Disease relevance of Sqle

• Expression of a full-length rat SE protein in Escherichia coli confirms this polypeptide as a functional SE [1].
• The relationship between the inhibition of cholesterol biosynthesis and occurrence of myopathy was studied in L6 myoblasts using two lines of cholesterol biosynthesis inhibitors, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (simvastatin) and squalene epoxidase inhibitors (TU-2078 and NB-598) [2].

High impact information on Sqle

• In contrast, intravitreal injection of NB-598, a specific inhibitor of squalene epoxidase, eliminated the conversion of newly synthesized squalene to sterols without obvious pathology [3].
• Supernatant protein factor is a 46-kDa cytosolic protein that stimulates squalene monooxygenase, a downstream enzyme in the cholesterol biosynthetic pathway [4].
• Squalene epoxidase (SE) (EC 1.14.99.7) catalyzes the first oxygenation step in sterol biosynthesis and is suggested to be one of the rate-limiting enzymes in this pathway [1].
• Rat SE cDNA was isolated by selecting yeast transformants expressing rat cDNA in the presence of transformants expressing rat cDNA in the presence of terbinafine, an inhibitor specific for fungal SE [1].
• Rat SE polypeptide deduced from the nucleotide sequence contains 573 amino acids, and its molecular weight is 63,950 Da [1].

Biological context of Sqle

• This region also contains a beta 1-alpha A-beta 2 motif, which is the consensus sequence for an FAD binding domain, suggesting that SE is a flavoenzyme [1].
• Following tellurium intoxication, there was up-regulation of squalene epoxidase activity both in liver (11-fold) and sciatic nerve (fivefold) [5].
• Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts [2].
• To investigate whether cholesterol also modulates microtubule stability in dendrites by modulating MAP2 phosphorylation, we examined the effect of compactin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and TU-2078 (TU), a squalene epoxidase inhibitor, on these parameters using cultured neurons [6].
• Inhibition kinetics revealed that EGCG inhibited SE in noncompetitive (K(I) = 0.74 microM), and non-time-dependent manner [7].

Anatomical context of Sqle

• Trypsin treatment of microsomes totally inactivates squalene epoxidase [8].
• In contrast to rat liver microsomal squalene epoxidase, the enzyme of CHO cells is only slightly activated by the autologous cytosolic fraction, whereas phosphatidylglycerol or rat liver cytosolic preparations are potent stimulators of this enzyme [9].
• Administration of tellurium (Te) in weaning rats causes a well-established demyelinating neuropathy induced by the inhibition in myelinating Schwann cells (SC) of the synthesis of cholesterol, a major component of the myelin sheath, at the level of squalene epoxidase [10].
• We suggest that tellurium feeding inhibits squalene epoxidase activity and that the consequent lack of cholesterol destabilizes myelin, thereby causing destruction of the larger internodes [11].
• The demyelination of peripheral nerves that results from exposure of developing rats to tellurium is due to inhibition of squalene epoxidase, a step in cholesterol biosynthesis [12].

Associations of Sqle with chemical compounds

• The expression of rat SE in the isolated terbinafine-resistant clone was confirmed by its survival in the presence of either terbinafine or an inhibitor specific for mammalian SE, NB-598, but not in the presence of both terbinafine and NB-598 [1].
• This deduced rat SE sequence is 30.2% identical to the ERG 1 gene, which encodes SE from an allylamine-resistant Saccharomyces cerevisiae mutant [1].
• Squalene-enriched, trypsinized microsomes display no squalene epoxidase activity either as such or when combined with normal microsomes [13].
• Neither Fraction A nor B alone has significant squalene epoxidase activity but combining the two affords a reconstituted system 5-fold higher in specific epoxidase activity than that of the original microsomes [14].
• Tellurite specifically affects squalene epoxidase: investigations examining the mechanism of tellurium-induced neuropathy [5].

Regulatory relationships of Sqle

• A soluble protein termed "supernatant protein factor" (SPF) that stimulates microsomal squalene epoxidase has been isolated in this laboratory (Ferguson, J.B., and Bloch, K. (1977) J. Biol. Chem. 252, 5381-5385) [15].
• We examined potassium tellurite (K2TeO3) and three organotellurium compounds for their ability to inhibit squalene epoxidase in Schwann cell cultures and to induce demyelination in weanling rats [16].

Other interactions of Sqle

• The accelerated degradation of HMG-CoA reductase in met-18b-2 cells, which is induced by the addition of MVA, was inhibited by the presence of the squalene synthase inhibitor, zaragozic acid/squalestatin, or the squalene epoxidase inhibitor, NB-598 [17].
• Regulation of rat liver microsomal squalene epoxidase: inactivation of the supernatant protein factor by nucleotides [18].
• The squalene epoxidase activity was reconstituted with the purified enzyme, NADPH-cytochrome P-450 reductase (EC 1.6.2.4), FAD, NADPH and molecular oxygen in the presence of Triton X-100 [19].

Analytical, diagnostic and therapeutic context of Sqle

• This is the first report of the molecular cloning of mammalian SE [1].
• The same detergent solubilizes the microsomal squalene epoxidase and the resulting supernatant can be separated into two components, A and B, by DEAE-cellulose chromatography [14].
• The accumulation of mRNA for hsc70, hsp70, c-fos, c-jun, and Erg-1 was localized coincidently and was restricted to the ischaemic area of the heart. mRNA for these genes was undetectable at the end of the ischaemic period (no reperfusion) [20].
• Photoaffinity labeling and site-directed mutagenesis of rat squalene epoxidase [21].

References