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Lss  -  lanosterol synthase (2,3-oxidosqualene...

Rattus norvegicus

Synonyms: 2,3-epoxysqualene--lanosterol cyclase, Lanosterol synthase, OSC, Osc, Oxidosqualene--lanosterol cyclase
 
 
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Disease relevance of Lss

 

High impact information on Lss

  • Cataract onset was associated with the specific combination of Lss and Fdft1 mutant alleles that decreased cholesterol levels in cataractous lenses to about 57% of normal [1].
  • A cDNA encoding rat oxidosqualene lanosterol-cyclase [lanosterol synthase; (S)-2,3-epoxysqualene mutase (cyclizing, lanosterol-forming), EC 5.4.99.7] was cloned and sequenced by a combination of PCR amplification, using primers based on internal amino acid sequence of the purified enzyme, and cDNA library screening by oligonucleotide hybridization [2].
  • This result provides the first information on the structural details of the active site of OSC and shows for the first time the ancient lineage of this vertebrate enzyme to ancestral eukaryotic and prokaryotic cyclases [3].
  • The sequence of the first 30 amino acids of this peptide were determined by Edman degradation and showed unexpectedly high similarity to the fungal OSC from Candida albicans (50% identity with Arg413-Val442) and to the bacterial squalene cyclase from Alicyclobacillus (formerly Bacillus) acidocaldarius (37% identity with Lys356-Leu385) [3].
  • Interestingly, the covalently modified DDXX(D/E) sequence of rat liver OSC showed surprising similarity to the putative allylic diphosphate binding site sequence of sesquiterpene cyclases and prenyl transferases [3].
 

Biological context of Lss

  • The resulting structure-activity relationships seem to validate the mechanism of action of these inhibitors as analogs of a pro-C-8 high-energy intermediate and delineate the minimal requirements for the design of efficient isoquinoline-based, or simplified, OSC inhibitors [4].
  • Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition) [5].
  • Enzyme inhibition kinetics using homogeneous mammalian oxidosqualene cyclases (OSC) were also examined for the previously reported S-19 analogue 4 [6].
  • The inhibition of 2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.7) (OSC) by new azasqualene derivatives, mimicking the proC-8 and proC-20 carbocationic high-energy intermediates of the cyclization of 2,3-oxidosqualene to lanosterol, was studied using pig liver microsomes, partially purified preparations of OSC, and yeast microsomes [7].
 

Associations of Lss with chemical compounds

  • These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC [5].
  • In the presence of 17, 19 and 21, only the intermediate metabolites 2,3-oxidosqualene and 2,3,22,23-dioxidosqualene accumulated, demonstrating a very specific inhibition of OSC [7].
  • Compound 21 was a competitive inhibitor of OSC, whereas 17 and 19 were noncompetitive inhibitors, and showed a biphasic time-dependent inactivation of OSC, their apparent binding constants being 250 microM and 213 microM, respectively [7].

References

  1. Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat. Mori, M., Li, G., Abe, I., Nakayama, J., Guo, Z., Sawashita, J., Ugawa, T., Nishizono, S., Serikawa, T., Higuchi, K., Shumiya, S. J. Clin. Invest. (2006) [Pubmed]
  2. Molecular cloning, characterization, and functional expression of rat oxidosqualene cyclase cDNA. Abe, I., Prestwich, G.D. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  3. Active site mapping of affinity-labeled rat oxidosqualene cyclase. Abe, I., Prestwich, G.D. J. Biol. Chem. (1994) [Pubmed]
  4. Structural and stereoelectronic requirements for the inhibition of mammalian 2,3-oxidosqualene cyclase by substituted isoquinoline derivatives. Barth, M.M., Binet, J.L., Thomas, D.M., de Fornel, D.C., Samreth, S., Schuber, F.J., Renaut, P.P. J. Med. Chem. (1996) [Pubmed]
  5. Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: optimization from lipid profiles. Brown, G.R., Hollinshead, D.M., Stokes, E.S., Clarke, D.S., Eakin, M.A., Foubister, A.J., Glossop, S.C., Griffiths, D., Johnson, M.C., McTaggart, F., Mirrlees, D.J., Smith, G.J., Wood, R. J. Med. Chem. (1999) [Pubmed]
  6. Synthesis and inhibition studies of sulfur-substituted squalene oxide analogues as mechanism-based inhibitors of 2,3-oxidosqualene-lanosterol cyclase. Stach, D., Zheng, Y.F., Perez, A.L., Oehlschlager, A.C., Abe, I., Prestwich, G.D., Hartman, P.G. J. Med. Chem. (1997) [Pubmed]
  7. Inhibition of 2,3-oxidosqualene cyclase and sterol biosynthesis by 10- and 19-azasqualene derivatives. Viola, F., Brusa, P., Balliano, G., Ceruti, M., Boutaud, O., Schuber, F., Cattel, L. Biochem. Pharmacol. (1995) [Pubmed]
 
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