Any feedback?
Please rate this page
(literature.php)
(0/150)

BRENDA support

Literature summary extracted from

  • Kumar, V.P.; Cisneros, J.A.; Frey, K.M.; Castellanos-Gonzalez, A.; Wang, Y.; Gangjee, A.; White, A.C.; Jorgensen, W.L.; Anderson, K.S.
    Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase (2014), Bioorg. Med. Chem. Lett., 24, 4158-4161 .
    View publication on PubMedView publication on EuropePMC

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
1.5.1.3 co-crystallization of the purified enzyme with inhibitor 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid and FdUMP in the TS site and NADPH and methotrexate in the DHFR site, X-ray diffraction structure determination and analysis at 3.45 A resolution, PDB ID 4Q0D Cryptosporidium hominis
2.1.1.45 co-crystallization of the purified enzyme with inhibitor 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid and FdUMP in the TS site and NADPH and methotrexate in the DHFR site, X-ray diffraction structure determination and analysis at 3.45 A resolution, PDB ID 4Q0D Cryptosporidium hominis

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.3 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid potent enzyme inhibitor with anti-cryptosporidial activity in cell culture, chemical synthesis, overview. The inhibitor forms several hydrogen bonds and van der Waals interactions with the DHFR active site residues, binding close to the nicotinamide ring of NADPH. The carbonyl oxygens of the catalytic D32 hydrogen bond with N3 of the inhibitor forming a fork that holds the inhibitor in optimal position bound to the enzyme Cryptosporidium hominis
1.5.1.3 FdUMP
-
 Cryptosporidium hominis
1.5.1.3 methotrexate
-
 Cryptosporidium hominis
2.1.1.45 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid potent enzyme inhibitor with anti-cryptosporidial activity in cell culture, chemical synthesis, overview. The inhibitor forms several hydrogen bonds and van der Waals interactions with the DHFR active site residues, binding close to the nicotinamide ring of NADPH. The carbonyl oxygens of the catalytic D32 hydrogen bond with N3 of the inhibitor forming a fork that holds the inhibitor in optimal position bound to the enzyme Cryptosporidium hominis
2.1.1.45 FdUMP
-
 Cryptosporidium hominis
2.1.1.45 methotrexate
-
 Cryptosporidium hominis

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+ Cryptosporidium hominis
-
 5,6,7,8-tetrahydrofolate + NADP+
-
 r
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP Cryptosporidium hominis
-
 dihydrofolate + dTMP
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.3 Cryptosporidium hominis Q27552
-
-
2.1.1.45 Cryptosporidium hominis A0A0S4TER9
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.3 7,8-dihydrofolate + NADPH + H+
-
 Cryptosporidium hominis 5,6,7,8-tetrahydrofolate + NADP+
-
 r
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP
-
 Cryptosporidium hominis dihydrofolate + dTMP
-
 ?

Synonyms

EC Number Synonyms Comment Organism
1.5.1.3 DFR-TS
-
 Cryptosporidium hominis
1.5.1.3 thymidylate synthase-dihydrofolate reductase
-
 Cryptosporidium hominis
2.1.1.45 DFR-TS
-
 Cryptosporidium hominis
2.1.1.45 thymidylate synthase-dihydrofolate reductase
-
 Cryptosporidium hominis

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.3 NADP+
-
 Cryptosporidium hominis
1.5.1.3 NADPH NADPH binds in an extended form making several hydrophobic and hydrogen bond interactions with the protein residues. The hydrophobic pocket consists of residues V9, A11, L25, I62 and T134 interacting with the pyrrolo[2,3-d]pyrimidine scaffold whereas T40 and F36 interact with the phenyl ring of inhibitor 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid Cryptosporidium hominis