Disease relevance of FDFT1

• Southern blot analysis of 66 esophageal adenocarcinomas demonstrated only CTSB and FDFT1 were consistently amplified in eight (12.1%) of the tumors [1].
• When expressed in E. coli, the hSQS cDNA directed the production of active enzyme [2].
• Overlap syndrome (OS) is mixed connective tissue disease combining some features of DM, SS and LES [3].
• Regulation of squalene synthetase in human hepatoma cell line Hep G2 by sterols, and not by mevalonate-derived non-sterols [4].
• Each specific syndrome associates with a restricted variety of ANAs, e.g. anti-La with primary SS, anti-Sm with SLE, anti-synthetase enzymes with myositis, anti-topoisomerase 1 (Scl 70) with scleroderma, and anti-centromere with CREST [5].

High impact information on FDFT1

• Northern blot analysis showed overexpression of CTSB and FDFT1 mRNA in all six of the amplified esophageal adenocarcinomas analyzed [1].
• Squalene synthetase activity in human fibroblasts: regulation via the low density lipoprotein receptor [6].
• The human SQS (hSQS) gene has an unusually complex promoter with multiple binding sites for the sterol regulatory element binding proteins SREBP-1a and SREBP-2, and for accessory transcription factors known to be involved in the control of other sterol-responsive genes [7].
• The two activities, presqualene pyrophosphate synthetase and squalene synthetase, copurified during isolation [8].
• The differential effects of relatively thick monoglyceride bilayers on proton transfer in both dioxolane-linked gA channels must relate to distinct interactions between the bilayers and the SS and RR dioxolanes [9].

Biological context of FDFT1

• Localization of the squalene synthase gene (FDFT1) to human chromosome 8p22-p23.1 [10].
• Real-time PCR helped validate the downregulation of SREBF1, HMGCS1, FDFT1, and HSD3B4 genes [11].
• By identifying sequences conserved between yeast SQS (ySQS) and PhS, we have cloned a 2-kb cDNA (hSQS) encoding human SQS, a protein of 417 amino acids with a predicted M(r) of 48,041, which has only limited homology to ySQS [2].
• The ribulose 1,5-bisphosphate carboxylase/oxygenase small subunit (Rubisco SS) genes are of similar size (approximately 1.4 kb) to transgenes present in GM plants [12].
• Children as a sensitive subgroup and their role in regulatory toxicology: DGPT workshop report [13].

Anatomical context of FDFT1

• SQS is a membrane-bound enzyme in both T. cruzi epimastigotes and Leishmania mexicana promastigotes with a dual subcellular localization, being almost evenly distributed between glycosomes and mitochondrial/microsomal vesicles [14].

Associations of FDFT1 with chemical compounds

• Among the new investigational agents are inhibitors of squalene synthetase, acylCoA: cholesterol acyltransferase, cholesteryl ester transfer protein, monocyte-macrophages and LDL cholesterol oxidation [15].
• The submillisecond closing events (flickers) and the single channel conductances to protons (g(H)) were studied in native gramicidin A (gA) and in the SS and RR diastereoisomers of dioxolane-linked gA channels in planar bilayers [16].
• In GMO/decane (thick) bilayers, the largest flicker frequency occurred in the SS channel (39 s(-1)), followed by the RR (4 s(-1)) and native gA channels (3 s(-1)) [16].
• Microsomal 3-hydroxy-3-methylglutaryl Coenzyme A reductase was inhibited greater than 90% by microM mevinolin, while squalene synthetase was insensitive to even 600 microM mevinolin [17].
• Three T. borchii genes coding for the most important regulatory enzymes of the isoprenoid biosynthesis, 3-hydroxy-3-methylglutaryl-CoA reductase, farnesyl-diphosphate synthase (FPPS) and squalene synthase (SQS), were cloned and characterised [18].

Other interactions of FDFT1

• In particular, the SS and OSC genes were coordinately induced at 8 days of incubation, and their expression persisted throughout the incubation period [19].
• The enzymes squalene synthetase, squalene epoxidase and oxidosqualene cyclase were identified as potential targets [20].

Analytical, diagnostic and therapeutic context of FDFT1

• Chromatin immunoprecipitation also shows that SREBP-1a is recruited efficiently to Red and FAS promoters but not to SQS [21].
• Squalene synthase (SQS, E.C. 2.5.1.21) catalyzes the first committed step in sterol biosynthesis and is currently under intense study as a possible target for cholesterol-lowering agents in humans, but it has not been investigated as a target for anti-parasitic chemotherapy [14].
• Human serum albumin was separated to two forms by high-performance liquid chromatography: mercaptalbumin (SH type) and nonmercaptalbumin (SS type) [22].
• Site-directed mutagenesis has identified conserved Asp, Tyr, and Phe residues that are essential for SQS activity [23].

References