Protein Prenyltransferases and Their Inhibitors: Structural and Functional Characterization

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 May 28

PMID 35628237

Authors

Aleksandra Marchwicka

Daria Kaminska

Mohsen Monirialamdari

Katarzyna M Blazewska

Edyta Gendaszewska-Darmach

Affiliations

Soon will be listed here.

Abstract

Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras superfamily. This covalent attachment of either a farnesyl (15 carbon) or a geranylgeranyl (20 carbon) isoprenoid group is catalyzed by four prenyltransferases, namely farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase-I), Rab geranylgeranyltransferase (GGTase-II), and recently discovered geranylgeranyltransferase type III (GGTase-III). Blocking small GTPase activity, namely inhibiting prenyltransferases, has been proposed as a potential disease treatment method. Inhibitors of prenyltransferase have resulted in substantial therapeutic benefits in various diseases, such as cancer, neurological disorders, and viral and parasitic infections. In this review, we overview the structure of FTase, GGTase-I, GGTase-II, and GGTase-III and summarize the current status of research on their inhibitors.

Citing Articles

Examining Farnesyltransferase Interaction With Cell-Permeable CaaX Peptides and the Role of the CaaX Motif in Biological Activity.

Klussmann M, Reuter J, Werner C, Neundorf I J Pept Sci. 2025; 31(4):e70009.

PMID: 40064612 PMC: 11893521. DOI: 10.1002/psc.70009.

Synthesis, Bioproduction and Bioactivity of Perillic Acid-A Review.

Rolim T, Sampaio A, Mazzei J, Moreira D, Siani A Molecules. 2025; 30(3).

PMID: 39942631 PMC: 11820084. DOI: 10.3390/molecules30030528.

Regulation of autophagy by protein lipidation.

Shao Y, Hu J, Li H, Lu K Adv Biotechnol (Singap). 2025; 2(4):33.

PMID: 39883197 PMC: 11709147. DOI: 10.1007/s44307-024-00040-w.

Itaconate facilitates viral infection via alkylating GDI2 and retaining Rab GTPase on the membrane.

Yin S, Tao Y, Li T, Li C, Cui Y, Zhang Y Signal Transduct Target Ther. 2024; 9(1):371.

PMID: 39730330 PMC: 11681089. DOI: 10.1038/s41392-024-02077-8.

In Silico Strategies for Characterizing Inner Cavities of Lipid-Binding Proteins.

Sacher S, Ray A Methods Mol Biol. 2024; 2888:305-320.

PMID: 39699739 DOI: 10.1007/978-1-0716-4318-1_20.

References

Gray J, von Delft F, Brennan P . Targeting the Small GTPase Superfamily through Their Regulatory Proteins. Angew Chem Int Ed Engl. 2019; 59(16):6342-6366. PMC: 7204875. DOI: 10.1002/anie.201900585. View

Kazmierczak A, Kusy D, Niinivehmas S, Gmach J, Joachimiak L, Pentikainen O . Identification of the Privileged Position in the Imidazo[1,2-a]pyridine Ring of Phosphonocarboxylates for Development of Rab Geranylgeranyl Transferase (RGGT) Inhibitors. J Med Chem. 2017; 60(21):8781-8800. DOI: 10.1021/acs.jmedchem.7b00811. View

Long S, Casey P, Beese L . Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate. Biochemistry. 1998; 37(27):9612-8. DOI: 10.1021/bi980708e. View

Farnsworth C, Wolda S, Gelb M, Glomset J . Human lamin B contains a farnesylated cysteine residue. J Biol Chem. 1989; 264(34):20422-9. PMC: 3443689. View

Coxon F, Joachimiak L, Najumudeen A, Breen G, Gmach J, Oetken-Lindholm C . Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT. Eur J Med Chem. 2014; 84:77-89. DOI: 10.1016/j.ejmech.2014.06.062. View

