Disease relevance of Squalene peroxide

• Evaluation of 2,3-oxidosqualene synthesis from [(14)C]mevalonate demonstrated that SPF also stimulated squalene monooxygenase (1.3-fold) in hepatoma cells [1].

High impact information on Squalene peroxide

• The mechanism and sequence of this cyclase are closely related to those of 2,3-oxidosqualene cyclases that catalyze the cyclization step in cholesterol biosynthesis [2].
• When sterol biosynthesis in oxygen-deprived wild type Saccharomyces cerevisiae was prevented by the presence of 2,3-iminosqualene, an inhibitor of 2,3-oxidosqualene cyclase, an absolute requirement for a sterol with a 24 beta-methyl group was found [3].
• Inhibition of cholesterol biosynthesis in Chinese hamster ovary cells by 4,4,10 beta-trimethyl-trans-decal-3 beta-ol. A specific 2,3-oxidosqualene cyclase inhibitor [4].
• A hem3 mutant was isolated which was also blocked between 2,3-oxidosqualene and lanosterol (erg12) [5].
• BIBB 515 (1-(4-chlorobenzoyl)-4-((4-(2-oxazolin-2-yl) benzylidene))piperidine) is a potent and selective inhibitor of 2,3-oxidosqualene cyclase (OSC) [EC 5.4.99.7] [6].

Biological context of Squalene peroxide

• It is therefore concluded that 2,3-oxidosqualene cyclase plays a crucial role in the regulation of intracellular cholesterol homeostasis [7].
• Effects of a novel 2,3-oxidosqualene cyclase inhibitor on cholesterol biosynthesis and lipid metabolism in vivo [6].
• Trisnorsqualene N-methylcyclopropylamine inhibited [3H]squalene conversion to [3H]lanosterol (IC50 = 12.0 microM) and caused [3H]-squalene epoxide to accumulate in microsomes, indicating that this derivative inhibited 2,3-oxidosqualene cyclase [8].
• Drug design based on biosynthetic studies: synthesis, biological activity, and kinetics of new inhibitors of 2,3-oxidosqualene cyclase and squalene epoxidase [9].
• Structure activity relationships of new inhibitors of mammalian 2,3-oxidosqualene cyclase designed from isoquinoline derivatives [10].

Anatomical context of Squalene peroxide

• The compounds inhibited squalene epoxidase and 2,3-oxidosqualene cyclase to varying degrees in microsomes from C. albicans and from rat liver [11].
• N-[(1,5,9)-trimethyldecyl]-4 alpha,10-dimethyl-8-aza-trans-decal-3 beta-ol, a new compound rationally designed to inhibit the 2,3-oxidosqualene cyclase (M. Taton et al., Biochem. biophys. Res. Commun. 138, 764, 1986) was studied as an inhibitor of cholesterol biosynthesis in Swiss 3T3 fibroblasts [12].
• The metabolism of squalene dimethylamine (I), a potent inhibitor of 2,3-oxidosqualene (SO) cyclase, and of sixteen other squalene derivatives was investigated in rat liver microsomes [13].

Associations of Squalene peroxide with other chemical compounds

• Because the components of this gene cluster are required for at least four clearly distinct enzymatic processes (2,3-oxidosqualene cyclization, beta-amyrin oxidation, glycosylation, and acylation), it is unlikely that the cluster has arisen as a consequence of duplication of a common ancestor [14].
• The triple mutant showed no detectable cyclization of squalene, but effectively cyclized 2,3-oxidosqualene to give mono- and pentacyclic triterpene products [15].
• In contrast AMO 1618, a known anticholesterolemic agent reported previously to act at the level of the 2,3-oxidosqualene cyclization step, was not found per se to act on the cyclases [16].
• Inhibition of sterol uptake could not be attributed to 2,3-oxidosqualene or 2,3;22,23-dioxidosqualene but was due to a nonsaturating level of ergosterol produced as a consequence of heme competency through a leaky erg7 mutation [17].
• The first committed step in ginsenoside synthesis is the cyclization of 2,3-oxidosqualene to dammarenediol II by oxidosqualene cyclase, dammarenediol synthase (DDS) [18].

Gene context of Squalene peroxide

• The gene encodes a 728-aa protein that displays homology with squalene-hopene cyclase, providing further evidence that erg7 is the gene encoding 2,3-oxidosqualene cyclase [19].
• The elevation of 2,3-oxidosqualene by ALA was correlated with a fivefold increase in the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 1.1.1.34) [17].
• The yeast lanosterol synthase deficient mutant SMY8 was complemented by the human gene, and a cell-free homogenate of SMY8 expressing the human gene was shown to convert 2,3-oxidosqualene to lanosterol [20].
• It is suggested that recombinant squalene epoxidase catalyzes the conversion of squalene to 2,3-oxidosqualene and of 2,3-oxidosqualene to 2,3;22,23-dioxidosqualene [21].
• However, higher concentrations of BIBX 79 that totally blocked 2,3-oxidosqualene cyclase led to an increase in HMG-CoA reductase activity [7].

Analytical, diagnostic and therapeutic context of Squalene peroxide

• The cDNA encoding cycloartenol synthase [EC 5.4.99.8] has been isolated from pea seedling by an efficient PCR using sets of degenerate primers based on the highly conserved sequences of the known 2,3-oxidosqualene cyclase cDNAs [22].

References