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• W2076535269 abstract "Protein farnesylation is a form of posttranslational modification that occurs in most, if not all, eukaryotic cells. Inhibitors of protein farnesyltransferase (PFTIs) have been developed as anticancer chemotherapeutic agents. Using the knowledge gained from the development of PFTIs for the treatment of cancer, researchers are currently investigating the use of PFTIs for the treatment of eukaryotic pathogens. This “piggy-back” approach not only accelerates the development of a chemotherapeutic agent for protozoan pathogens but is also a means of mitigating the costs associated with de novo drug design. PFTIs have already been shown to be efficacious in the treatment of eukaryotic pathogens in animal models, including both Trypanosoma brucei, the causative agent of African sleeping sickness, and Plasmodium falciparum, one of the causative agents of malaria. Here, current evidence and progress are summarized that support the targeting of protein farnesyltransferase for the treatment of parasitic diseases. Protein farnesylation is a form of posttranslational modification that occurs in most, if not all, eukaryotic cells. Inhibitors of protein farnesyltransferase (PFTIs) have been developed as anticancer chemotherapeutic agents. Using the knowledge gained from the development of PFTIs for the treatment of cancer, researchers are currently investigating the use of PFTIs for the treatment of eukaryotic pathogens. This “piggy-back” approach not only accelerates the development of a chemotherapeutic agent for protozoan pathogens but is also a means of mitigating the costs associated with de novo drug design. PFTIs have already been shown to be efficacious in the treatment of eukaryotic pathogens in animal models, including both Trypanosoma brucei, the causative agent of African sleeping sickness, and Plasmodium falciparum, one of the causative agents of malaria. Here, current evidence and progress are summarized that support the targeting of protein farnesyltransferase for the treatment of parasitic diseases. Parasitic diseases continue to have a major impact on morbidity and mortality in tropical and subtropical regions. Among these, malaria causes ∼300 million infections annually, with 1–3 million deaths occurring in Africa (1World Health OrganizationMalaria and African trypanosomiasis. 2004; (Accessed October 20, 2005 at)http://www.who.int/tdr/diseasesGoogle Scholar). The emergence and spread of parasites resistant to existing antimalarial agents is largely responsible for the recent increase in malaria-related mortality. Another reemerging disease is African sleeping sickness (African trypanosomiasis), with an estimated 50,000 deaths in 2002 (1World Health OrganizationMalaria and African trypanosomiasis. 2004; (Accessed October 20, 2005 at)http://www.who.int/tdr/diseasesGoogle Scholar). The increasing burden of these diseases, along with the inadequacies of current drugs for African sleeping sickness in terms of safety, efficacy, and ease of administration, have led investigators to seek new chemotherapeutic agents (2May J. Meyer C.G. Chemoresistance in falciparum malaria.Trends Parasitol. 2003; 19: 432-435Google Scholar, 3White N.J. Antimalarial drug resistance.J. Clin. Invest. 2004; 113: 1084-1092Google Scholar). Among the current drug targets under study are enzymes involved in protein prenylation, or the posttranslational modification of proteins by the covalent modification by isoprenyl lipids, C15 farnesyl and C20 geranylgeranyl (4Chakrabarti D. Azam T. DelVecchio C. Qiu L.B. Park Y. Allen C.M. Protein prenyl transferase activities of Plasmodium falciparum.Mol. Biochem. Parasitol. 