Disease relevance of Fdft1

• Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver [1].
• This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease [2].
• In this paper we describe the preparation of some biphenylquinuclidine derivatives and their evaluation as inhibitors of squalene synthase in order to explore their potential in the treatment of the parasitic diseases leishmaniasis and Chagas disease [3].

High impact information on Fdft1

• In phenotypically Slp negative mice the plasma/serum levels of Ss correlate with the C4 activity (P less than 0.001) [4].
• Treatment of Ss with C1 cleaves a 7,000-8,000-mol wt fragment from the alpha-chain [4].
• Consistent with this observation, the SREBP-1 -/- animals manifested elevated levels of mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase, farnesyl diphosphate synthase, and squalene synthase [5].
• In the present study, the squalene synthase inhibitor squalestatin reduced the cholesterol content of cells and prevented the accumulation of PrP(Sc) in three prion-infected cell lines (ScN2a, SMB, and ScGT1 cells) [6].
• Crystal structure of human squalene synthase. A key enzyme in cholesterol biosynthesis [7].

Biological context of Fdft1

• Overexpression of SS increased de novo cholesterol biosynthesis with increased 3-hydroxy-3-methyglutaryl-CoA (HMG-CoA) reductase activity, in spite of the downregulation of its own mRNA expression [1].
• The compound inhibited rat liver microsomal squalene synthase (IC50 = 1 nM) and 7-dehydrocholesterol (7DHC) reductase (IC50 = 1 microM; Lewis et al. 1995) [8].
• Comparative squalene synthase gene expression in mouse liver and testis [9].
• Using a probe obtained by PCR amplification, a full-length cDNA encoding squalene synthase was isolated from a mouse liver cDNA library [10].
• In Arabidopsis, SS-like genes form a multigene family, compatible with a possible function as antifeedants and antibacterial compounds [11].

Anatomical context of Fdft1

• Consistently, the SS enzymatic activities were reduced by 50% in the liver and testis [12].
• Because our previous studies indicated that squalestatin 1 treatment induces CYP2B expression in primary cultures of rat hepatocytes as a direct consequence of squalene synthase inhibition, we investigated possible underlying mechanisms [13].
• The activities of branch-point enzymes FPP-synthase, squalene synthase, cis-prenyltransferase, trans-prenyltransferase and NPHB-transferase were substantially increased in control but not in PPARalpha-null mice after treatment with peroxisome proliferators [14].

Associations of Fdft1 with chemical compounds

• Squalene synthase (SS) catalyzes the reductive head-to-head condensation of two molecules of farnesyl diphosphate to form squalene, the first specific intermediate in the cholesterol biosynthetic pathway [12].
• Squalene synthase (SS) is the first committed enzyme for cholesterol biosynthesis, located at a branch point in the mevalonate pathway [1].
• RNA from various mouse organs was analyzed by Northern hybridization to determine the response of squalene synthase (SQS) mRNA to dietary cholesterol, or lovastatin and cholestyramine, administration [9].
• Some bisphosphonates used for the treatment of bone disorders are also potent inhibitors of squalene synthase, a critical enzyme for sterol biosynthesis [15].
• These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K(i) values in the low nanomolar to subnanomolar range in the absence or presence of 20 microM inorganic pyrophosphate [2].

Other interactions of Fdft1

• Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits [16].
• The suggested mechanism of hypocholesterolemic effect is the inhibition of squalene synthase and 7DHC reductase [8].
• The mice homozygous for the disrupted SS gene (SS-/-) were embryonic lethal around midgestation [12].
• In vivo studies in mice confirmed our earlier observations that inhibition of squalene synthase by zaragozic acid A was accompanied by an increase in the incorporation of label from [3H]mevalonate into farnesyl-diphosphate (FPP)-derived isoprenoic acids (J. D. Bergstrom et al., 1993, Proc. Natl. Acad. Sci. USA 90, 80-84) [17].

Analytical, diagnostic and therapeutic context of Fdft1

• We used gene targeting to knock out the mouse SS gene [12].
• Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia [16].
• Molecular cloning and functional expression of a cDNA for mouse squalene synthase [10].
• Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy [2].

References