Squalene monooxygenase – a target for hypercholesterolemic therapy

Abstract

Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafi ne, naftifi ne, butenafi ne) are in clinical use, whereas mammalian enzymes ' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both suffi cient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.

Phytocomposition and pharmacological importance of Paris polyphylla (Smith.) and needs of its conservation in Arunachal Pradesh, India

“…Monoamine precursor (monoamine precursor is useful in the treatment of depression) (Bernard and Caroll, 1971), Squalene monooxygenase -Inhibitor* (squalene epoxidase is on the biosynthetic pathway leading to cholesterol, inhibitors of this enzyme may also find application in treatment of hypertension, (Belter et al, 2011 Beta adrenergic receptor blocker* (Reduce chance of cardiac attack), endothelium derived relaxing factor promoter*, Eendoanesthetic, endocrinoprotective, energizer, fertility enhancer, memory enhancer, trypsin enhancer, HIV-RT -inhibitor*, Quninine-reductase-inducer (Muriel et al, 2006), radioprotective, Regulate calcium metabolism, ruminatonic, Suppress HMG-CoA reductase activity (used to lower serum cholesterol as a means of reducing the risk for cardiovascular disease)*. 44 0.50 .gamma,-Sitosterol PPAR gamma agonist* reduce obesity and type-II diabetes* 45 0.62 7.beta.-hydroxydiosgenin 17-beta-hydroxysteroid dehydrogenase-inhibitor (inhibitors of 17beta-HSDs are useful tools to elucidate the role of these enzymes in particular biological systems or for a therapeutic purpose, especially to block the formation of active hydroxysteroids that stimulate estrogeno-sensitive pathologies (breast, ovarian, and endometrium cancers) and androgeno-sensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc.…”

“…Sci., 3(2): 143-150 (2018) The phytocompositions of the ethanol extract of P. polyphylla stem shows that this herb contain numbers of useful compounds which could be used in the treatment of numbers of health problems like hypertension, parkinson's disease, tumour formation, as an antidote, coronary protection, fertility problems, availability of zinc, increase immune system etc. Among the 45 five total compounds, Linolein, 2-mono was found to cover highest area percentage in TIC peak report with 20.21%, Palmitin, 2-mono was found to occupy 9.15 percent in area % of TIC peak table, these compound has been reported to be useful in the treatment of depression (Bernard and Caroll, 1971), cholesterol control* and anti-hypertensive (Belter et al, 2011). Some of the major compounds present in P. polyphylla and their Anti-cancer (Esophagus), Increase zinc bioavaiabiity, Antidote (Emetine), Decrease C-teleopeptide excretion (to reduce risk of Peget bone disease), fertility enhancing, endocrine protective, Endothelium derived relaxing factor promoter( in parasympathetic coronary vasodilation)* 30 1.07 17-Hydroxy-4,4-Dimethyl estran-3-One 17-beta-hydroxysteroid dehydrogenase-inhibitor (prevent breast, ovarian, and endometrium cancers) and androgeno-sensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc (Poirier, 2003; (Aryl-hydrocarbon dehydrogenase-inhibitor (to stop carcinogen (Kinoshita and Gelboin, 1972).…”

“…Some of the major compounds present in P. polyphylla and their Anti-cancer (Esophagus), Increase zinc bioavaiabiity, Antidote (Emetine), Decrease C-teleopeptide excretion (to reduce risk of Peget bone disease), fertility enhancing, endocrine protective, Endothelium derived relaxing factor promoter( in parasympathetic coronary vasodilation)* 30 1.07 17-Hydroxy-4,4-Dimethyl estran-3-One 17-beta-hydroxysteroid dehydrogenase-inhibitor (prevent breast, ovarian, and endometrium cancers) and androgeno-sensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc (Poirier, 2003; (Aryl-hydrocarbon dehydrogenase-inhibitor (to stop carcinogen (Kinoshita and Gelboin, 1972). 31 9.15 Palmitin, 2-mono Monoamine precursor (monoamine precursor is useful in the treatment of depression) (Bernard and Caroll, 1971), squalene monooxygenaseInhibitor* (squalene epoxidase is on the biosynthetic pathway leading to cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia (Belter et al, 2011). …”

Ubiquitin Ligases in Cholesterol Metabolism

“…SM is a microsomal flavin monooxygenase that catalyzes the first oxygenation step during cholesterol synthesis, the conversion of squalene to the squalene-2,-3-epoxide (Fig. 1) [37]. As one of the target genes of SREBP-2, the transcription of SM is regulated by sterols [37].…”

The cholesterol biosynthesis enzyme oxidosqualene cyclase is a new target to impair tumour angiogenesis and metastasis dissemination

“…More recently, itraconazole has been shown to impair tumor growth and angiogenesis in primary xenograft models of human non-small cell lung cancer11 and in a mouse model of medulloblastoma12 and terbinafine has been shown to inhibit tumor growth and angiogenesis13. Terbinafine is an effective inhibitor of squalene monooxygenase14, while itraconazole blocks sterol biosynthesis by inhibiting 14-demethylase15 (Figure 1A). Both compounds inhibit the sterol biosynthetic pathway after the formation of prenyl intermediates, suggesting that the anti-angiogenic effect should be based on a mechanism other than inhibition of the mevalonate pathway and of isoprenoid biosynthesis, which has been suggested as a cause of the anti-angiogenic and anti-tumoral activity observed in statins78.…”