1998; 94: 175-184Google Scholar, 5Chakrabarti D. Da Silva T. Barger J. Paquette S. Patel H. Patterson S. Allen C.M. Protein farnesyltransferase and protein prenylation in Plasmodium falciparum.J. Biol. Chem. 2002; 277: 42066-42073Google Scholar, 6Yokoyama K. Lin Y. Stuart K.D. Gelb M.H. Prenylation of proteins in Trypanosoma brucei.Mol. Biochem. Parasitol. 1997; 87: 61-69Google Scholar, 7Yokoyama K. Zimmerman K. Scholten J. Gelb M.H. Differential prenyl pyrophosphate binding to mammalian protein geranylgeranyltransferase-I and protein farnesyltransferase and its consequence on the specificity of protein prenylation.J. Biol. Chem. 1997; 272: 3944-3952Google Scholar). The isoprenyl lipid modification of proteins has been shown to be critical for various cellular activities in mammals and yeast, including proliferation and apoptosis (8Sebti S.M. Der C.J. Opinion. Searching for the elusive targets of farnesyltransferase inhibitors.Nat. Rev. Cancer. 2003; 3: 945-951Google Scholar, 9Sebti S.M. Blocked pathways: FTIs shut down oncogene signals.Oncologist. 2003; 8: 30-38Google Scholar). Growth of the protozoan parasites has been shown to be severely impaired by the inhibition of protein farnesylation compared with mammalian cells, suggesting high potential of the enzyme protein farnesyltransferase (PFT) as an antiparasitic drug target (5Chakrabarti D. Da Silva T. Barger J. Paquette S. Patel H. Patterson S. Allen C.M. Protein farnesyltransferase and protein prenylation in Plasmodium falciparum.J. Biol. Chem. 2002; 277: 42066-42073Google Scholar, 10Carrico D. Ohkanda J. Kendrick H. Yokoyama K. Blaskovich M.A. Bucher C.J. Buckner F.S. Van Voorhis W.C. Chakrabarti D. Croft S.L. et al.In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability.Bioorg. Med. Chem. 2004; 12: 6517-6526Google Scholar, 11Nallan L. Bauer K.D. Bendale P. Rivas K. Yokoyama K. Horney C.P. Pendyala P.R. Floyd D. Lombardo L.J. Williams D.K. et al.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.J. Med. Chem. 2005; 48: 3704-3713Google Scholar, 12Wiesner J. Kettler K. Sakowski J. Ortmann R. Katzin A.M. Kimura E.A. Silber K. Klebe G. Jomaa H. Schlitzer M. Farnesyltransferase inhibitors inhibit the growth of malaria parasites in vitro and in vivo.Angew. Chem. Int. Ed. Engl. 2004; 43: 251-254Google Scholar, 13Yokoyama K. Trobridge P. Buckner F.S. Scholten J. Stuart K.D. Van Voorhis W.C. Gelb M.H. The effects of protein farnesyltransferase inhibitors on trypanosomatids: inhibition of protein farnesylation and cell growth.Mol. Biochem. Parasitol. 1998; 94: 87-97Google Scholar).The isoprenoid synthesis pathway from mevalonic acid in many eukaryotes, including trypanosomatids (or deoxy-xylulose in Apicomplexa, including Plasmodium and Toxoplasma, and plants) is essential for the production of sterols, dolichol, ubiquinone, and other isoprene derivatives in many eukaryotic cells. Indeed, these pathways have been the study of recent efforts to develop other antiparasitic chemotherapeutic agents, especially the targeting of isoprenoid pyrophosphate synthesis by nitrogen-containing bisphosphonates (14Garzoni L.R. Caldera A. Meirelles M.N. de Castro S.L. Docampo R. Meints G.A. Oldfield E. Urbina J.A. Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi.Int. J. Antimicrob. Agents. 2004; 23: 273-285Google Scholar, 15Montalvetti A. Fernandez A. Sanders J.M. Ghosh S. Van Brussel E. Oldfield E. Docampo R. Farnesyl pyrophosphate synthase is an essential enzyme in Trypanosoma brucei. In vitro RNA interference and in vivo inhibition studies.J. Biol. Chem. 2003; 278: 17075-17083Google Scholar, 16Yardley V. Khan A.A. Martin M.B. Slifer T.R. Araujo F.G. Moreno S.N. Docampo R. Croft S.L. Oldfield E. In vivo activities of farnesyl pyrophosphate synthase inhibitors against Leishmania donovani and Toxoplasma gondii.Antimicrob. Agents Chemother. 