Disease relevance of SQLE

• The cDNA for human squalene monooxygenase, a key enzyme in the committed pathway for cholesterol biosynthesis, was amplified from a human liver cDNA library and cloned, and the protein was expressed in Escherichia coli and purified [1].
• Mechanisms of pharmacological rescue of trafficking-defective hERG mutant channels in human long QT syndrome [2].
• From these observations, squalene epoxidase inhibitor is expected to be highly effective in the treatment of hypercholesterolemia and also is very useful as a research tool for studying the regulation of cholesterol metabolism [3].
• We propose that an increase in cardiac calcium current and reduced trafficking of hERG channels to the cell surface cause QT prolongation and torsade de pointes in patients treated with As(2)O(3) [4].
• The human ether-a-go-go related gene (hERG) can be inhibited by marketed drugs, and this inhibition may lead to QT prolongation and possibly fatal cardiac arrhythmia [5].

Psychiatry related information on SQLE

• The main factors studied are context characteristics and constructs of attitude, social influence, self-efficacy (SE) and perceived barriers [6].
• OBJECTIVES: Study aim was to adapt a Dutch/English version of the diabetes management self-efficacy (SE) scale for use with a Turkish population and evaluate its psychometric properties [7].
• This study aimed at exploring the existing predominant critical thinking disposition(s) of baccalaureate nursing students and the relationship among their critical thinking (CT), self-esteem (SE), and state anxiety (SA) [8].

High impact information on SQLE

• Maximal amounts of 12-HETE were 126 +/- 21 pmol/10(6) cells (+/- SE), and concentration-response curves yielded half-maximal levels for 12-HETE similar to PGE2 at 2 microM AA [9].
• Two enzymes, squalene monooxygenase and oxidosqualene cyclase, are the minimum necessary for initial biosynthesis of sterols from squalene [10].
• In this work, 19 protein gene sequences for eukaryotic squalene monooxygenase and 12 protein gene sequences for eukaryotic oxidosqualene cyclase were compared with all available complete and partial prokaryotic genomes [10].
• We found that 1a and 1b N-terminal fragments bind in a direct and dose-dependent manner. hERG1 hetero-oligomerization occurs in the endoplasmic reticulum where co-expression of N-terminal fragments with hERG1 subunits disrupted oligomerization and core glycosylation [11].
• Alternate transcripts of the human ether-à-go-go-related gene (hERG1) encode two subunits, hERG 1a and 1b, which form potassium channels regulating cardiac repolarization, neuronal firing frequency, and neoplastic cell growth [11].

Chemical compound and disease context of SQLE

• 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 [12].
• Feeding weanling rats a diet containing 1% elemental tellurium causes a transient, peripheral demyelination due to the disruption of cholesterol synthesis in Schwann cells secondary to inhibition of squalene monooxygenase [13].
• To study the potential mechanisms of tellurium toxicity in humans, three likely in vivo metabolites of tellurium (tellurite, dimethyltellurium dichloride, and dimethyltelluride) were tested as inhibitors of purified human squalene monooxygenase [13].
• Combined hERG channel inhibition and disruption of trafficking in drug-induced long QT syndrome by fluoxetine: a case-study in cardiac safety pharmacology [14].
• Three data sets related to angiotensin converting enzyme inhibition, squalene epoxidase inhibition and HIV protease inhibition were used to investigate the outcome of hypothesis optimisation [15].

Biological context of SQLE

• PCR evidence localizes human SQLE to chromosome 8 by using the NIGMS (National Institute of General Medical Sciences) Human/Rodent Somatic Cell Hybrid Mapping Panel 2 as template [16].
• The result shows that human SQLE is most tightly linked to D8S508, which is reported to be located at 8q24.13-qter (lod score 7.87) [16].
• Localization of the squalene epoxidase gene (SQLE) to human chromosome region 8q24.1 [16].
• Regulation of squalene epoxidase (SE) gene expression was studied in comparison with those of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and low density lipoprotein (LDL) receptor [17].
• The entire human SE gene was about 24 kb long and organized into 11 exons with 10 introns [18].

Anatomical context of SQLE

• Transcriptional regulation of squalene epoxidase by sterols and inhibitors in HeLa cells [17].
• We previously reported that the N470D mutation is retained in the endoplasmic reticulum (ER) but can be rescued to the plasma membrane by hERG channel blocker E-4031 [2].
• We have reported previously that NB-598 competitively inhibits human squalene epoxidase and strongly inhibits cholesterol synthesis from [14C]acetate in cultured cells [3].
• Here we show that SPF and PG also stimulate squalene uptake per se by microsomes as well as stimulate squalene epoxidase [19].
• Regulation of squalene epoxidase in the cholesterol biosynthetic pathway was studied in a human hepatoma cell line, HepG2 cells [20].

Associations of SQLE with chemical compounds

• The increase of SE mRNA in HeLa cells grown in LPDS was preventable in a dose-dependent manner by feeding cells with 25-hydroxycholesterol or cholesterol [17].
• These results suggest that sterol produced endogenously can also regulate SE expression at the level of transcription [17].
• Overexpression/selection using the sterol synthesis inhibitors terbinafine (TBF, targeting squalene epoxidase) and itraconazole (ITZ, targeting lanosterol C(14)-demethylase) yielded nine new resistance loci [21].
• NB-598: a potent competitive inhibitor of squalene epoxidase [22].
• Grapefruit juice increased the mean felodipine area under the plasma concentration-time curve (AUC) (mean +/- SE, 55 +/- 9 nmol. h/L versus 29 +/- 6 nmol. h/L; P <.05) and the plasma peak drug concentration (16 +/- 3 nmol/L versus 8 +/- 2 nmol/L, P <.05) and decreased the dehydrofelodipine/felodipine AUC ratio compared with those of water [23].

Regulatory relationships of SQLE

• We found that decreasing OSBP expression by approximately 90% did not affect 25-HC-induced inhibition of transcription of 3-hydoxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and squalene epoxidase to any extent [24].

Other interactions of SQLE

• Three erg genes (erg1, erg2 and erg3) have been identified and characterized [25].
• Both proteins were 2-3-fold more active than wild-type reductase with NADH in reconstitution assays with cytochrome P-450 1A2 and with squalene monooxygenase [26].
• These results demonstrate that the induction of LDL receptor activity by NB-598 is due to increases in mRNA and protein through the inhibition of cholesterol synthesis at the squalene epoxidase step [3].
• It is further suggested that squalene epoxidase activity is suppressed only by sterols, not by nonsterol derivative(s) of mevalonate, in contrast to the regulation of HMG-CoA reductase [20].
• The enzymes squalene synthetase, squalene epoxidase and oxidosqualene cyclase were identified as potential targets [12].

Analytical, diagnostic and therapeutic context of SQLE

• To refine the localization of human SQLE further, PCR on the Stanford G3 Radiation Hybrid Panel was performed [16].
• Moreover, fluorescence in situ hybridization also maps human SQLE to 8q24.1 [16].
• An increased expression of SE mRNA and protein content in mouse L929 cells grown in 10% lipoprotein-deficient fetal bovine serum (LPDS) for 48 h was found by performing immunoblot and Northern blot analyses when compared with the culture in the presence of fetal bovine serum (FBS) [17].
• Here, RT-PCR was used to monitor the circadian expression of ether-a-go-go-related gene (Erg) potassium channel isoforms and Erg1 splice variants [27].
• Comparative molecular field analysis (CoMFA) of fungal squalene epoxidase inhibitors exhibiting antifungal activity reported in terms of minimum inhibitory concentration (MIC) was performed [28].

References