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Literature summary for 1.5.1.3 extracted from

  • Srinivasan, B.; Skolnick, J.
    Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors (2015), FEBS J., 282, 1922-1938 .
    View publication on PubMedView publication on EuropePMC

Application

Application Comment Organism
drug development the enzyme represents an attractive target for inhibitor design to disrupt systems that require rapid DNA turnover, e.g. proliferating cancer cells and pathogenic microbes Escherichia coli

Inhibitors

Inhibitors Comment Organism Structure
1-(4-nitrophenyl)-3-[4-[4-[(4-nitrophenyl)carbamoylamino]phenoxy]phenyl]urea NSC80735, complete inhibition at 1 mM Escherichia coli
1-N,4-N-bis(4-aminophenyl)benzene-1,4-dicarboxamide NSC55152, complete inhibition at 1 mM Escherichia coli
11H-benzo[b][1]benzazepine NSC123458, 87% inhibition at 1 mM Escherichia coli
6,7-bis(4-aminophenyl)pteridine-2,4-diamine NSC61642 Escherichia coli
7-[(4-aminophenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine NSC309401, AMPQD, a substrate analogue with the quinazoline-1, 3-diamine group, tight-binding inhibitor, complete inhibition at 1 mM, competitive inhibition of dihydrofolate binding. Potently inhibits the enzyme by competitive displacement of the substrate dihydrofolic acid, uncompetitive inhibition versus NADPH, the inhibitor has a markedly increased affinity for the NADPH-bound form of the enzyme. The mode of binding of the inhibitor to the enzyme-NADPH binary complex conforms to the slow-onset, tight-binding model Escherichia coli
7H-pyrrolo(3,2-f)quinazoline-1,3-diamine NSC339578 Escherichia coli
7H-pyrrolo[3,2-f]quinazoline-1,3-diamine PQD, the lack of (4-aminophenyl)-methyl group at position 7 abolishes the slow-onset of inhibition Escherichia coli
methotrexate NSC740 Escherichia coli
methylbenzoprim NSC382035 Escherichia coli
additional information 7H-pyrrolo(3,2-f) quinazoline-1, 3-diamine (PQD) inhibition kinetics, overview Escherichia coli
pemetrexed NSC698037 Escherichia coli
pralatrexate NSC754230 Escherichia coli

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
additional information Michaelis-Menten kinetics Escherichia coli

Natural Substrates/ Products (Substrates)

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

Organism

Organism UniProt Comment Textmining
Escherichia coli P0ABQ4
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
7,8-dihydrofolate + NADPH + H+
-
Escherichia coli 5,6,7,8-tetrahydrofolate + NADP+
-
r

Synonyms

Synonyms Comment Organism
DHFR
-
Escherichia coli

Cofactor

Cofactor Comment Organism Structure
NADP+
-
Escherichia coli
NADPH
-
Escherichia coli

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
additional information
-
additional information inhibition kinetics, overview Escherichia coli
0.00000742
-
7-[(4-aminophenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine pH 7.3, 22°C Escherichia coli