title: Different analogues of farnesyl pyrophosphate inhibit squalene synthase and protein:farnesyltransferase to different extents.
abstract: The inhibitory potency of farnesyl pyrophosphate analogues was investigated on two farnesyl pyrophosphate-consuming enzymes: squalene synthase, a secondary regulation site in the cholesterol synthesis pathway, and protein:farnesyl transferase, which plays a role in the function of Ras-proteins. For the transferase determination a rapid in vitro assay, using Sepharose-bound Ras-peptides, was developed. The distinct farnesyl pyrophosphate analogues showed a different order of potency in the inhibition of these two enzymes. Using the farnesyl transferase assay with pre-p21Ha-ras as substrate the same result was obtained. The difference observed in the in vitro assays was also reflected in the inhibition of cholesterol synthesis, protein prenylation in general and Ha-ras farnesylation in Rat-1.H-ras13 cells, a rat fibroblast cell line that overproduces human p21Ha-ras. This work shows that farnesyl pyrophosphate analogues can be developed for specific inhibition of different processes such as cholesterol synthesis and protein prenylation.
authors.affiliation: Gaubius Laboratory, TNO-PG, Leiden, The Netherlands.
authors.forename: L H
authors.initials: LH
authors.lastname: Cohen
authors.forename: A R
authors.initials: AR
authors.lastname: Valentijn
authors.forename: L
authors.initials: L
authors.lastname: Roodenburg
authors.forename: R E
authors.initials: RE
authors.lastname: Van Leeuwen
authors.forename: R H
authors.initials: RH
authors.lastname: Huisman
authors.forename: R J
authors.initials: RJ
authors.lastname: Lutz
authors.forename: G A
authors.initials: GA
authors.lastname: Van der Marel
authors.forename: J H
authors.initials: JH
authors.lastname: Van Boom
mesh_terms: D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012717:Sesquiterpenes; D014166:Transferases / Q000037:antagonists & inhibitors*
chemical_list: D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D013186:Farnesyl-Diphosphate Farnesyltransferase; D015689:Oncogene Protein p21(ras)