Disease relevance of squalene

• A cell-free extract of E. coli transformed with the recombinant plasmid, in the presence of NADPH and Mg2+, efficiently converted [14C]farnesyl diphosphate into squalene [1].
• Freshly isolated hairy cells from the peripheral blood of patients with hairy cell leukemia (HCL) synthesize 3-5-fold greater amounts of cholesterol, lanosterol, and squalene from [1-14C]-acetate than do normal human peripheral blood mononuclear cells under basal conditions of culture (i.e., in the presence of low-density lipoprotein) [2].
• Killing of tumor cells in vitro by macrophages from mice given injections of squalene-treated cell wall skeleton of Nocardia rubra [3].
• The influence of mineral oil, squalane, squalene, or peanut oil on the antitumor activity of emulsified Bacillus Calmette-Guérin cell walls or emulsified trehalose-6,6'-dimycolate was studied in mice, each with an established transplant of a syngeneic fibrosarcoma [4].
• Cholesterol synthesis inhibition distal to squalene upregulates biliary phospholipid secretion and counteracts cholelithiasis in the genetically prone C57L/J mouse [5].

Psychiatry related information on squalene

• Squalene was detected from 1/4 m greater than the standard tick attractants, attracted a greater percentage of ticks (75 compared with 0-43%) and featured a rapid response time (< 30 min) [6].

High impact information on squalene

• The active site of the enzyme is located in a large central cavity that is of suitable size to bind squalene in its required conformation and that is lined by aromatic residues [7].
• Methyl sterols, expressed either per cholesterol or bile acids, were higher and squalene was lower in the gallbladder bile than in the hepatic bile [8].
• The zaragozic acids are very potent inhibitors of squalene synthase that inhibit cholesterol synthesis and lower plasma cholesterol levels in primates [9].
• Two enzymes, squalene monooxygenase and oxidosqualene cyclase, are the minimum necessary for initial biosynthesis of sterols from squalene [10].
• The amino acid sequence of CPPase aligns closely with that of the chain elongation prenyltransferase farnesyl diphosphate synthase rather than squalene synthase or phytoene synthase, which catalyze c1'-2-3 cyclopropanation reactions similar to the CPPase reaction [11].

Chemical compound and disease context of squalene

• To enhance the efficacy of a DNA vaccine against pseudorabies virus (PRV), we evaluated the adjuvant properties of plasmids coding for gamma interferon or interleukin-12, of CpG immunostimulatory motifs, and of the conventional adjuvants dimethyldioctadecylammonium bromide in water (DDA) and sulfolipo-cyclodextrin in squalene in water [12].
• In dogs, NB-598, a potent competitive squalene epoxidase inhibitor has been reported to exhibit signs of dermatitis like toxicity which has been attributed by some reviewers to accumulation of squalene in skin cells [13].
• Pravastatin inhibited the cholesterol synthesis in human hepatoma cell line Hep G2 less than simvastatin and lovastatin, which is reflected in the upregulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and squalene synthase [14].
• In addition, squalene did not protect the NBL cells from carboplatin, cyclophosphamide, etoposide and doxorubicin-induced toxicity [15].
• In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity. implications in cancer chemotherapy [15].

Biological context of squalene

• The deduced amino acid sequence of the rat enzyme showed significant homology to the known oxidosqualene cyclases (OSCs) from yeast and plant (39-44% identity) and still retained 17-26% identity to two bacterial squalene cyclases (EC 5.4.99.-) [16].
• This measurement of daily cholesterol synthesis by squalene kinetics minimizes patient inconvenience, is suitable for outpatient studies, and yields results in 4 weeks or less [17].
• The proapoptotic effect of statins was seen only when the inhibition of acetate incorporation into sterols was >95% and was fully reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate but not by isopentenyl adenosine, ubiquinone, or squalene, suggesting a role for prenylated proteins in the regulation of VSMC apoptosis [18].
• Rats made congenic for Oia3 on chromosome 10 become susceptible to squalene-induced arthritis [19].
• Chloroquine inhibits cyclization of squalene oxide to lanosterol in mammalian cells [20].