2002; 46: 929-931Google Scholar). Organisms belonging to the group Apicomplexa contain the nonmevalonate pathway of isoprenoid biosynthesis. One enzyme in this pathway is 2C-methyl-d-erythritol 4-phosphate synthase (IspC protein), which is inhibited by fosmidomycin (17Jomaa H. Wiesner J. Sanderbrand S. Altincicek B. Weidemeyer C. Hintz M. Turbachova I. Eberl M. Zeidler J. Lichtenthaler H.K. et al.Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs.Science. 1999; 285: 1573-1576Google Scholar). This has led to a clinical trial using fosmidomycin and clindamycin in combinational therapy for the treatment of malaria (18Missinou M.A. Borrmann S. Schindler A. Issifou S. Adegnika A.A. Matsiegui P.B. Binder R. Lell B. Wiesner J. Baranek T. et al.Fosmidomycin for malaria.Lancet. 2002; 360: 1941-1942Google Scholar). This review will discuss the current efforts and progress in developing inhibitors of protein farnesyltransferase (PFTIs) as antiparasitic agents.PROTEIN PRENYLATION IN HIGHER EUKARYOTIC CELLSProtein prenylation refers to the posttranslational modification of proteins by the covalent attachment of a 15 carbon farnesyl or a 20 carbon geranylgeranyl group. The structure of both the farnesyl and geranylgeranyl groups appended to proteins was determined in the early 1990s by Glomset, Gelb, and Farnsworth (19Glomset J.A. Gelb M.H. Farnsworth C.C. Prenyl proteins in eukaryotic cells: a new type of membrane anchor.Trends Biochem. Sci. 1990; 15: 139-142Google Scholar). This type of posttranslational modification creates a hydrophobic tail that facilitates membrane association as well as protein-protein interactions. Among known prenylated proteins are small GTPases, including Ras, Rac, Rho, and Rab, which play a role in cell signal transduction, vesicle trafficking, and cell cycle progression (20Tamanoi F. Kato-Stankiewicz J. Jiang C. Machado I. Thapar N. Farnesylated proteins and cell cycle progression.J. Cell. Biochem. Suppl. 2001; 37: 64-70Google Scholar).Protein prenylation is mediated by three distinct enzymes: PFT, protein geranylgeranyltransferase type I (PGGT-I), and PGGT-II. PFT recognizes a CaaX motif at the C terminus of specific proteins and transfers a farnesyl from farnesyl pyrophosphate to the thiol group of the cysteine: the CaaX motif is a cysteine followed by two amino acids (typically aliphatic) and a terminal amino acid, X, which is typically a Ser, Met, Ala, or Gln (21Sinensky M. Recent advances in the study of prenylated proteins.Biochim. Biophys. Acta. 2000; 1484: 93-106Google Scholar). PFT is a zinc-dependent heterodimeric enzyme with an α- and a β-subunit. PGGT-I shares the same α-subunit as PFT but has a distinct β-subunit. PGGT-I catalyzes the attachment of geranylgeranyl to proteins with the CaaX motif, in which X is usually a Leu or Phe (22Yokoyama K. McGeady P. Gelb M.H. Mammalian protein geranylgeranyltransferase-I: substrate specificity, kinetic mechanism, metal requirements, and affinity labeling.Biochemistry. 1995; 34: 1344-1354Google Scholar). For both PFT and PGGT-I, other residues may be tolerated in the X position (23Reid T.S. Terry K.L. Casey P.J. Beese L.S. Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity.J. Mol. Biol. 2004; 343: 417-433Google Scholar). After the action of either PFT or PGGT-I, a prenyl protein-specific protease cleaves the terminal tripeptide from the prenylated protein (24Trueblood C.E. Boyartchuk V.L. Picologlou E.A. Rozema D. Poulter C.D. Rine J. The CaaX proteases, Afc1p and Rce1p, have overlapping but distinct substrate specificities.Mol. Cell. Biol. 2000; 20: 4381-4392Google Scholar). The final step is methylation of the terminal carboxylic acid by a prenyl protein-specific methyltransferase (25Farh L. Mitchell D.A. Deschenes R.J. Farnesylation and proteolysis are sequential, but distinct steps in the CaaX box modification pathway.Arch. Biochem. Biophys. 