Different analogues of farnesyl pyrophosphate inhibit squalene synthase and protein: Farnesyltransferase to different extents

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...

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Bibliographic Details
Published in:Biochemical pharmacology 1995-03, Vol.49 (6), p.839-845
Main Authors: Cohen, Louis H., Valentijn, Adrianus R.P.M., Roodenburg, Loes, Van Leeuwen, Rick E.W., Huisman, R.Holger, Lutz, Robert J., Van Der Marel, Gijs A., Van Boom, Jacques H.
Format: Article
Language:English
Subjects:
Alkyl and Aryl Transferases
Amino Acid Sequence
Animals
Cells, Cultured
cholesterol synthesis inhibitors
farnesyl pyrophosphate analogues
Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors
farnesyltransferase assay
Humans
Microsomes, Liver - enzymology
Molecular Sequence Data
Oncogene Protein p21(ras) - biosynthesis
Oncogene Protein p21(ras) - metabolism
Polyisoprenyl Phosphates - chemistry
Polyisoprenyl Phosphates - pharmacology
protein
protein prenylation inhibitors
ras farnesylation
Rats
Sesquiterpenes
Transferases - antagonists & inhibitors
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Summary: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-p21 Ha-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.Hras13 cells, a rat flbroblast cell line that overproduces human p21 Ha-ras. This work shows that farnesyl pyrophosphate analogues can be developed for specific inhibition of different processes such as cholesterol synthesis and protein prenylation.
ISSN:0006-2952
1873-2968
DOI:10.1016/0006-2952(94)00454-T