title: Human isoprenoid synthase enzymes as therapeutic targets.
abstract: In the human body, the complex biochemical network known as the mevalonate pathway is responsible for the biosynthesis of all isoprenoids, which consists of a vast array of metabolites that are vital for proper cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The down-stream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D. In the past, interest in prenyl synthase inhibitors focused mainly on the role of the FPP in lytic bone diseases. More recently pre-clinical and clinical studies have strongly implicated high levels of protein prenylation in a plethora of human diseases, including non-skeletal cancers, the progression of neurodegenerative diseases and cardiovascular diseases. In this review, we focus mainly on the potential therapeutic value of down-regulating the biosynthesis of FPP, GGPP, and squalene. We summarize the most recent drug discovery efforts and the structural data available that support the current on-going studies.
authors.affiliation: Department of Biochemistry, McGill University Montreal, QC, Canada.
authors.forename: Jaeok
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Chemistry, McGill University Montreal, QC, Canada.
authors.forename: Alexios N
authors.initials: AN
authors.lastname: Matralis
authors.affiliation: Department of Biochemistry, McGill University Montreal, QC, Canada ; Department of Microbiology and Immunology, McGill University Montreal, QC, Canada.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Berghuis
authors.affiliation: Department of Biochemistry, McGill University Montreal, QC, Canada ; Department of Chemistry, McGill University Montreal, QC, Canada.
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
keywords: farnesyl pyrophosphate; geranylgeranyl pyrophosphate; isoprenoids; mevalonate pathway; squalene
references.citation: Prostate Cancer Prostatic Dis. 2012 Sep;15(3):250-5
references.pmid: 22450844
references.citation: Neurology. 2007 Aug 28;69(9):878-85
references.pmid: 17724290
references.citation: Curr Pharm Des. 2010;16(27):2961-9
references.pmid: 20722615
references.citation: Bioorg Med Chem. 2002 Feb;10(2):385-400
references.pmid: 11741787
references.citation: J Med Chem. 2000 Oct 5;43(20):3641-52
references.pmid: 11020278
references.citation: Clin Cancer Res. 2007 Dec 15;13(24):7264-70
references.pmid: 18094406
references.citation: Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):80-4
references.pmid: 8419946
references.citation: J Med Chem. 2002 Sep 26;45(20):4571-80
references.pmid: 12238936
references.citation: J Bone Miner Res. 2008 Jun;23(6):826-36
references.pmid: 18558816
references.citation: Comput Struct Biotechnol J. 2013 Apr 02;5:e201302011
references.pmid: 24688704
references.citation: Angew Chem Int Ed Engl. 2013 Jan 21;52(4):1110-21
references.pmid: 23280829
references.citation: J Biol Chem. 2000 Sep 29;275(39):30610-7
references.pmid: 10896663
references.citation: Circulation. 1998 Mar 31;97(12):1129-35
references.pmid: 9537338
references.citation: J Med Chem. 2002 May 23;45(11):2185-96
references.pmid: 12014956
references.citation: JAMA. 2011 Jun 22;305(24):2556-64
references.pmid: 21693744
references.citation: JAMA Neurol. 2013 Apr;70(4):488-95
references.pmid: 23400560
references.citation: J Med Chem. 2013 Apr 25;56(8):3330-8
references.pmid: 23581491
references.citation: J Med Chem. 2006 Sep 21;49(19):5804-14
references.pmid: 16970405
references.citation: Assay Drug Dev Technol. 2007 Apr;5(2):205-14
references.pmid: 17477829
references.citation: Biochem Pharmacol. 2003 Dec 1;66(11):2133-9
references.pmid: 14609738
references.citation: Nat Rev Mol Cell Biol. 2010 Aug;11(8):579-92
references.pmid: 20651708
references.citation: ChemMedChem. 2006 Feb;1(2):267-73
references.pmid: 16892359
references.citation: BMC Med. 2007 Jul 19;5:20
references.pmid: 17640385
references.citation: Oncogene. 1997 Sep;15(11):1283-8
references.pmid: 9315095
references.citation: J Med Chem. 2014 Jul 10;57(13):5764-76
references.pmid: 24911527
references.citation: Intern Med J. 2002 Sep-Oct;32(9-10):486-90
