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EC Number

Catalytic Site Atlas

CSA LITERATURE entry for 1ra2

E.C. namedihydrofolate reductase
SpeciesEscherichia coli (Bacteria)
E.C. Number (IntEnz)
CSA Homologues of 1ra2There are 58 Homologs
CSA Entries With UniProtID P0ABQ4
CSA Entries With EC Number
PDBe Entry 1ra2
PDBSum Entry 1ra2
MACiE Entry 1ra2

Literature Report

IntroductionMuch interest has been generated in this enzyme due to its potential as a target for antibacterial and anticancer drugs. Being involved in the reduction of folate to tetrahydrofolate, it is essential in the synthesis of purines and thymidylate for DNA. It is ubiquitous throughout evolution, but always most important in cells which are dividing rapidly, hence its value as a drug target against infections and cancer.
MechansimUnusually, catalysis in this enzyme is dependent on a number of non-polar residues. The chief exception is Asp27 (numbering for E. coli), which acts as a proton relay, protonating the substrate via an ordered water molecule. Site-directed mutagenesis of this residue to asparagine has demonstrated its importance for catalysis, although in eukaryotic enzymes it is replaced by a Glu residue. Two mainchain carbonyls, of Ile5 and Ile94, constrain the pteridine ring in the right plane to receive protons; the sidechains of these residues are not conserved, although they are always hydrophobic. Four other conserved hydrophobic residues are implicated in catalysis by close examination of the structure and mutational analysis. Met20 (replaced by Leu in most eukaryotes) may create a hydrophobic environment around N5 of folate in order to push the positive charge on the ring on to C6, where it can receive hydride. Phe31 sterically forces the pteridine ring close to the nicotinamide, while Leu28 and Leu54 are both suggested to constrain the folate ring system.

Catalytic Sites for 1ra2

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription

Literature References

Bystroff C.
Crystal structures of Escherichia coli dihydrofolate reductase: the NADP+ holoenzyme and the folate.NADP+ ternary complex. Substrate binding and a model for the transition state
Biochemistry 1990 29 3263-3277
PubMed: 2185835
Brown KA.
Exploring the molecular mechanism of dihydrofolate reductase
Faraday Discuss 1992 93 217-224
PubMed: 1290933