1995; 318: 113-121Google Scholar, 26Buckner F.S. Kateete D.P. Lubega G.W. Van Voorhis W.C. Yokoyama K. Trypanosoma brucei prenylated-protein carboxyl methyltransferase prefers farnesylated substrates.Biochem. J. 2002; 367: 809-816Google Scholar, 27Hasne M.P. Lawrence F. Characterization of prenylated protein methyltransferase in Leishmania.Biochem. J. 1999; 342: 513-518Google Scholar). Both of these subsequent enzymatic steps have been shown to be required for the proper localization of certain mammalian proteins and are currently being investigated as additional chemotherapeutic targets (28Michaelson D. Ali W. Chiu V.K. Bergo M. Silletti J. Wright L. Young S.G. Philips M. Postprenylation CAAX processing is required for proper localization of Ras but not Rho GTPases.Mol. Biol. Cell. 2005; 16: 1606-1616Google Scholar, 29Winter-Vann A.M. Casey P.J. Post-prenylation-processing enzymes as new targets in oncogenesis.Nat. Rev. Cancer. 2005; 5: 405-412Google Scholar). The third prenylation enzyme, PGGT-II, catalyzes the addition of two geranylgeranyl groups onto the terminal residues of proteins ending with CC, CCXX, or CXC motifs. To date, proteins modified by PGGT-II have been exclusively members of the Rab low molecular weight G protein family (21Sinensky M. Recent advances in the study of prenylated proteins.Biochim. Biophys. Acta. 2000; 1484: 93-106Google Scholar).Because of the discoveries that the Ras oncogene is farnesylated and that this modification is required for the proper localization and function of Ras (30Reiss Y. Goldstein J.L. Seabra M.C. Casey P.J. Brown M.S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides.Cell. 1990; 62: 81-88Google Scholar, 31Maltese W.A. Sheridan K.M. Repko E.M. Erdman R.A. Post-translational modification of low molecular mass GTP-binding proteins by isoprenoid.J. Biol. Chem. 1990; 265: 2148-2155Google Scholar, 32Casey P.J. Solski P.A. Der C.J. Buss J.E. p21ras is modified by a farnesyl isoprenoid.Proc. Natl. Acad. Sci. USA. 1989; 86: 8323-8327Google Scholar), protein prenylation has received significant attention as a potential anticancer chemotherapeutic target (33Sebti S.M. Adjei A.A. Farnesyltransferase inhibitors.Semin. Oncol. 2004; 31: 28-39Google Scholar, 34Zhu K. Hamilton A.D. Sebti S.M. Farnesyltransferase inhibitors as anticancer agents: current status.Curr. Opin. Investig. Drugs. 2003; 4: 1428-1435Google Scholar, 35Ohkanda J. Lockman J.W. Yokoyama K. Gelb M.H. Croft S.L. Kendrick H. Harrell M.I. Feagin J.E. Blaskovich M.A. Sebti S.M. et al.Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity.Bioorg. Med. Chem. Lett. 2001; 11: 761-764Google Scholar). Mutations in Ras are associated with 20–25% of human cancers and 90% of pancreatic carcinomas (34Zhu K. Hamilton A.D. Sebti S.M. Farnesyltransferase inhibitors as anticancer agents: current status.Curr. Opin. Investig. Drugs. 2003; 4: 1428-1435Google Scholar). Numerous pharmaceutical companies have initiated drug discovery programs to generate PFTIs for the treatment of cancer. The first PFTI, which was described in 1993, was found in a chemical library screen based on the ability to inhibit yeast PFT activity (36Hara M. Akasaka K. Akinaga S. Okabe M. Nakano H. Gomez R. Wood D. Uh M. Tamanoi F. Identification of Ras farnesyltransferase inhibitors by microbial screening.Proc. Natl. Acad. Sci. USA. 1993; 90: 2281-2285Google Scholar). There are currently >2,000 primary publications on PFT inhibitors and >300 patents worldwide. Four companies have entered clinical trials for the development of PFTIs as a cancer chemotherapeutic agent: Janssen/Johnson & Johnson, Schering-Plough, Merck, and Bristol-Myers Squibb (37Rao S. Cunningham D. de Gramont A. Scheithauer W. Smakal M. Humblet Y. Kourteva G. Iveson T. Andre T. Dostalova J. et al.Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer.J. Clin. Oncol. 2004; 22: 3950-3957Google Scholar, 38Heymach J.V. Johnson D.H. Khuri F.R. Safran H. Schlabach L.L. Yunus F. DeVore III, R.F. De Porre P.M. Richards H.M. Jia X. et al.Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer.Ann. Oncol. 2004; 15: 1187-1193Google Scholar, 39Taveras A.G. Kirschmeier P. Baum C.M. Sch-66336 (sarasar) and other benzocycloheptapyridyl farnesyl protein transferase inhibitors: discovery, biology and clinical observations.Curr. Top. Med. Chem. 2003; 3: 1103-1114Google Scholar, 40Hahn S.M. Bernhard E.J. Regine W. Mohiuddin M. Haller D.G. Stevenson J.P. Smith D. Pramanik B. Tepper J. DeLaney T.F. et al.A phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer.Clin. Cancer Res. 2002; 8: 1065-1072Google Scholar, 41Marzo I. Perez-Galan P. Giraldo P. Lopez-Royuela N. Gomez-Benito M. Larrad L. Lasierra P. Rubio-Felix D. Anel A. Naval J. Farnesyltransferase inhibitor BMS-214662 induces apoptosis in B-cell chronic lymphocytic leukemia cells.Leukemia. 2004; 18: 1599-1604Google Scholar, 42Papadimitrakopoulou V. Agelaki S. Tran H.T. Kies M. Gagel R. Zinner R. Kim E. Ayers G. Wright J. Khuri F. Phase I study of the farnesyltransferase inhibitor BMS-214662 given weekly in patients with solid tumors.Clin. Cancer Res. 2005; 11: 4151-4159Google Scholar). Janssen/Johnson & Johnson and Schering-Plough are advancing to late clinical trials for the use of PFTIs in the treatment of certain leukemias (43Doll R.J. Kirschmeier P. Bishop W.R. Farnesyltransferase inhibitors as anticancer agents: critical crossroads.Curr. Opin. Drug Discov. Devel. 2004; 7: 478-486Google Scholar). To date, PFTIs have proven to be relatively nontoxic in clinical trials and effective when combined with other chemotherapeutic agents for the treatment of certain cancers in vivo (43Doll R.J. Kirschmeier P. Bishop W.R. Farnesyltransferase inhibitors as anticancer agents: critical crossroads.Curr. Opin. Drug Discov. Devel. 2004; 7: 478-486Google Scholar, 44Graaf M.R. Richel D.J. van Noorden C.J. Guchelaar H.J. Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer.Cancer Treat. Rev. 2004; 30: 609-641Google Scholar). Because of strong interest in the development of PFTIs for the treatment of cancer, there is a wealth of pharmacologic information about PFTIs. This pharmacologic information, the lack of toxicity, and a rich source of small-molecule PFTI libraries provide an excellent opportunity for the “piggy-back” investigation of PFTIs for the treatment of tropical diseases such as malaria and African sleeping sickness.PFT IN PATHOGENIC PROTOZOAProtein prenylation occurs in a wide variety of pathogenic protozoa, including Trypanosoma brucei (6Yokoyama K. Lin Y. Stuart K.D. Gelb M.H. Prenylation of proteins in Trypanosoma brucei.Mol. Biochem. Parasitol. 1997; 87: 61-69Google Scholar, 45Field H. Blench I. Croft S. Field M.C. Characterisation of protein isoprenylation in procyclic form Trypanosoma brucei.Mol. Biochem. Parasitol. 1996; 82: 67-80Google Scholar), Trypanosoma cruzi (46Buckner F.S. Eastman R.T. Nepomuceno-Silva J.L. Speelmon E.C. Myler P.J. Van Voorhis W.C. Yokoyama K. Cloning, heterologous expression, and substrate specificities of protein farnesyltransferases from Trypanosoma cruzi and Leishmania major.Mol. Biochem. Parasitol. 