Literature summary for 1.5.1.3 extracted from

Bennett, B.C.; Wan, Q.; Ahmad, M.F.; Langan, P.; Dealwis, C.G.
X-ray structure of the ternary MTX-NADPH complex of the anthrax dihydrofolate reductase: a pharmacophore for dual-site inhibitor design (2009), J. Struct. Biol., 166, 162-171.

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Application

Application	Comment	Organism
drug development	DHFR is a valid drug target	Bacillus anthracis

Crystallization (Commentary)

Crystallization (Comment)	Organism
enzyme in ternary complex with NADPH and inhibitor methotrexate, soaking of crystals in 0.1 M Bis-Tris, pH 5.5, 0.2 M CaCl2 and 22.5% w/v PEG 3350 supplemented with 5 mM beta-NADPH at 4°C for 8 h, cryoprotection with 20% v/v glycerol and 5 mM beta-NADPH, X-ray diffraction structure determination and analysis at 2.3 A resolution	Bacillus anthracis

Inhibitors

Inhibitors	Comment	Organism	Structure
2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone) oxime	i.e. 373265, a dual-site inhibitor, that targets both the substrate and cofactor binding site, docking modelling, overview	Bacillus anthracis
6-amino-3-pentadecylphenyl beta-D-glucoside	i.e. 1357, a dual-site inhibitor, that targets both the substrate and cofactor binding site	Bacillus anthracis
methotrexate	-	Bacillus anthracis
additional information	the enzyme from Bacillus anthracis is naturally resistant to trimethoprim, at least in part due to the presence of a Phe96 substitution in the putative trimethoprim binding site of the enzyme. Inhibitor development by virtual screening for dual-site inhibitors, overview	Bacillus anthracis

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
7,8-dihydrofolate + NADPH + H+	Bacillus anthracis	-	5,6,7,8-tetrahydrofolate + NADP+	-	?

Organism

Organism	UniProt	Comment	Textmining
Bacillus anthracis	Q81R22	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
7,8-dihydrofolate + NADPH + H+	-	Bacillus anthracis	5,6,7,8-tetrahydrofolate + NADP+	-	?

Synonyms

Synonyms	Comment	Organism
DHFR	-	Bacillus anthracis

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
25	-	assay at	Bacillus anthracis

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7.1	-	assay at	Bacillus anthracis

Cofactor

Cofactor	Comment	Organism	Structure
NADPH	binding strutcure and conformation, the adenine moiety adopts an off-plane tilt of nearly 90° and this orientation is stabilized by hydrogen bonds to functionally conserved Arg residues, hydrid transfer and structural role in catalytic mechanism, overview	Bacillus anthracis

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
0.0165	-	pH 7.1, 25°C	Bacillus anthracis	6-amino-3-pentadecylphenyl beta-D-glucoside
0.074	-	pH 7.1, 25°C	Bacillus anthracis	2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone) oxime

General Information

General Information	Comment	Organism
physiological function	DHFR is essential for the survival and pathogenesis of anthrax. DHFR is required for de novo DNA synthesis and amino acid synthesis	Bacillus anthracis

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Release 2023.1 (January 2023)