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Literature summary for 1.5.1.3 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
Search for more literature for 1.5.1.3

Crystallization (Commentary)

Crystallization (Comment) Organism
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

Inhibitors Comment Organism Structure
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
FdUMP
-
 Cryptosporidium hominis
methotrexate
-
 Cryptosporidium hominis

Natural Substrates/ Products (Substrates)

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

Organism

Organism UniProt Comment Textmining
Cryptosporidium hominis Q27552
-
-

Substrates and Products (Substrate)

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

Synonyms

Synonyms Comment Organism
DFR-TS
-
 Cryptosporidium hominis
thymidylate synthase-dihydrofolate reductase
-
 Cryptosporidium hominis

Cofactor

Cofactor Comment Organism Structure
NADP+
-
 Cryptosporidium hominis
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