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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 portion of the human lanosterol synthase cDNA was cloned from a brain cDNA library and determined its nucleotide sequence and the predicted human protein shows 83% identity to its rat and 40% to its yeast homolog.
Abstract: In order to contribute to the development of the transcriptional map of human chromosome 21 (HC21) we have used exon trapping to identify portions of HC21 genes. Using pools of random HC21-specific cosmids from the LL21NC02-Q library and cosmids from 21q22.3 we have identified five different coding regions with strong homology to the lanosterol synthase genes of rat and yeast. This enzyme catalyzes the cyclization of squalene-2,3-epoxide lanosterol, which is the parental compound of all steroids in mammals. Using somatic cell hybrids and HC21 yeast artificial chromosomes (YACS) and cosmids, we mapped the human lanosterol synthase cDNA gene to 2lq22.3 between markers D21S25 and 21qter. Cosmid Q7G8 from the LL21NC02-Q library and YAC 145D8 from the CEPH HC21 contig contain this human gene. We cloned a portion of the human lanosterol synthase cDNA (almost 85% of the coding region) from a brain cDNA library and determined its nucleotide sequence. The predicted human protein shows 83% identity to its rat and 40% to its yeast homolog. No obvious candidate human disease exists for lanosterol synthase deficiency and the role (if any) of triplication of this gene in the various phenotypes of trisomy 21 is unknown.

17 citations

Journal ArticleDOI
TL;DR: The E3 ubiquitin ligase membrane-associated ring-CH-type finger 6 (MARCH6), known to control earlier rate-limiting steps in cholesterol synthesis, also control levels of LDM and the terminal cholesterol synthesis enzyme, 24-dehydrocholesterol reductase, and indicates new facets in the control of cholesterol synthesis.
Abstract: Cholesterol synthesis is a tightly controlled pathway, with over 20 enzymes involved. Each of these enzymes can be distinctly regulated, helping to fine-tune the production of cholesterol and its functional intermediates. Several enzymes are degraded in response to increased sterol levels, whilst others remain stable. We hypothesised that an enzyme at a key branch point in the pathway, lanosterol 14α-demethylase (LDM) may be post-translationally regulated. Here, we show that the preceding enzyme, lanosterol synthase is stable, whilst LDM is rapidly degraded. Surprisingly, this degradation is not triggered by sterols. However, the E3 ubiquitin ligase membrane-associated ring-CH-type finger 6 (MARCH6), known to control earlier rate-limiting steps in cholesterol synthesis, also control levels of LDM and the terminal cholesterol synthesis enzyme, 24-dehydrocholesterol reductase. Our work highlights MARCH6 as the first example of an E3 ubiquitin ligase that targets multiple steps in a biochemical pathway and indicates new facets in the control of cholesterol synthesis.

17 citations

Journal Article
TL;DR: In this paper, the product specificity of OSC at the hydride/methyl-shifting stage is shown to be determined by the stabilization of the cationic intermediates, as the precursor of lanosterol is in fact not the most stable intermediate for wild-type OSC.
Abstract: Oxidosqualene-lanosterol cyclase (OSC) is a key enzyme in the biosynthesis of cholesterol. The catalytic mechanism and the product specificity of OSC have herein been studied using QM/MM calculations. According to our calculations, the protonation of the epoxide ring of oxidosqualene is rate-limiting. Wild-type OSC (which generates lanosterol), and the mutants H232S (which generates parkeol) and H232T (which generates protosta-12,24-dien-3-β-ol) were modeled, in order to explain the product specificity thereof. We show that the product specificity of OSC at the hydride/methyl-shifting stage is unlikely to be achieved by the stabilization of the cationic intermediates, as the precursor of lanosterol is in fact not the most stable cationic intermediate for wild-type OSC. The energy barriers for the product-determining conversions are instead found to be related to the product specificity of different OSC mutants, and we thus suggest that the product specificity of OSC is likely to be controlled by kinetics, rather than thermodynamics.

17 citations

Journal ArticleDOI
TL;DR: Inotodiol 1a has been stereospecifically synthesised from lanosterol in six steps and Horeau's method utilised to demonstrate the R-configuration at C-22.

17 citations

Journal ArticleDOI
TL;DR: The absence of feedback regulation of cholesterol biosynthesis in hepatomas suggests the possibility of substitution of cholesterol with its biosynthetic precursors (7-dehydrocholesterol or lanosterol), which is much less effective in supporting vital cell functions (including barrier properties of natural membranes) compared to cholesterol.

17 citations


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