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Lanosterol

About: Lanosterol is a research topic. Over the lifetime, 1239 publications have been published within this topic receiving 36737 citations. The topic is also known as: (3β)-lanosta-8,24-dien-3-ol & (3β,20R)-lanosta-8,24-dien-3-ol.


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Journal ArticleDOI
TL;DR: A convergent asymmetric synthesis of 11-fluoro-2,3oxidosqualene (11-FOS, 14 ), which was cyclized by bacterial squalene:hopane cyclase to a bridged ether, was presented in this article.

31 citations

Journal ArticleDOI
TL;DR: Triterpene cyclases constitute a family of enzymes that catalyze diverse and complex carbocationic cyclization/rearrangement reactions of squalene and (3S)-2,3-oxidosqualene (OS) to generate a distinct array of sterols and triterpenes as mentioned in this paper.
Abstract: Triterpene cyclases constitute a family of enzymes that catalyze diverse and complex carbocationic cyclization/rearrangement reactions of squalene and (3S)-2,3-oxidosqualene (OS) to generate a distinct array of sterols and triterpenes. A major determinant for the triterpenoid diversity is believed to be the precise control of conformation between substrate and enzyme, as well as the position of the carbocation intermediate formation. For example, both oxidosqualene-lanosterol cyclase (ERG7, EC 5.4.99.7) and oxidosqualene-cycloartenol synthase (CAS, EC 5.4.99.8) bind oxidosqualene in a chair–boat– chair conformation, initiate and propagate cyclization to form a protosteryl cation, and then promote 1,2-shifts of hydride and methyl groups to the lanosteryl C8 cation. The lanosterol formation is accomplished through the final deprotonation, abstracting a proton originally at C9 or after a hydride shift from C9 to C8. Cycloartenol is formed after a hydride shift from C9 to C8, followed by 9b,19-cyclopropane ring closure. Elegant molecular-genetic and bioorganic investigations have recently identified several amino acid residues that are critical in probing putative active sites and determining prod-

31 citations

Journal ArticleDOI
TL;DR: Several critical residues from oxidationosqualene-lanosterol cyclase (ERG7) from Saccharomyces cerevisiae and oxidosqualenecycloartenol synthase (CAS) from Arabidopsis thaliana are identified and demonstrated their roles in facilitating tetracyclic formation and/or stabilizing the lanosteryl cation for deprotonation.
Abstract: Oxidosqualene cyclases catalyze the biotransformation of acyclic (3S)-2,3-oxidosqualene (OS) to a variety of polycyclic sterols and triterpenoids, generating over 100 distinct triterpenoid skeletons with the formula C30H50O. [1–3,4 and references therein] Product specificity is species-dependent and precisely controlled by the prefolded substrate conformation as well as by interactions between the carbocationic intermediate for deprotonation and the functional groups of catalytic amino acid residues of the enzyme. The transformation mechanisms of this single class of enzymes can vary widely. For example, the triterpenes lanosterol, cycloartenol, and parkeol are formed from a preorganized chair–boat–chair substrate conformation of OS, and cationic cyclization to the protosteryl cation is followed by skeletal rearrangements until the final deprotonation step. Formation of the pentacyclic b-amyrin and lupeol proceed similarly except that OS is in the chair–chair–chair conformation (this results in stereochemical differences in the products relative to the chair–boat–chair substrate conformation), and the cationic cyclization to the dammarenyl cation is followed by annulation of a fifth ring. Various strategies have been used to probe the complex cyclization/rearrangement reaction mechanism, both for the purpose of understanding these complex enzymes and also to engineer cyclases to generate new product profiles. For example, site-directed mutagenesis was used to identify the residues responsible for the product specificity of b-amyrin synthase (PNY) and lupeol synthase (OEW). Two residues of PNY from Panax ginseng, Trp259 and Tyr261, were found to play important roles in the reaction mechanism to direct b-amyrin and/or lupeol formation. We and others independently identified several critical residues from oxidosqualene-lanosterol cyclase (ERG7) from Saccharomyces cerevisiae and oxidosqualenecycloartenol synthase (CAS) from Arabidopsis thaliana, and demonstrated their roles in facilitating tetracyclic formation and/or stabilizing the lanosteryl cation for deprotonation, as

30 citations

Journal ArticleDOI
TL;DR: This is the first report demonstrating the existence of the genes encoding squalene epoxidase and lanosterol synthase in prokaryotes by establishing the enzyme activities.
Abstract: Sterol biosynthesis by prokaryotic organisms is very rare. Squalene epoxidase and lanosterol synthase are prerequisite to cyclic sterol biosynthesis. These two enzymes, from the methanotrophic bacterium Methylococcus capsulatus, were functionally expressed in Escherichia coli. Structural analyses of the enzymatic products indicated that the reactions proceeded in a complete regio- and stereospecific fashion to afford (3S)-2,3-oxidosqualene from squalene and lanosterol from (3S)-2,3-oxidosqualene, in full accordance with those of eukaryotes. However, our result obtained with the putative lanosterol synthase was inconsistent with a previous report that the prokaryote accepts both (3R)- and (3S)-2,3-oxidosqualenes to afford 3-epi-lanosterol and lanosterol, respectively. This is the first report demonstrating the existence of the genes encoding squalene epoxidase and lanosterol synthase in prokaryotes by establishing the enzyme activities. The evolutionary aspect of prokaryotic squalene epoxidase and lanosterol synthase is discussed.

30 citations

Journal ArticleDOI
TL;DR: Co results in a qualitative as well as a quantitative difference in the 4,4-dimethyl sterol fraction which arises during cholesterol biosynthesis from mevalonic acid, suggesting that enzymic reduction of the sterol side chain occurs predominantly at a stage after that of lanosterol.
Abstract: Cholesterol biosynthesis was studied in rat liver subcellular fractions incubated with dl-[2-14C]mevalonic acid under gas phases consisting of either N2+O2 (90:10) or CO+O2 (90:10). CO inhibits cholesterol biosynthesis from [2-14C]mevalonic acid and results in a large accumulation of radioactive 4,4-dimethyl sterols. Separation of the components of the 4,4-dimethyl sterol fraction showed that lanosterol and dihydrolanosterol are the major components that accumulate during cholesterol biosynthesis in an atmosphere containing CO, whereas 14-demethyl-lanosterol and 14-demethyldihydrolanosterol are the major components of the much less intensely radioactive 4,4-dimethyl sterol fraction isolated from incubations with N2+O2 as the gas phase. The identities of lanosterol, dihydrolanosterol and 14-demethyldihydrolanosterol were confirmed by both radiochemical and physicochemical methods, including g.l.c. and combined g.l.c.–mass spectrometry. CO therefore results in a qualitative as well as a quantitative difference in the 4,4-dimethyl sterol fraction which arises during cholesterol biosynthesis from mevalonic acid. The specific radioactivity of the [14C]lanosterol biosynthesized in the presence of CO was lower than that of its companion, [14C]dihydrolanosterol. The relative amounts of 4,4-dimethyl-Δ24-sterols and 4,4-dimethyl-24,25-dihydrosterols present in each type of incubation suggest that enzymic reduction of the sterol side chain occurs predominantly at a stage after that of lanosterol.

30 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202331
202261
202120
202023
201914
201822