references.pmid: 12380704
references.citation: Physiol Rev. 2001 Jan;81(1):153-208
references.pmid: 11152757
references.citation: Lancet. 2000 Nov 11;356(9242):1627-31
references.pmid: 11089820
references.citation: J Clin Pharmacol. 2003 Feb;43(2):154-62
references.pmid: 12616668
references.citation: Bone. 2008 May;42(5):841-7
references.pmid: 18314405
references.citation: J Immunol. 2011 Nov 15;187(10):5099-113
references.pmid: 22013129
references.citation: Bioorg Med Chem. 2002 Feb;10(2):401-14
references.pmid: 11741788
references.citation: Br J Pharmacol. 2003 Jul;139(5):881-2
references.pmid: 12839859
references.citation: Clin Cancer Res. 2012 Nov 15;18(22):6249-59
references.pmid: 23032740
references.citation: Acta Crystallogr C. 2010 Jun;66(Pt 6):m166-70
references.pmid: 20522941
references.citation: Drug Metab Dispos. 2008 Oct;36(10):2043-9
references.pmid: 18625688
references.citation: Blood. 2012 Jun 7;119(23):5374-83
references.pmid: 22498739
references.citation: J Biol Chem. 2004 Mar 5;279(10):8526-9
references.pmid: 14672944
references.citation: Bioorg Med Chem. 2013 Apr 15;21(8):2229-2240
references.pmid: 23477945
references.citation: J Biol Chem. 1999 Dec 24;274(52):37046-52
references.pmid: 10601262
references.citation: J Neurochem. 2008 Mar;104(6):1433-9
references.pmid: 18088381
references.citation: Bioorg Med Chem. 2006 Jun 15;14(12):4130-6
references.pmid: 16517172
references.citation: J Med Chem. 2007 Nov 29;50(24):5967-75
references.pmid: 17975902
references.citation: J Biol Chem. 1993 Nov 25;268(33):24832-7
references.pmid: 8227045
references.citation: J Med Chem. 2013 Oct 24;56(20):7939-50
references.pmid: 23998921
references.citation: BMC Cancer. 2014 Apr 09;14:248
references.pmid: 24716791
references.citation: Circulation. 2011 May 10;123(18):1925-8
references.pmid: 21518979
references.citation: J Clin Endocrinol Metab. 2009 Feb;94(2):538-44
references.pmid: 19050050
references.citation: Bone. 2011 Jul;49(1):82-8
references.pmid: 21349354
references.citation: Osteoporos Int. 2012 Aug;23(8):2107-16
references.pmid: 21983795
references.citation: Biochim Biophys Acta. 2010 Aug;1801(8):896-905
references.pmid: 20382260
references.citation: Biochem J. 1967 Jul;104(1):57-70
references.pmid: 4292002
references.citation: J Immunol. 2009 Jun 15;182(12):8118-24
references.pmid: 19494338
references.citation: Ann N Y Acad Sci. 1997 Sep 26;826:128-46
references.pmid: 9329686
references.citation: Biochem Biophys Res Commun. 1999 Oct 5;263(3):754-8
references.pmid: 10512752
references.citation: Circ Res. 2005 Dec 9;97(12):1232-5
references.pmid: 16339495
references.citation: J Control Release. 2010 Aug 17;146(1):76-83
references.pmid: 20462513
references.citation: Toxicol Appl Pharmacol. 2007 Aug 15;223(1):39-45
references.pmid: 17599378
references.citation: Chem Biol Drug Des. 2013 Jun;81(6):742-8
references.pmid: 23421555
references.citation: J Am Chem Soc. 2009 Apr 15;131(14):5153-62
references.pmid: 19309137
references.citation: Clin Neuropharmacol. 1999 Sep-Oct;22(5):295-7
references.pmid: 10516882
references.citation: Prog Nucleic Acid Res Mol Biol. 2001;65:157-95
references.pmid: 11008488
references.citation: Immunol Rev. 2007 Feb;215:59-76
references.pmid: 17291279
references.citation: Nat Biotechnol. 2004 May;22(5):513-9
references.pmid: 15122286
references.citation: Mol Pharm. 2013 Mar 4;10(3):1111-8
references.pmid: 23327778
references.citation: N Engl J Med. 1999 Mar 4;340(9):737-8
references.pmid: 10068336
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: Proteins. 2006 Jan 1;62(1):80-8
references.pmid: 16288456
references.citation: J Med Chem. 2012 Apr 12;55(7):3201-15
references.pmid: 22390415
references.citation: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7829-34
references.pmid: 16684881
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12479-84
references.pmid: 15308774
references.citation: Mol Neurobiol. 2012 Aug;46(1):179-85
references.pmid: 22692983
references.citation: Eur J Pharmacol. 2010 Sep 1;641(1):35-40
references.pmid: 20519142
