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Catalytic Site Atlas

CSA LITERATURE entry for 1d8d

E.C. nameprotein farnesyltransferase
SpeciesRattus norvegicus (Rat)
E.C. Number (IntEnz)
CSA Homologues of 1d8dThere are 107 Homologs
CSA Entries With UniProtID Q04631
CSA Entries With EC Number
PDBe Entry 1d8d
PDBSum Entry 1d8d
MACiE Entry 1d8d

Literature Report

IntroductionFarnesyltransferase (FTase) is an important zinc metalloenzyme that is responsible for the specific transfer of a 15 carbon isoprenoid farnesyl from farnesyldiphosphate (FPP) to peptide substrates containing a characteristic carboxy-terminal CAAX motif. Within the motif, C is the cysteine that is farnesylated, 'A' represents an aliphatic residue and X is the terminal residue, normally methionine, serine, alanine or glutamine. Much research has been carried out on FTase since the group of substrate peptides it farnesylates includes the Ras family of proteins, the oncogenic forms of which are implicated in cell transformation.
MechansimThe difficulty in obtaining experimental evidence for the mechanism of FTase has led to increased interest in computation studies of the enzyme. A quantum mechanical active-site model has elucidated key transition states of the reaction, and allowed the first description of the mechanism.
The farnesylation of the cysteine residue from the peptide substrate is thought to proceed via a concerted associative mechanism, with partial dissociative character, as previously postulated form experimental studies. The FPP unit attacks the peptide Cys sulphur, forming a covalent bond to the residue and displacing the Zn metal. The metal centre is crucial in polarising the S-C bond, enhancing its electrophilic character.
The free coordination site left on the Zn is filled by the second carboxylate of the metal binding Asp297(B). The Mg divalent cation present is proposed to stabilise the build up of negative charge on the diphosphate moiety and is implicated in activating the leaving group.

Catalytic Sites for 1d8d

Literature References

Notes:Even though the Mg is catalytically important, it is not essential. It also isn't present in the pdb file, so it cannot be annotated.
Sousa SF
The search for the mechanism of the reaction catalyzed by farnesyltransferase.
Chemistry 2009 15 4243-4247
PubMed: 19301336