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Catalytic Site Atlas

CSA LITERATURE entry for 1grc

E.C. namephosphoribosylglycinamide formyltransferase
SpeciesEscherichia coli (Bacteria)
E.C. Number (IntEnz)
CSA Homologues of 1grcThere are 32 Homologs
CSA Entries With UniProtID P08179
CSA Entries With EC Number
PDBe Entry 1grc
PDBSum Entry 1grc
MACiE Entry 1grc

Literature Report

IntroductionGlycinamide Ribonucleotide Transformylase (GAR transformylase) catalyses the first two formyl transfers in the de novo purine biosynthetic pathway and forms the C-8 atom of the purine ring. GAR transformylase has been a target for developing novel antifolate drugs to be used in cancer chemotherapy. Due to its biological and pharmacological significance, it has been the subject of intensive studies.
MechansimFolate binding induces active site rearrangements involving Asp144 and His108, which place the protonated imidazolium partnered in a salt bridge to the carboxylate in a position to activate the formyl group of the cofactor by donating a proton to the formyl oxygen. Asn106 also interacts with the folate, and may fine-tune the location of the formyl group. A low-dielectric active site environment favors the free base form of the amino group of GAR, poised to attack the activated formyl group to form presumably a tetrahedral intermediate in the transfer process. A proton is switched from GAR to the N10 of folate mediated by a catalytic H2 O molecule, followed by breakdown of the tetrahedral intermediate and product release. The positioning of the catalytic H2 O molecule may also be assisted by Asp144.

Catalytic Sites for 1grc

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisA108108macie:sideChainActs as a general acid by activating the formyl group of the cofactor by donating a proton to the formyl oxygen. Aso stabilises transition state via hydrogen bonding to create an oxyanion hole.
AsnA106106macie:sideChainForms a hydrogen bond to the formyl group during to stabilise the transition state via formation of an oxyanion hole.
AspA144144macie:sideChainForms a salt bridge with his108. Essential as maintains the correct protonation state of the general acid his108.

Literature References

Shim JH
Catalytic mechanism of Escherichia coli glycinamide ribonucleotide transformylase probed by site-directed mutagenesis and pH-dependent studies.
Biochemistry 1999 38 10024-10031
PubMed: 10433709