references.citation: Ann Oncol. 2009 Jan;20(1):137-45
references.pmid: 18647964
references.citation: Invest New Drugs. 2011 Oct;29(5):912-20
references.pmid: 20480384
references.citation: J Biol Chem. 1966 Sep 10;241(17):3970-87
references.pmid: 4288360
references.citation: Lancet. 2010 Dec 11;376(9757):1989-99
references.pmid: 21131037
references.citation: Int J Immunopathol Pharmacol. 2011 Jan-Mar;24(1):139-48
references.pmid: 21496396
references.citation: Lancet. 2010 Feb 27;375(9716):735-42
references.pmid: 20167359
references.citation: Clin Genet. 2009 Jan;75(1):19-29
references.pmid: 19054015
references.citation: Br J Pharmacol. 2003 Jul;139(5):911-8
references.pmid: 12839864
references.citation: J Pharmacol Exp Ther. 2011 May;337(2):540-6
references.pmid: 21335425
references.citation: J Med Chem. 2011 Aug 11;54(15):5583-91
references.pmid: 21702499
references.citation: N Engl J Med. 2009 Feb 12;360(7):679-91
references.pmid: 19213681
references.citation: Bioorg Med Chem. 2010 Nov 1;18(21):7402-12
references.pmid: 20888243
references.citation: Biochem Pharmacol. 2010 Mar 1;79(5):777-83
references.pmid: 19819230
references.citation: Neurobiol Aging. 1990 Nov-Dec;11(6):601-7
references.pmid: 1704106
references.citation: J Med Chem. 2008 Apr 10;51(7):2187-95
references.pmid: 18327899
references.citation: J Med Chem. 2014 Mar 27;57(6):2568-81
references.pmid: 24568631
references.citation: J Biol Chem. 1978 Oct 25;253(20):7227-33
references.pmid: 701246
references.citation: J Biol Chem. 1992 Jun 15;267(17):11705-8
references.pmid: 1601846
references.citation: Bone. 2009 Dec;45(6):1153-60
references.pmid: 19699819
references.citation: J Med Chem. 1995 Jul 7;38(14):2596-605
references.pmid: 7629799
references.citation: Ann Oncol. 2009 Jan;20(1):117-20
references.pmid: 18689864
references.citation: Oncol Res. 2010;18(10):493-501
references.pmid: 20681408
references.citation: Nat Biotechnol. 2007 Jan;25(1):71-5
references.pmid: 17211405
references.citation: J Cardiovasc Pharmacol. 2008 Jun;51(6):573-80
references.pmid: 18520953
references.citation: Nat Cell Biol. 2014 Apr;16(4):357-66
references.pmid: 24658687
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7
references.pmid: 17535895
references.citation: Int J Cardiol. 2003 Aug;90(2-3):317-21
references.pmid: 12957768
references.citation: J Biol Chem. 1997 May 30;272(22):14093-7
references.pmid: 9162034
references.citation: Clin Cancer Res. 2009 Apr 15;15(8):2942-8
references.pmid: 19351752
references.citation: Nat Chem Biol. 2009 Apr;5(4):227-35
references.pmid: 19219049
references.citation: J Control Release. 2013 Apr 28;167(2):175-88
references.pmid: 23395668
references.citation: J Biol Chem. 2006 Aug 4;281(31):22004-22012
references.pmid: 16698791
references.citation: Br J Pharmacol. 2006 Feb;147(4):437-45
references.pmid: 16402039
references.citation: Nature. 2011 Mar 24;471(7339):467-72
references.pmid: 21430775
references.citation: Arch Biochem Biophys. 1998 Jul 1;355(1):84-92
references.pmid: 9647670
references.citation: Bioorg Med Chem Lett. 2008 Mar 15;18(6):1840-4
references.pmid: 18295483
references.citation: J Biol Chem. 1997 May 30;272(22):14459-64
references.pmid: 9162087
references.citation: Biochem Biophys Res Commun. 2011 Apr 22;407(4):663-7
references.pmid: 21420384
references.citation: ACS Med Chem Lett. 2013 Sep 04;4(10):932-6
references.pmid: 24900587
references.citation: J Biol Chem. 2012 May 25;287(22):18750-7
references.pmid: 22474324
references.citation: Mol Neurobiol. 2014 Aug;50(1):214-20
references.pmid: 24474514
references.citation: Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6243s-6249s
references.pmid: 17062708
references.citation: J Med Chem. 1993 May 14;36(10):1501-4
references.pmid: 8496919
references.citation: BMC Struct Biol. 2012 Dec 12;12:32
references.pmid: 23234314
references.citation: J Med Chem. 1997 Jul 4;40(14):2123-5
references.pmid: 9216829
references.citation: Biochemistry. 1975 Jan 14;14(1):50-4
references.pmid: 1109590
references.citation: Ann Pharmacother. 2006 Feb;40(2):290-4
references.pmid: 16449543
references.citation: J Med Chem. 1996 Jan 5;39(1):207-16
