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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: The findings indicate that androgens may promote cholesterol biosynthesis in the meibomian gland, and this research demonstrates that testosterone stimulates a significant increase in the mRNA levels of mevalonate kinase, phosphomeValonate Kinase, and phosphomevalonates kinase.
Abstract: Purpose: We tested our hypothesis that testosterone increases the meibomian gland gene expression of numerous enzymes in the cholesterol biosynthetic pathway. Methods: Meibomian glands were obtained from castrated mice treated with vehicle or testosterone for 2 weeks. Tissues were processed for the analysis of selected mRNAs by real-time PCR. Results: Our research demonstrates that testosterone stimulates a significant increase in the mRNA levels of mevalonate kinase, phosphomevalonate kinase, mevalonate pyrophosphate decarboxylase, isopentenyl pyrophosphate isomerase, geranylgeranyl pyrophosphate synthase, squalene epoxidase, lanosterol synthase, lanosterol demethylase, and Δ 7-sterol reductase. Conclusions: Our findings indicate that androgens may promote cholesterol biosynthesis in the meibomian gland.

32 citations

Journal ArticleDOI
TL;DR: This study discovers that a marine bacterium produces two arborinols, a class of lipids previously identified only in flowering plants, and identifies two isoarborinol-like lipids, eudoraenol and adriaticol, produced by the aerobic marine heterotrophic bacterium EudoraeaAdriatica.
Abstract: Cyclic triterpenoids are a broad class of polycyclic lipids produced by bacteria and eukaryotes. They are biologically relevant for their roles in cellular physiology, including membrane structure and function, and biochemically relevant for their exquisite enzymatic cyclization mechanism. Cyclic triterpenoids are also geobiologically significant as they are readily preserved in sediments and are used as biomarkers for ancient life throughout Earth's history. Isoarborinol is one such triterpenoid whose only known biological sources are certain angiosperms and whose diagenetic derivatives (arboranes) are often used as indicators of terrestrial input into aquatic environments. However, the occurrence of arborane biomarkers in Permian and Triassic sediments, which predates the accepted origin of angiosperms, suggests that microbial sources of these lipids may also exist. In this study, we identify two isoarborinol-like lipids, eudoraenol and adriaticol, produced by the aerobic marine heterotrophic bacterium Eudoraea adriatica Phylogenetic analysis demonstrates that the E. adriatica eudoraenol synthase is an oxidosqualene cyclase homologous to bacterial lanosterol synthases and distinct from plant triterpenoid synthases. Using an Escherichia coli heterologous sterol expression system, we demonstrate that substitution of four amino acid residues in a bacterial lanosterol synthase enabled synthesis of pentacyclic arborinols in addition to tetracyclic sterols. This variant provides valuable mechanistic insight into triterpenoid synthesis and reveals diagnostic amino acid residues to differentiate between sterol and arborinol synthases in genomic and metagenomic datasets. Our data suggest that there may be additional bacterial arborinol producers in marine and freshwater environments that could expand our understanding of these geologically informative lipids.

32 citations

Journal ArticleDOI
TL;DR: The synthesis and biological evaluation of three new sulfur-substituted oxidosqualene (OS) analogues are presented, and the S-18 analogue 3 showed the most potent inhibition toward the rat liver enzyme and showed potent, selective inhibition against the fungal enzyme, making it the most powerful OSC inhibitor known to date.
Abstract: The synthesis and biological evaluation of three new sulfur-substituted oxidosqualene (OS) analogues (1-3) are presented. In these analogues, C-11, C-15, or C-18 in the OS skeleton was replaced by sulfur. The sulfur position in the OS skeleton was chosen to disrupt one or more key processes involved in cyclization: (a) the folding of the B-ring into a boat conformation, (b) the anti-Markovnikov cyclization leading to the C-ring, or (c) the formation of the D-ring during the lanosterol biosynthesis. Enzyme inhibition kinetics using homogeneous mammalian oxidosqualene cyclases (OSC) were also examined for the previously reported S-19 analogue 4. The four analogues were potent inhibitors of mammalian OSCs (IC50 = 0.05-2.3 microM for pig and rat liver OSC) and fungal cell-free Candida albicans OSC (submicromolar IC50 values). In particular, the S-18 analogue 3 showed the most potent inhibition toward the rat liver enzyme (IC50 = 50 nM) and showed potent, selective inhibition against the fungal enzyme (IC50 = 0.22 nM, 10-fold more potent than the S-19 analogue 4). Thus, 3 is the most potent OSC inhibitor known to date. The Ki values ranged from 0.5 to 4.5 microM for pig OSC, with 3 and 4 showing about 10-fold higher potency for rat liver OSC. Interestingly, the S-18 analogue 3 showed time-dependent irreversible inhibition with homogeneous pig liver OSC (kinact = 0.06 min-1) but not with rat OSC.

32 citations

Journal ArticleDOI
TL;DR: A combinatorial library was prepared and used to identify lead compounds that inhibit the growth of Trypanosoma cruzi, Leishmania mexicana amazonensis, and Pneumocystis carinii in culture.
Abstract: Small-molecule oxidosqualene cyclase (OSC) inhibitors were found to be effective in assays against cloned OSC-like enzymes from human pathogens. A combinatorial library was prepared and used to identify lead compounds that inhibit the growth of Trypanosoma cruzi, Leishmania mexicana amazonensis, and Pneumocystis carinii in culture. Selectivity for the microorganisms in preference to mammalian cells was observed.

31 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

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