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Lanosterol synthase

About: Lanosterol synthase is a research topic. Over the lifetime, 164 publications have been published within this topic receiving 5954 citations. The topic is also known as: lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase) & lanosterol synthase.


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Journal ArticleDOI
TL;DR: It is shown that the methyl-29 group is critical to the correct folding of 1, with lesser contributions from the other branched methyl groups, such as methyl-26, -27, and -28.
Abstract: Lanosterol synthase catalyzes the polycyclization reaction of (3S)-2,3-oxidosqualene (1) into tetracyclic lanosterol 2 by folding 1 in a chair-boat-chair-chair conformation. 27-Nor- and 29-noroxidosqaulenes (7 and 8, respectively) were incubated with this enzyme to investigate the role of the methyl groups on 1 for the polycyclization cascade. Compound 7 afforded two enzymatic products, namely, 30-norlanosterol (12) and 26-normalabaricatriene (13; 12/13 9:1), which were produced through the normal chair-boat-chair-chair conformation and an atypical chair-chair-boat conformation, respectively. Compound 8 gave two products 14 and 15 (14/15 4:5), which were generated by the normal and the unusual polycyclization pathways through a chair-chair-boat-chair conformation, respectively. It is remarkable that the twist-boat structure for the B-ring formation was changed to an energetically favored chair structure for the generation of 15. Surprisingly, 14 and 15 consisted of a novel 6,6,6,6-fused tetracyclic ring system, thus differing from the 6,6,6,5-fused lanosterol skeleton. Together with previous results, we conclude that the methyl-29 group is critical to the correct folding of 1, with lesser contributions from the other branched methyl groups, such as methyl-26, -27, and -28. Furthermore, we demonstrate that the methyl-29 group has a crucial role in the formation of the five-membered D ring of the lanosterol scaffold.

15 citations

Journal ArticleDOI
TL;DR: From an actinomycete strain, Streptomyces sp.
Abstract: From an actinomycete strain, Streptomyces sp. K99-5041, lanopylins A1, B1, A2 and B2 were isolated as new natural products that inhibited the reaction of recombinant human lanosterol synthase. The crude extract from the whole broth of this strain was fractionated by silica gel column chromatography to afford an active fraction that showed a single spot on TLC. Detailed analyses of this fraction with liquid chromatography-atmospheric pressure chemical ionization mass spectrometry revealed that it contained 20 homologous compounds with differing side chain lengths. The fraction was separated by preparative HPLC to afford four of these homologues, lanopylins A1, B1, A2 and B2. Detailed spectroscopic analyses of these isolated compounds led to the identification of their structures. Lanopylins A1 and B1 were (3E)-isohexadecylmethylidene-2-methyl-1-pyrroline and (3E)-hexadecylmethylidene-2-methyl-1-pyrroline, respectively, and lanopylins A2 and B2 were homologues with the insertion of one cis-ethylenylidene in the side chain of lanopylins A1 and B1, respectively. These compounds inhibited recombinant human lanosterol synthase with IC50 values of 15, 18, 33, and 41μM, respectively.

15 citations

Journal ArticleDOI
TL;DR: It is demonstrated that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.

15 citations

Journal ArticleDOI
TL;DR: In vivo inhibition of 2,3-oxidosqualene:lanosterol cyclase by Ro 48-8071 results in an indirect down-regulation of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) activity, which is attributed to increased levels of oxysterols, produced upon partial inhibition of OSC, that suppress HMGR and other sterol-responsive genes.

15 citations

Journal ArticleDOI
TL;DR: A cDNA for oxidosqualene:lanosterol cyclase (OSLC) was cloned and sequenced from the fungus Cephalosporium caerulens, that produces a steroidal antibiotic, helvolic acid, and the active site residues, H234 and D456, were chosen for site-directed mutagenesis experiments.

15 citations

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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20216
20206
20194
20188
201711
20165