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Literature summary for 1.5.1.3 extracted from

  • Cody, V.; Pace, J.; Namjoshi, O.; Gangjee, A.
    Structure-activity correlations for three pyrido[2,3-d]pyrimidine antifolates binding to human and Pneumocystis carinii dihydrofolate reductase (2015), Acta Crystallogr. Sect. F, 71, 799-803 .
    View publication on PubMedView publication on EuropePMC

Crystallization (Commentary)

Crystallization (Comment) Organism
purified enzyme complexed with inhibitor N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine, and NADPH, hanging drop vapor diffusion method, mixing of 11.4-14.1 mg/ml protein in 50 mM MES, pH 6.0, 100 ml KCl, and a tenfold excess of NADPH and inhibitor, with reservoir solution containiing 35% PEG 2000, 49 mM MES, pH 6.0, and 100 mM KCl, equilibration against a reservoir solution consisting of 0.1 M HEPES pH 7.5, 25% PEG 2000 MM, X-ray diffraction structure determination and analyis at 1.61 A resolution, modeling Pneumocystis carinii
purified enzyme complexed with inhibitor N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine, and NADPH, X-ray diffraction structure determination and analyis Pneumocystis jirovecii
purified enzyme in ternary complex with inhibitors N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine or N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine, and NADPH, hanging drop vapor diffusion method, mixing of 7.9 mg/ml protein in 100 mM K2HPO4, pH 6.9, and 30% saturated ammonium sufate, and a tenfold excess of NADPH and inhibitor, with reservoir solution consisting of 100 mM K2HPO4, pH 6.9, 60% saturated ammonium sulfate, and 3% v/v ethanol, X-ray diffraction structure determination and analysis at 1.54 A resolution, modeling Homo sapiens

Protein Variants

Protein Variants Comment Organism
F69N site-directed mutagenesis Pneumocystis carinii

Inhibitors

Inhibitors Comment Organism Structure
additional information design and synthesis of a series of bicyclic pyrido[2,3-d]pyrimidines that contain an N6-(substituted phenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine scaffold in which the substituted aniline is directly attached to the 6-position of the pyrido[2,3-d] pyrimidine ring as selective and potent inhibitors of pathogenic sources of dihydrofolate reductase (DHFR) such as Pneumocystis jirovecii, a causative agent of pneumonia in HIV/AIDS patients. Analysis of the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue in the series, N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine with enzyme from Homosapiens, Pneumocystis carinii, and Pneumocystis jirovecii, overview Homo sapiens
additional information design and synthesis of a series of bicyclic pyrido[2,3-d]pyrimidines that contain an N6-(substituted phenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine scaffold in which the substituted aniline is directly attached to the 6-position of the pyrido[2,3-d] pyrimidine ring as selective and potent inhibitors. Analysis of the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue in the series, N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine with enzyme from Homosapiens, Pneumocystis carinii, and Pneumocystis jirovecii, overview Pneumocystis carinii
additional information design and synthesis of a series of bicyclic pyrido[2,3-d]pyrimidines that contain an N6-(substituted phenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine scaffold in which the substituted aniline is directly attached to the 6-position of the pyrido[2,3-d] pyrimidine ring as selective and potent inhibitors of the enzyme. Analysis of the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue in the series, N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine with enzyme from Homosapiens, Pneumocystis carinii, and Pneumocystis jirovecii, overview Pneumocystis jirovecii
N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis, the trifluorophenyl ring occupies a position near the enzyme cofactor-binding site, with close intermolecular contacts with Asp21, Ser59 and Ile60 Homo sapiens
N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis Pneumocystis carinii
N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis Pneumocystis jirovecii
N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis Homo sapiens
N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis Pneumocystis carinii
N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis Pneumocystis jirovecii
N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis Homo sapiens
N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis Pneumocystis carinii
N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine binding complex structure analysis Pneumocystis jirovecii
N6-methyl-N6-phenylpyrido[2,3-d]pyrimidine-2,4,6-triamine
-
Homo sapiens
N6-methyl-N6-phenylpyrido[2,3-d]pyrimidine-2,4,6-triamine
-
Pneumocystis carinii
N6-methyl-N6-phenylpyrido[2,3-d]pyrimidine-2,4,6-triamine
-
Pneumocystis jirovecii
piritrexim
-
Homo sapiens
piritrexim
-
Pneumocystis carinii
piritrexim
-
Pneumocystis jirovecii

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
7,8-dihydrofolate + NADPH + H+ Homo sapiens
-
5,6,7,8-tetrahydrofolate + NADP+
-
r
7,8-dihydrofolate + NADPH + H+ Pneumocystis carinii
-
5,6,7,8-tetrahydrofolate + NADP+
-
r
7,8-dihydrofolate + NADPH + H+ Pneumocystis jirovecii
-
5,6,7,8-tetrahydrofolate + NADP+
-
r

Organism

Organism UniProt Comment Textmining
Homo sapiens P00374
-
-
Pneumocystis carinii P16184
-
-
Pneumocystis jirovecii Q9UUP5
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
7,8-dihydrofolate + NADPH + H+
-
Homo sapiens 5,6,7,8-tetrahydrofolate + NADP+
-
r
7,8-dihydrofolate + NADPH + H+
-
Pneumocystis carinii 5,6,7,8-tetrahydrofolate + NADP+
-
r
7,8-dihydrofolate + NADPH + H+
-
Pneumocystis jirovecii 5,6,7,8-tetrahydrofolate + NADP+
-
r

Synonyms

Synonyms Comment Organism
DHFR
-
Homo sapiens
DHFR
-
Pneumocystis carinii
DHFR
-
Pneumocystis jirovecii
hDHFR
-
Homo sapiens
pcDHFR
-
Pneumocystis carinii
pcDHFR
-
Pneumocystis jirovecii

Cofactor

Cofactor Comment Organism Structure
NADP+
-
Homo sapiens
NADP+
-
Pneumocystis carinii
NADP+
-
Pneumocystis jirovecii
NADPH
-
Homo sapiens
NADPH
-
Pneumocystis carinii
NADPH
-
Pneumocystis jirovecii