2002; 122: 181-188Google Scholar), Leishmania species (46Buckner F.S. Eastman R.T. Nepomuceno-Silva J.L. Speelmon E.C. Myler P.J. Van Voorhis W.C. Yokoyama K. Cloning, heterologous expression, and substrate specificities of protein farnesyltransferases from Trypanosoma cruzi and Leishmania major.Mol. Biochem. Parasitol. 2002; 122: 181-188Google Scholar), Plasmodium falciparum (4Chakrabarti D. Azam T. DelVecchio C. Qiu L.B. Park Y. Allen C.M. Protein prenyl transferase activities of Plasmodium falciparum.Mol. Biochem. Parasitol. 1998; 94: 175-184Google Scholar, 5Chakrabarti D. Da Silva T. Barger J. Paquette S. Patel H. Patterson S. Allen C.M. Protein farnesyltransferase and protein prenylation in Plasmodium falciparum.J. Biol. Chem. 2002; 277: 42066-42073Google Scholar), Toxoplasma gondii (47Ibrahim M. Azzouz N. Gerold P. Schwarz R.T. Identification and characterisation of Toxoplasma gondii protein farnesyltransferase.Int. J. Parasitol. 2001; 31: 1489-1497Google Scholar), Giardia lamblia (48Lujan H.D. Mowatt M.R. Chen G.Z. Nash T.E. Isoprenylation of proteins in the protozoan Giardia lamblia.Mol. Biochem. Parasitol. 1995; 72: 121-127Google Scholar), and Entamoeba histolytica (49Kumagai M. Makioka A. Takeuchi T. Nozaki T. Molecular cloning and characterization of a protein farnesyltransferase from the enteric protozoan parasite Entamoeba histolytica.J. Biol. Chem. 2004; 279: 2316-2323Google Scholar). Cloning and characterization of the PFT enzyme from trypanosomatid parasites was originally described by our group (46Buckner F.S. Eastman R.T. Nepomuceno-Silva J.L. Speelmon E.C. Myler P.J. Van Voorhis W.C. Yokoyama K. Cloning, heterologous expression, and substrate specificities of protein farnesyltransferases from Trypanosoma cruzi and Leishmania major.Mol. Biochem. Parasitol. 2002; 122: 181-188Google Scholar, 50Buckner F.S. Yokoyama K. Nguyen L. Grewal A. Erdjument-Bromage H. Tempst P. Strickland C.L. Xiao L. Van Voorhis W.C. Gelb M.H. Cloning, heterologous expression, and distinct substrate specificity of protein farnesyltransferase from Trypanosoma brucei.J. Biol. Chem. 2000; 275: 21870-21876Google Scholar). PFT enzymatic activity was detected in cytosolic fractions of T. brucei using the yeast Ras1 protein containing the C-terminal CaaX sequence Cys-Val-Ile-Met as a substrate (6Yokoyama K. Lin Y. Stuart K.D. Gelb M.H. Prenylation of proteins in Trypanosoma brucei.Mol. Biochem. Parasitol. 1997; 87: 61-69Google Scholar). T. brucei PFT was subsequently isolated and purified using affinity chromatography with the CaaX peptide Ser-Ser-Cys-Ala-Leu-Met (51Yokoyama K. Trobridge P. Buckner F.S. Van Voorhis W.C. Stuart K.D. Gelb M.H. Protein farnesyltransferase from Trypanosoma brucei. A heterodimer of 61- and 65-kDa subunits as a new target for antiparasite therapeutics.J. Biol. Chem. 1998; 273: 26497-26505Google Scholar). Similar to mammalian PFT, T. brucei PFT is a heterodimer. However, the subunits are larger, owing to numerous peptide segment insertions. These insertions are predicted, by molecular modeling using the known mammalian PFT structure, to be in loops on the surface of the protein and distant from the active site (46Buckner F.S. Eastman R.T. Nepomuceno-Silva J.L. Speelmon E.C. Myler P.J. Van Voorhis W.C. Yokoyama K. Cloning, heterologous expression, and substrate specificities of protein farnesyltransferases from Trypanosoma cruzi and Leishmania major.Mol. Biochem. Parasitol. 