Effect of squalestatin 1 on the biosynthesis of the mevalonate pathway lipids.
The effects of squalestatin 1 on rat brain and liver homogenates and on Chinese hamster ovary tissue culture cells have been investigated. This compound effectively inhibits squalene biosynthesis in a highly selective manner. Cytoplasmic farnesyl pyrophosphate and geranylgeranyl pyrophosphate synthases are not affected, which is also the case for microsomal cis-prenyltransferase. In tissue culture cells, squalestatin 1 inhibits cholesterol biosynthesis completely, but does not alter dolichol synthesis or protein isoprenylation to a great extent. Incorporation of [3H]mevalonate into ubiquinone-9 and -10 increases 3-4-fold, probably as a result of increased synthesis of this lipid. Squalestatin 1 appears not only to be an effective inhibitor of cholesterol biosynthesis, but also to be more specific than other inhibitors used earlier in various in vitro and in vivo systems.
Thelin
A
A
Department of Biochemistry, Stockholm University, Sweden.
Peterson
E
E
Hutson
J L
JL
McCarthy
A D
AD
Ericsson
J
J
Dallner
G
G
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016466:CHO Cells; D006224:Cricetinae; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes; D014233:Tricarboxylic Acids / Q000494:pharmacology*; D014451:Ubiquinone / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008055:Lipids; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D014451:Ubiquinone; C004808:farnesyl pyrophosphate; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid