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Catalytic Site Atlas

CSA LITERATURE entry for 1p4r

E.C. namephosphoribosylaminoimidazolecarboxamide formyltransferase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 2.1.2.3
CSA Homologues of 1p4rThere are 11 Homologs
CSA Entries With UniProtID P31939
CSA Entries With EC Number 2.1.2.3
PDBe Entry 1p4r
PDBSum Entry 1p4r
MACiE Entry 1p4r

Literature Report

IntroductionThe enzyme AITC is bifunctional being involved in the production of IMP, the final product of the de novo purine synthesis pathway.. The catalytic centre described here catalyses the first step in AIRC activity, the formylation of AICAR to form 5-formyl AICAR which can then be cyclised by the second catalytic centre. The enzyme shows a high degree of sequence conservation among organisms from E.coli to man, but does not show homology to other formyl transferases, suggesting that the bifunctionality has evolved from one gene rather than two.
MechansimThe cofactor which supplies the formyl group is N10-formyl-tetrahydrofolate (10-f-THF). During the reaction nucleophilic attack by the amino group of AICAR, facilitated by deprotonation by His 267, forms a tetrahedral intermediate, stabilised by Lys 266 and Asn 431. This collapses following protonation of the cofactor by Lys 266 to release the product. His 267 is activated towards its role as a general base by Asn 431 and His 593.
Reaction

Catalytic Sites for 1p4r

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AsnA431431macie:sideChainStabilises tetrahedral intermediate through hydrogen bonding, and also acts to modify the pKa of His 267 to allow it to function as a general acid base.
LysA266266macie:sideChainStabilises transition state by forming electrostatic interactions with the negatively charged oxygen of the tetrahedral intermediate, then protonates the THF cofactor to allow it to act as a leaving group for the reaction so that the tetrahedral intermediate collapses.
HisA592592macie:sideChainActs as a primer by modifying the pKa of His 267 so that it can act as a general acid base during the reaction.
HisA267267macie:sideChainDeprotonates AICAR to allow its amino group to attack THF as a nucleophile, forming the tetrahedral intermediate that collapses to the product.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
AsnB431431macie:sideChainStabilises tetrahedral intermediate through hydrogen bonding, and also acts to modify the pKa of His 267 to allow it to function as a general acid base.
LysB266266macie:sideChainStabilises transition state by forming electrostatic interactions with the negatively charged oxygen of the tetrahedral intermediate, then protonates the THF cofactor to allow it to act as a leaving group for the reaction so that the tetrahedral intermediate collapses.
HisB592592macie:sideChainActs as a primer by modifying the pKa of His 267 so that it can act as a general acid base during the reaction.
HisB267267macie:sideChainDeprotonates AICAR to allow its amino group to attack THF as a nucleophile, forming the tetrahedral intermediate that collapses to the product.

Annotated By Reference To The Literature - Site 3 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrA104104macie:sideChainDeprotonates the second nitrogen of the substrate to allow the nitrogen to form a double bond and water to be eliminated from the substrate.
IleA126126macie:mainChainAmideForms part of oxyanion hole with Gly 127, with peptide bond NH group forming favourable hydrogen bond to the tetrahedral intermediate's negatively charged oxygen atom.
GlyA127127macie:mainChainAmideForms part of oxyanion hole with Ile 125, with hydrogen bonding from the peptide backbone stabilising the tetrahedral intermediate's negatively charged oxygen.
LysA137137macie:sideChainAllows water to protonate the nitrogen atom of the intermediate by transferring a proton to the water to replace the one stripped off by the substrate.
LysA6666macie:sideChainModifies the pKa of Tyr 104 to allow it to act as a base and remove a proton from the substrate.

Annotated By Reference To The Literature - Site 4 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrB104104macie:sideChainDeprotonates the second nitrogen of the substrate to allow the nitrogen to form a double bond and water to be eliminated from the substrate.
IleB126126macie:mainChainAmideForms part of oxyanion hole with Gly 127, with peptide bond NH group forming favourable hydrogen bond to the tetrahedral intermediate's negatively charged oxygen atom.
GlyB127127macie:mainChainAmideForms part of oxyanion hole with Ile 125, with hydrogen bonding from the peptide backbone stabilising the tetrahedral intermediate's negatively charged oxygen.
LysB137137macie:sideChainAllows water to protonate the nitrogen atom of the intermediate by transferring a proton to the water to replace the one stripped off by the substrate.
LysB6666macie:sideChainModifies the pKa of Tyr 104 to allow it to act as a base and remove a proton from the substrate.

Literature References

Notes:
Shim JH
Evaluation of the catalytic mechanism of AICAR transformylase by pH-dependent kinetics, mutagenesis, and quantum chemical calculations.
J Am Chem Soc 2001 123 4687-4696
PubMed: 11457277
Wolan DW
Structural insights into the avian AICAR transformylase mechanism.
Biochemistry 2002 41 15505-15513
PubMed: 12501179
Cheong CG
Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates.
J Biol Chem 2004 279 18034-18045
PubMed: 14966129
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