2002; 122: 181-188Google Scholar, 51Yokoyama K. Trobridge P. Buckner F.S. Van Voorhis W.C. Stuart K.D. Gelb M.H. Protein farnesyltransferase from Trypanosoma brucei. A heterodimer of 61- and 65-kDa subunits as a new target for antiparasite therapeutics.J. Biol. Chem. 1998; 273: 26497-26505Google Scholar). Insertions are also observed in T. cruzi, Leishmania species, and P. falciparum PFTs (5Chakrabarti D. Da Silva T. Barger J. Paquette S. Patel H. Patterson S. Allen C.M. Protein farnesyltransferase and protein prenylation in Plasmodium falciparum.J. Biol. Chem. 2002; 277: 42066-42073Google Scholar, 46Buckner F.S. Eastman R.T. Nepomuceno-Silva J.L. Speelmon E.C. Myler P.J. Van Voorhis W.C. Yokoyama K. Cloning, heterologous expression, and substrate specificities of protein farnesyltransferases from Trypanosoma cruzi and Leishmania major.Mol. Biochem. Parasitol. 2002; 122: 181-188Google Scholar), but their function is as yet unknown. The CaaX substrate specificity differs in T. brucei PFT compared with mammalian PFT, with a higher preference for substrates with a Met or Gln at the X position. Alteration of four amino acid residues in the putative X binding pocket in the active site of T. brucei could be responsible for the restricted peptide substrate specificity and suggests the potential for developing parasite-specific PFT inhibitors (50Buckner F.S. Yokoyama K. Nguyen L. Grewal A. Erdjument-Bromage H. Tempst P. Strickland C.L. Xiao L. Van Voorhis W.C. Gelb M.H. Cloning, heterologous expression, and distinct substrate specificity of protein farnesyltransferase from Trypanosoma brucei.J. Biol. Chem. 2000; 275: 21870-21876Google Scholar).P. falciparum PFT was first characterized by Chakrabarti et al. (4Chakrabarti D. Azam T. DelVecchio C. Qiu L.B. Park Y. Allen C.M. Protein prenyl transferase activities of Plasmodium falciparum.Mol. Biochem. Parasitol. 1998; 94: 175-184Google Scholar, 5Chakrabarti D. Da Silva T. Barger J. Paquette S. Patel H. Patterson S. Allen C.M. Protein farnesyltransferase and protein prenylation in Plasmodium falciparum.J. Biol. Chem. 2002; 277: 42066-42073Google Scholar). After partial purification by (NH4)2SO4 precipitation and anion-exchange chromatography, it was shown that the CaaX substrate specificity was similar to that of T. brucei PFT, favoring a Met or Gln in the terminal position. Metabolic radiolabeling of prenylated cellular proteins with [3H]farnesol demonstrated the incorporation of 3H into 50 kDa proteins and some lower molecular mass proteins. The 50 kDa proteins were analyzed and found to be modified by a farnesyl group; the lower molecular mass proteins, however, were found to be geranylgeranylated, presumably after the conversion of farnesol into both farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Our group later showed that the 50 kDa farnesylated proteins, but not the lower molecular mass geranylgeranylated proteins, were specifically inhibited by PFTIs (11Nallan L. Bauer K.D. Bendale P. Rivas K. Yokoyama K. Horney C.P. Pendyala P.R. Floyd D. Lombardo L.J. Williams D.K. et al.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.J. Med. Chem. 2005; 48: 3704-3713Google Scholar). Using synchronized P. falciparum, Chakrabarti et al. (5Chakrabarti D. Da Silva T. Barger J. Paquette S. Patel H. Patterson S. Allen C.M. Protein farnesyltransferase and protein prenylation in Plasmodium falciparum.J. Biol. Chem. 2002; 277: 42066-42073Google Scholar) demonstrated the stage-specific incorporation of prenylation precursors, the highest amount of incorporation occurring in the trophozoite (mid erythrocytic stage) to schizont (cell division stage) and schizont to ring (early erythrocytic stage) transition states in the erythrocytic life cycle of the parasite.Using a polyclonal antibody raised against rat PFT, Ibrahim et al. (47Ibrahim M. Azzouz N. Gerold P. Schwarz R.T. Identification and characterisation of Toxoplasma gondii protein farnesyltransferase.Int. J. Parasitol. 