Farnesyltransferase is a member of the prenyltransferases family which also includes geranylgeranyltransferase types I (EC 2.5.1.59) and II (EC 2.5.1.60) [2]. Protein farnesyltransferase catalyses the post-translational formation of a thioether linkage between the C-1 of an isoprenyl group and a cysteine residue fourth from the C-terminus of a protein (ie to the CaaX motif, where 'a' is an aliphatic amino acid and 'X' is usually serine, methionine, alanine or glutamine; leucine for EC 2.5.1.59) [4]. Farnesyltransferase is a dimer, composed of an alpha and beta subunit and requires Mg²⁺ and Zn²⁺ ions as cofactors. The active site is located between the subunits. Prenylation creates a hydrophobic domain on protein tails which acts as a membrane anchor.

Substrates of the prenyltransferases include Ras, Rho, Rab, other Ras-related small GTP-binding proteins, G-protein γ-subunits, nuclear lamins, centromeric proteins and many proteins involved in visual signal transduction.

In relation to the causative association between oncogenic Ras proteins and cancer, farnesyltransferase has become an important mechanistic drug discovery target.

* Key recommended reading is highlighted with an asterisk

* Gao S, Yu R, Zhou X. (2016) The Role of Geranylgeranyltransferase I-Mediated Protein Prenylation in the Brain. Mol Neurobiol, 53 (10): 6925-6937. [PMID:26666664]

* Shen M, Pan P, Li Y, Li D, Yu H, Hou T. (2015) Farnesyltransferase and geranylgeranyltransferase I: structures, mechanism, inhibitors and molecular modeling. Drug Discov Today, 20 (2): 267-76. [PMID:25450772]

Shen Y, Qiang S, Ma S. (2015) The Recent Development of Farnesyltransferase Inhibitors as Anticancer and Antimalarial Agents. Mini Rev Med Chem, 15 (10): 837-57. [PMID:25963569]

* Wang M, Casey PJ. (2016) Protein prenylation: unique fats make their mark on biology. Nat Rev Mol Cell Biol, 17 (2): 110-22. [PMID:26790532]

* Zhao Y, Wu TY, Zhao MF, Li CJ. (2020) The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease. J Biol Chem, 295 (15): 5152-5162. [PMID:32139507]

1. Angibaud P, Bourdrez X, Devine A, End DW, Freyne E, Ligny Y, Muller P, Mannens G, Pilatte I, Poncelet V et al.. (2003) 5-imidazolyl-quinolinones, -quinazolinones and -benzo-azepinones as farnesyltransferase inhibitors. Bioorg Med Chem Lett, 13 (9): 1543-7. [PMID:12699751]

2. Casey PJ, Seabra MC. (1996) Protein prenyltransferases. J Biol Chem, 271 (10): 5289-92. [PMID:8621375]

3. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P, Venet M, Sanz G, Poignet H, Skrzat S et al.. (2001) Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res, 61 (1): 131-7. [PMID:11196150]

4. Furfine ES, Leban JJ, Landavazo A, Moomaw JF, Casey PJ. (1995) Protein farnesyltransferase: kinetics of farnesyl pyrophosphate binding and product release. Biochemistry, 34 (20): 6857-62. [PMID:7756316]

5. Hunt JT, Ding CZ, Batorsky R, Bednarz M, Bhide R, Cho Y, Chong S, Chao S, Gullo-Brown J, Guo P et al.. (2000) Discovery of (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity. J Med Chem, 43 (20): 3587-95. [PMID:11020273]

6. Kohl NE, Wilson FR, Mosser SD, Giuliani E, deSolms SJ, Conner MW, Anthony NJ, Holtz WJ, Gomez RP, Lee TJ et al.. (1994) Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci USA, 91 (19): 9141-5. [PMID:8090782]

7. Lee H, Lee J, Lee S, Shin Y, Jung W, Kim JH, Park K, Kim K, Cho HS, Ro S et al.. (2001) A novel class of highly potent, selective, and non-peptidic inhibitor of Ras farnesyltransferase (FTase). Bioorg Med Chem Lett, 11 (23): 3069-72. [PMID:11714612]

8. Lerner EC, Qian Y, Blaskovich MA, Fossum RD, Vogt A, Sun J, Cox AD, Der CJ, Hamilton AD, Sebti SM. (1995) Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem, 270 (45): 26802-6. [PMID:7592920]