Zverina E, Lamphear C, Wright E, Fierke C . Recent advances in protein prenyltransferases: substrate identification, regulation, and disease interventions. Curr Opin Chem Biol. 2012; 16(5-6):544-52. PMC: 3518607. DOI: 10.1016/j.cbpa.2012.10.015. View

Lu J, Chan L, Fiji H, Dahl R, Kwon O, Tamanoi F . In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I. Mol Cancer Ther. 2009; 8(5):1218-26. PMC: 2888841. DOI: 10.1158/1535-7163.MCT-08-1122. View

Palsuledesai C, Distefano M . Protein prenylation: enzymes, therapeutics, and biotechnology applications. ACS Chem Biol. 2014; 10(1):51-62. PMC: 4301080. DOI: 10.1021/cb500791f. View

Marin-Ramos N, Balabasquer M, Ortega-Nogales F, Torrecillas I, Gil-Ordonez A, Marcos-Ramiro B . A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia. J Med Chem. 2019; 62(13):6035-6046. DOI: 10.1021/acs.jmedchem.9b00145. View

10.

Fukasawa M, Varlamov O, Eng W, Sollner T, Rothman J . Localization and activity of the SNARE Ykt6 determined by its regulatory domain and palmitoylation. Proc Natl Acad Sci U S A. 2004; 101(14):4815-20. PMC: 387331. DOI: 10.1073/pnas.0401183101. View

11.

Brioschi M, Martinez Fernandez A, Banfi C . Exploring the biochemistry of the prenylome and its role in disease through proteomics: progress and potential. Expert Rev Proteomics. 2017; 14(6):515-528. DOI: 10.1080/14789450.2017.1332998. View

12.

Lane K, Beese L . Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J Lipid Res. 2006; 47(4):681-99. DOI: 10.1194/jlr.R600002-JLR200. View

13.

Tsubamoto M, Khanh Le T, Li M, Watanabe T, Matsumi C, Parvatkar P . A Guanidyl-Based Bivalent Peptidomimetic Inhibits K-Ras Prenylation and Association with c-Raf. Chemistry. 2019; 25(59):13531-13536. DOI: 10.1002/chem.201903129. View

14.

Dolence J, Rozema D, Poulter C . Yeast protein farnesyltransferase. Site-directed mutagenesis of conserved residues in the beta-subunit. Biochemistry. 1997; 36(30):9246-52. DOI: 10.1021/bi970039p. View

15.

Bon R, Guo Z, Stigter E, Wetzel S, Menninger S, Wolf A . Structure-guided development of selective RabGGTase inhibitors. Angew Chem Int Ed Engl. 2011; 50(21):4957-61. DOI: 10.1002/anie.201101210. View

16.

Seabra M, Brown M, Slaughter C, Sudhof T, Goldstein J . Purification of component A of Rab geranylgeranyl transferase: possible identity with the choroideremia gene product. Cell. 1992; 70(6):1049-57. DOI: 10.1016/0092-8674(92)90253-9. View

17.

Metibemu D . vHTS and 3D-QSAR for the Identification of Novel Phyto-inhibitors of Farnesyltransferase: Validation of Ascorbic Acid inhibition of Farnesyltransferase in an Animal Model of Breast Cancer. Drug Res (Stuttg). 2021; 71(6):341-347. DOI: 10.1055/a-1422-1885. View

18.

Kazi A, Xiang S, Yang H, Chen L, Kennedy P, Ayaz M . Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRAS-Driven Patient-Derived Pancreatic Tumors. Clin Cancer Res. 2019; 25(19):5984-5996. PMC: 6774803. DOI: 10.1158/1078-0432.CCR-18-3399. View

19.

Reiss Y, Goldstein J, Seabra M, Casey P, Brown M . Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell. 1990; 62(1):81-8. DOI: 10.1016/0092-8674(90)90242-7. View

20.

Hunt J, Ding C, Batorsky R, Bednarz M, Bhide R, Cho Y . 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. 2000; 43(20):3587-95. DOI: 10.1021/jm000248z. View