Anatomical context of squalene

• Of this squalene, 80% is located in the central neutral lipid droplet and 20% is bound to the microsomal membranes [21].
• Moreover, they reflect intracellular transfer of labeled squalene from microsomes to the lipid droplet [21].
• Subcellular localization of squalene synthase in rat hepatic cells. Biochemical and immunochemical evidence [22].
• Metabolism of squalene in human fat cells. Demonstration of a two-pool system [21].
• Human adipose tissue has been shown to contain exceptionally high concentrations of squalene [21].

Associations of squalene with other chemical compounds

• Enzyme assays in vitro with crude cell extracts show that the biosynthetic conversion of mevalonate to squalene and the conversion of squalene to lanosterol are not impaired in the mutant cells [23].
• Moreover, SP600125 repressed the basal expression of the endogenous LDL receptor in a gene-specific manner, whereas the expression of squalene synthase, sterol response element-binding protein-1, and beta-actin was not altered by SP600125 [24].
• Expression of cDNA clones encoding S. pombe or hybrid human-S. cerevisiae squalene synthetases reversed the ergosterol requirement of S. cerevisiae cells bearing ERG9 gene disruptions, showing that these enzymes can functionally replace the S. cerevisiae enzyme [25].
• Serum and hepatic cholestanol, squalene and noncholesterol sterols in man: a study on liver transplantation [26].
• Squalestatin 1 is a potent, selective inhibitor of squalene synthase, a key enzyme in cholesterol biosynthesis; in vitro, 50% inhibition of enzyme activity is observed at a concentration of 12 +/- 5 nM (range of 4-22 nM) [27].

Gene context of squalene

• Chromosomal integration of ERG1 ERG7 at their loci in erg26-1ts ets1-1 and erg26-1ts and ets2-1 mutants, respectively, results in the loss of accumulation of squalene and squalene epoxide, re-accumulation of 4-carboxysterols and cell inviability at high temperature [28].
• Dolichol formation is examined in three Saccharomyces cerevisiae strains with mutations in the ERG20 gene encoding farnesyl diphosphate synthase (mevalonic acid pathway) and/or the ERG9 gene encoding squalene synthase (sterol synthesis pathway) differing in the amount and chain length of the polyisoprenoids synthesized [29].
• Cloning and characterization of the Arabidopsis thaliana SQS1 gene encoding squalene synthase--involvement of the C-terminal region of the enzyme in the channeling of squalene through the sterol pathway [30].
• Analysis by high-performance thin-layer chromatography (HPTLC) of (14)C-acetate-labeled lipids showed a dose-dependent increase in synthesis of sebaceous-specific lipid (i.e., squalene) induced by NDP alpha-MSH [31].
• 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 [32].

Analytical, diagnostic and therapeutic context of squalene

• Following intravenous infusion of [14C]MVA and [3H]cholesterol, there was a rapid appearance of [14C]squalene in the kidneys that exhibited a significantly longer half-life than plasma or hepatic squalene [33].
• One successful arthritis trigger was squalene, which is approved for vaccinations in humans and has been implicated in Gulf War syndrome [19].
• Nonesterified cholesterol and fatty acids, cholesteryl esters, triacylglycerols, and squalene were quantitated in re-endothelialized and de-endothelialized aorta by thin-layer chromatography and fluorometric analysis [34].
• Gas chromatography/mass spectrometry analyses demonstrate that erg26-1ts ets1-1 and erg26-1ts ets2-1 cells do not accumulate 4-carboxysterols, rather these cells have increased levels of squalene and squalene epoxide, respectively. ets1-1 and ets2-1 cells accumulate these same sterol intermediates [28].
• Analyses by thin layer and high pressure liquid chromatography of the nonsaponifiable lipid fraction from cultures incubated with chloroquine show an accumulation of radioactivity in the region of squalene oxide [20].

References