references.pmid: 8568810
references.citation: ACS Chem Biol. 2012 Aug 17;7(8):1429-35
references.pmid: 22625864
references.citation: J Pharmacol Exp Ther. 2001 Feb;296(2):235-42
references.pmid: 11160603
references.citation: Neurobiol Dis. 2009 Aug;35(2):251-7
references.pmid: 19464372
references.citation: Nature. 1990 Feb 1;343(6257):425-30
references.pmid: 1967820
references.citation: World J Urol. 2013 Apr;31(2):345-50
references.pmid: 22407328
references.citation: Biochemistry. 2014 Mar 4;53(8):1360-72
references.pmid: 24512202
references.citation: J Med Chem. 1995 Oct 13;38(21):4157-60
references.pmid: 7473541
references.citation: Circulation. 2011 May 10;123(18):1974-85
references.pmid: 21518985
references.citation: J Med Chem. 1991 Jun;34(6):1912-4
references.pmid: 2061928
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15018-23
references.pmid: 8986756
references.citation: Nat Chem Biol. 2010 Sep;6(9):660-6
references.pmid: 20711197
references.citation: Bone. 2011 Jul;49(1):2-19
references.pmid: 21555003
references.citation: Oncology. 2004;67(5-6):351-8
references.pmid: 15713990
references.citation: J Physiol. 2009 Jan 15;587(1):219-30
references.pmid: 19001041
references.citation: J Pharmacol Exp Ther. 2007 Dec;323(3):794-804
references.pmid: 17804677
references.citation: J Med Chem. 2002 Nov 21;45(24):5406-9
references.pmid: 12431068
references.citation: Bone. 2011 Jul;49(1):20-33
references.pmid: 21497677
references.citation: J Neurochem. 2014 May;129(4):559-72
references.pmid: 24329875
references.citation: Neoplasia. 2010 Jul;12(7):571-8
references.pmid: 20651986
references.citation: Lancet. 1997 Jan 18;349(9046):151-4
references.pmid: 9111537
references.citation: Bioorg Med Chem. 2010 Oct 15;18(20):7212-20
references.pmid: 20832326
references.citation: Acta Crystallogr F Struct Biol Commun. 2014 Mar;70(Pt 3):299-304
references.pmid: 24598914
references.citation: Bioorg Med Chem. 2004 Nov 15;12(22):5899-908
references.pmid: 15498666
references.citation: Proteins. 2008 Nov 1;73(2):431-9
references.pmid: 18442135
references.citation: Br J Pharmacol. 2008 Jul;154(5):949-57
references.pmid: 18587443
references.citation: Chem Biol. 2010 Jun 25;17(6):551-5
references.pmid: 20609404
references.citation: J Med Chem. 1996 Feb 2;39(3):657-60
references.pmid: 8576905
references.citation: J Alzheimers Dis. 2006 Dec;10(4):399-406
references.pmid: 17183151
references.citation: J Med Chem. 1996 Jul 19;39(15):2971-9
references.pmid: 8709131
references.citation: J Lipid Res. 1992 Nov;33(11):1569-82
references.pmid: 1464741
references.citation: J Clin Oncol. 2006 Jul 1;24(19):2981-4
references.pmid: 16769983
references.citation: J Pharmacol Exp Ther. 1997 May;281(2):746-52
references.pmid: 9152381
references.citation: Pharmacopsychiatry. 2003 Sep;36 Suppl 2:S120-6
references.pmid: 14574625
references.citation: Biochim Biophys Acta. 2012 Dec;1820(12):1926-39
references.pmid: 22884656
references.citation: ChemMedChem. 2010 May 3;5(5):770-6
references.pmid: 20209564
references.citation: Bioorg Med Chem. 2011 Mar 15;19(6):1930-49
references.pmid: 21353782
references.citation: Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3044-8
references.pmid: 8159703
references.citation: Bioorg Med Chem. 2012 May 1;20(9):3072-93
references.pmid: 22464687
references.citation: J Lipid Res. 2005 Dec;46(12):2531-58
references.pmid: 16207929
references.citation: Angew Chem Int Ed Engl. 2010 Feb 1;49(6):1136-8
references.pmid: 20039246
references.citation: J Biol Chem. 1997 Feb 14;272(7):3944-52
references.pmid: 9020098
references.citation: J Med Chem. 2000 Feb 24;43(4):609-12
references.pmid: 10691687
references.citation: J Biochem. 2007 Sep;142(3):377-81
references.pmid: 17646172
references.citation: Bioorg Med Chem. 2012 Sep 15;20(18):5583-91
references.pmid: 22884353
references.citation: J Lipid Res. 2012 Jun;53(6):1176-82
references.pmid: 22448028
references.citation: N Engl J Med. 2011 Oct 13;365(15):1396-405
references.pmid: 21995387
references.citation: Adv Drug Deliv Rev. 2005 May 25;57(7):995-1010
references.pmid: 15876400