2001; 31: 1489-1497Google Scholar) immunoprecipitated and identified the T. gondii PFT enzyme. PFT enzyme activity was confirmed using a CaaX-containing lamin substrate. Incubating tachyzoites (intracellular replicative form) with radiolabeled farnesol or geranylgeraniol demonstrated the in vivo prenylation of proteins, with the geranylgeranylation of proteins of 29 kDa and the farnesylation of proteins of 47 kDa (47Ibrahim M. Azzouz N. Gerold P. Schwarz R.T. Identification and characterisation of Toxoplasma gondii protein farnesyltransferase.Int. J. Parasitol. 2001; 31: 1489-1497Google Scholar). Inhibition of the T. gondii PFT enzyme occurred using hydrophobic the peptidomimetic inhibitors FTase Inhibitor I and II (Fig. 1). However, these inhibitors had no effect against the inhibition of PFT enzyme activity in intact parasites, presumably because of poor cellular penetration, as indicated by normal radiolabeling of proteins with [3H]farnesol in inhibitor-treated cultures (47Ibrahim M. Azzouz N. Gerold P. Schwarz R.T. Identification and characterisation of Toxoplasma gondii protein farnesyltransferase.Int. J. Parasitol. 2001; 31: 1489-1497Google Scholar).Although the PFT enzyme of G. lamblia has not been isolated, prenylation of proteins has been demonstrated in this primitive eukaryote (48Lujan H.D. Mowatt M.R. Chen G.Z. Nash T.E. Isoprenylation of proteins in the protozoan Giardia lamblia.Mol. Biochem. Parasitol. 1995; 72: 121-127Google Scholar). [3H]mevalonic acid was specifically incorporated into cellular proteins of 50 and 20–30 kDa. After cleavage with methyl iodide, the isoprenoid substituents of these proteins were subjected to HPLC analysis and found to run with the same retention time as farnesol and geranylgeraniol (48Lujan H.D. Mowatt M.R. Chen G.Z. Nash T.E. Isoprenylation of proteins in the protozoan Giardia lamblia.Mol. Biochem. Parasitol. 1995; 72: 121-127Google Scholar). Inhibitors of PFT, such as limonene (Fig. 1), perillic acid, and perillyl alcohol, showed a dose-dependent effect on trophozoite (the replicative form of Giardia) growth in vitro (48Lujan H.D. Mowatt M.R. Chen G.Z. Nash T.E. Isoprenylation of proteins in the protozoan Giardia lamblia.Mol. Biochem. Parasitol. 1995; 72: 121-127Google Scholar); however, these agents are not very potent inhibitors of PFTs, and it is difficult to judge whether inhibition of Giardia PFT is the reason for the growth arrest.Based on a genome search, Kumagai et al. (49Kumagai M. Makioka A. Takeuchi T. Nozaki T. Molecular cloning and characterization of a protein farnesyltransferase from the enteric protozoan parasite Entamoeba histolytica.J. Biol. Chem. 2004; 279: 2316-2323Google Scholar) have identified and characterized PFT in E. histolytica. Interestingly, it was found that E. histolytica PFT does not preferentially modify proteins with a terminal Met residue. Instead, E. histolytica PFT favors CaaX substrates with smaller terminal amino acids, Ala and Ser, which suggests an altered binding cleft for the CaaX substrate. In further support of the altered substrate specificity of E. histolytica PFT, this PFT has a higher resistance to the CaaM peptidomimetic FTI-276 (Fig. 1) compared with other PFT enzymes (49Kumagai M. Makioka A. Takeuchi T. Nozaki T. Molecular cloning and characterization of a protein farnesyltransferase from the enteric protozoan parasite Entamoeba histolytica.J. Biol. Chem. 2004; 279: 2" @default.
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• W2076535269 title "Thematic review series: Lipid Posttranslational Modifications. Fighting parasitic disease by blocking protein farnesylation" @default.
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