzi 7,8-dihydrofolate + NADP+
-
 ?
1.5.1.3 folate + NADPH + H+
-
 Trypanosoma brucei brucei 7,8-dihydrofolate + NADP+
-
 ?
1.5.1.33 7,8-dihydrobiopterin + NADPH + H+
-
 Trypanosoma brucei brucei 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?
1.5.1.33 7,8-dihydrofolate + NADPH + H+
-
 Trypanosoma cruzi 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
1.5.1.33 biopterin + NADPH + H+
-
 Trypanosoma brucei brucei 7,8-dihydrobiopterin + NADP+
-
 ?
1.5.1.33 folate + NADPH + H+
-
 Trypanosoma cruzi 7,8-dihydrofolate + NADP+
-
 ?

Subunits

EC Number Subunits Comment Organism
1.5.1.33 homotetramer PTR1 is a homotetramer with four equivalent active sites and four NADPH binding sites. Each single alpha/beta-domain subunit is constructed around an NADPH binding Rossman-fold repeat that is composed of seven parallel beta-sheets that are between three alpha-helices on either side Trypanosoma brucei brucei

Synonyms

EC Number Synonyms Comment Organism
1.5.1.3 DHFR
-
 Trypanosoma cruzi
1.5.1.3 DHFR
-
 Trypanosoma brucei brucei
1.5.1.3 dihydrofolate reductase
-
 Trypanosoma cruzi
1.5.1.3 dihydrofolate reductase
-
 Trypanosoma brucei brucei
1.5.1.3 tcptr1
-
 Trypanosoma cruzi
1.5.1.33 pteridine reductase 1
-
 Trypanosoma brucei brucei
1.5.1.33 pteridine reductase 1
-
 Trypanosoma cruzi
1.5.1.33 PTR1
-
 Trypanosoma brucei brucei
1.5.1.33 PTR1
-
 Trypanosoma cruzi
1.5.1.33 tcptr1
-
 Trypanosoma cruzi

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.3 NADPH
-
 Trypanosoma cruzi
1.5.1.3 NADPH
-
 Trypanosoma brucei brucei
1.5.1.33 NADPH dependent on Trypanosoma brucei brucei
1.5.1.33 NADPH dependent on Trypanosoma cruzi

General Information

EC Number General Information Comment Organism
1.5.1.3 evolution PTR1 is a short-chain dehydrogenase reductase family member. The trypanosomatid PTR1s are structurally very similar, sequence comparisons Trypanosoma brucei brucei
1.5.1.3 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 Trypanosoma cruzi
1.5.1.3 metabolism key enzymes involved in trypanosome folate metabolism are dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) Trypanosoma cruzi
1.5.1.3 metabolism key enzymes involved in trypanosome folate metabolism are dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) Trypanosoma brucei brucei
1.5.1.3 additional information isozyme TcPTR1 has no crystal structure, so for this study a structure is calculated using homology modeling with TcPTR2 as a template Trypanosoma cruzi
1.5.1.3 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 Trypanosoma brucei brucei
1.5.1.3 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 Trypanosoma brucei brucei
1.5.1.3 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 Trypanosoma cruzi
1.5.1.33 evolution PTR1 is a short-chain dehydrogenase reductase family member. The trypanosomatid PTR1s are structurally very similar, sequence comparisons Trypanosoma brucei brucei
1.5.1.33 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 Trypanosoma cruzi
1.5.1.33 metabolism key enzymes involved in trypanosome folate metabolism are dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) Trypanosoma brucei brucei
1.5.1.33 metabolism key enzymes involved in trypanosome folate metabolism are dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) Trypanosoma cruzi
1.5.1.33 additional information isozyme TcPTR1 has no crystal structure, so for this study a structure is calculated using homology modeling with TcPTR2 as a template Trypanosoma cruzi
1.5.1.33 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 Trypanosoma brucei brucei
1.5.1.33 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 Trypanosoma brucei brucei
1.5.1.33 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 Trypanosoma cruzi