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Literature summary for 1.5.1.3 extracted from

  • Oefner, C.; Parisi, S.; Schulz, H.; Lociuro, S.; Dale, G.E.
    Inhibitory properties and X-ray crystallographic study of the binding of AR-101, AR-102 and iclaprim in ternary complexes with NADPH and dihydrofolate reductase from Staphylococcus aureus (2009), Acta Crystallogr. Sect. D, 65, 751-757.
    View publication on PubMed

Crystallization (Commentary)

Crystallization (Comment) Organism
wild-type enzyme or mutant F98Y in ternary complex with cofactor NADPH and inhibitors AR-101, AR-102, or iclaprim, hanging-drop vapour-diffusion technique at 24°C, mixing of 30 mg/ml protein with 5 mM NADPH and 0.3 mg/ml inhibitor in 25% PEG 3350, 200 mM NaCl, and 100 mM bis-tris, pH 5.5, X-ray diffraction structure determination and analysis at 2.1-2.5 A resolution Staphylococcus aureus

Protein Variants

Protein Variants Comment Organism
F98Y site-directed mutagenesis, the mutant enzyme shows reduced sensitivity to inhibitors compared to the wild-type enzyme, structure comparison to the wild-type, overview Staphylococcus aureus

Inhibitors

Inhibitors Comment Organism Structure
AR-101 i.e. 5-[(2R)-2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-ylmethyl]pyrimidine-2,4-diamine, binding structure from crystal structure, the cyclopropyl-dimethoxychromene moiety interacts with the conserved residues Leu28, Val31, Ile50 and Leu54 forming a hydrophobic pocket in the enzyme Staphylococcus aureus
Ar-102 i.e. 5-[(2S)-2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-ylmethyl]pyrimidine-2,4-diamine, binding structure from crystal structure, the cyclopropyl-dimethoxychromene moiety interacts with the conserved residues Leu28, Val31, Ile50 and Leu54 forming a hydrophobic pocket in the enzyme Staphylococcus aureus
iclaprim binding structure from crystal structure Staphylococcus aureus
trimethoprim
-
Staphylococcus aureus

Organism

Organism UniProt Comment Textmining
Staphylococcus aureus P0A017
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
7,8-dihydrofolate + NADPH + H+ the conserved residues Leu28, Val31, Ile50 and Leu54 forming a hydrophobic pocket in the enzyme are the binding site for the p-aminobenzamide moiety of the substrate dihydrofolate Staphylococcus aureus 5,6,7,8-tetrahydrofolate + NADP+
-
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Synonyms

Synonyms Comment Organism
DHFR
-
Staphylococcus aureus

Cofactor

Cofactor Comment Organism Structure
NADPH
-
Staphylococcus aureus

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.0000002
-
iclaprim wild-type enzyme Staphylococcus aureus
0.00000022
-
Ar-102 wild-type enzyme Staphylococcus aureus
0.00000023
-
AR-101 wild-type enzyme Staphylococcus aureus
0.0000009
-
AR-101 mutant F98Y Staphylococcus aureus
0.0000026
-
iclaprim mutant F98Y Staphylococcus aureus
0.0000035
-
Ar-102 mutant F98Y Staphylococcus aureus
0.000006
-
trimethoprim wild-type enzyme Staphylococcus aureus
0.0001
-
trimethoprim mutant F98Y Staphylococcus aureus