54274-53-2Relevant academic research and scientific papers
Sterol biosynthesis by a prokaryote: First in vitro identification of the genes encoding squalene epoxidase and lanosterol synthase from Methylococcus capsulatus
Nakano, Chiaki,Motegi, Akihiro,Sato, Tsutomu,Onodera, Masayuki,Hoshino, Tsutomu
, p. 2543 - 2550 (2007)
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.
Catalytic enantioselective synthesis of (3S)-2,3-oxidosqualene
Corey,Yi,Matsuda
, p. 2319 - 2322 (1992)
An efficient and simple enantioselective process is described for the synthesis of (3S)-2,3-oxidosqualene (1) which provides this valuable compound contaminated with only 4% of the R enantiomer. The synthesis employs a chiral catalyst which is efficiently recovered for use.
Sequential enzymatic epoxidation involved in polyether lasalocid biosynthesis
Minami, Atsushi,Shimaya, Mayu,Suzuki, Gaku,Migita, Akira,Shinde, Sandip S.,Sato, Kyohei,Watanabe, Kenji,Tamura, Tomohiro,Oguri, Hiroki,Oikawa, Hideaki
, p. 7246 - 7249 (2012)
Enantioselective epoxidation followed by regioselective epoxide opening reaction are the key processes in construction of the polyether skeleton. Recent genetic analysis of ionophore polyether biosynthetic gene clusters suggested that flavin-containing monooxygenases (FMOs) could be involved in the oxidation steps. In vivo and in vitro analyses of Lsd18, an FMO involved in the biosynthesis of polyether lasalocid, using simple olefin or truncated diene of a putative substrate as substrate mimics demonstrated that enantioselective epoxidation affords natural type mono- or bis-epoxide in a stepwise manner. These findings allow us to figure out enzymatic polyether construction in lasalocid biosynthesis.
Design and characterization of Squalene-Gusperimus nanoparticles for modulation of innate immunity
Navarro Chica, Carlos E.,de Haan, Bart J.,Faas,Smink, Alexandra M.,Sierra, Ligia,de Vos, Paul,López, Betty L.
, (2020/10/02)
Immunosuppressive drugs are widely used for the treatment of autoimmune diseases and to prevent rejection in organ transplantation. Gusperimus is a relatively safe immunosuppressive drug with low cytotoxicity and reversible side effects. It is highly hydrophilic and unstable. Therefore, it requires administration in high doses which increases its side effects. To overcome this, here we encapsulated gusperimus as squalene-gusperimus nanoparticles (Sq-GusNPs). These nanoparticles (NPs) were obtained from nanoassembly of the squalene gusperimus (Sq-Gus) bioconjugate in water, which was synthesized starting from squalene. The size, charge, and dispersity of the Sq-GusNPs were optimized using the response surface methodology (RSM). The colloidal stability of the Sq-GusNPs was tested using an experimental block design at different storage temperatures after preparing them at different pH conditions. Sq-GusNPs showed to be colloidally stable, non-cytotoxic, readily taken up by cells, and with an anti-inflammatory effect sustained over time. We demonstrate that gusperimus was stabilized through its conjugation with squalene and subsequent formation of NPs allowing its controlled release. Overall, the Sq-GusNPs have the potential to be used as an alternative in approaches for the treatment of different pathologies where a controlled release of gusperimus could be required.
Investigation of the Effects of Squalene and Squalene Epoxides on the Homeostasis of Coenzyme Q10 in Rats by UPLC-Orbitrap MS
Yu, Wenjing,Sun, Kaiju,Zhang, Liying,Wan, Xilin,Chen, Changbao,Su, Rui,Liu, Yifei,Wang, Hongfeng,Yang, Hongmei
, (2020/08/05)
Squalene has been used as a dietary supplement for a long history due to its potential cancer-preventive function. However, the mechanism has not been investigated in detail yet. Therefore, the aim of this study is to see if the plasma coenzyme Q10 (CoQ10) level will be altered by gavage of squalene and oxidosqualenes to rats. In the present work, a sensitive and simple high-performance analytical method based on ultra-high-performance liquid chromatography coupled with an Orbitrap mass spectrometry (UPLC-Orbitrap-MS) was developed for the quantification of CoQ10 in rat plasma. Coenzyme Q9 (CoQ9) was employed as the internal standard. CoQ10 was determined after acetonitrile-mediated plasma protein precipitation using UPLC-Orbitrap-MS in negative ion mode. Intragastric administration of squalene and the two squalene epoxides into rats once daily for several days elevated the level of CoQ10 in their plasma, but there was no significant difference between high-dose (286 mg/kg) and low-dose (143 mg/kg) groups. Intragastric administration of squalene once a day for 5 consecutive days and oxidosqualenes once a day for 3 consecutive days is necessary for reaching the steady-state level of CoQ10. Our present findings indicate that squalene and oxidosqualenes may be useful for stimulating the synthesis of CoQ10 in rats.
Nanolipid-trehalose conjugates and nano-assemblies as putative autophagy inducers
Colombo, Eleonora,Biocotino, Michele,Frapporti, Giulia,Randazzo, Pietro,Christodoulou, Michael S.,Piccoli, Giovanni,Polito, Laura,Seneci, Pierfausto,Passarella, Daniele
, (2019/09/10)
The disaccharide trehalose is an autophagy inducer, but its pharmacological application is severely limited by its poor pharmacokinetics properties. Thus, trehalose was coupled via suitable spacers with squalene (in 1:2 and 1:1 stoichiometry) and with betulinic acid (1:2 stoichiometry), in order to yield the corresponding nanolipid-trehalose conjugates 1-Sq-mono, 2-Sq-bis and 3-Be-mono. The conjugates were assembled to produce the corresponding nano-assemblies (NAs) Sq-NA1, Sq-NA2 and Be-NA3. The synthetic and assembly protocols are described in detail. The resulting NAs were characterized in terms of loading and structure, and tested in vitro for their capability to induce autophagy. Our results are presented and thoroughly commented upon.
Functional characterization of squalene epoxidase and NADPH-cytochrome P450 reductase in Dioscorea zingiberensis
Song, Wei,Yan, Shan,Li, Yi,Feng, Shan,Zhang, Jia-jiao,Li, Jia-ru
, p. 822 - 827 (2019/02/05)
Dioscorea zingiberensis is a perennial medicinal herb rich in a variety of pharmaceutical steroidal saponins. Squalene epoxidase (SE) is the key enzyme in the biosynthesis pathways of triterpenoids and sterols, and catalyzes the epoxidation of squalene in coordination with NADPH-cytochrome P450 reductase (CPR). In this study, we cloned DzSE and DzCPR gene sequences from D. zingiberensis leaves, encoding proteins with 514 and 692 amino acids, respectively. Recombinant proteins were successfully expressed in vitro, and enzymatic analysis indicated that, when SE and CPR were incubated with the substrates squalene and NADPH, 2,3-oxidosqualene was formed as the product. Subcellular localization revealed that both the DzSE and DzCPR proteins are localized to the endoplasmic reticulum. The changes in transcription of DzSE and DzCPR were similar in several tissues. DzSE expression was enhanced in a time-dependent manner after methyl jasmonate (MeJA) treatments, while DzCPR expression was not inducible.
Translation of nanomedicines from lab to industrial scale synthesis: The case of squalene-adenosine nanoparticles
Dormont, Flavio,Rouquette, Marie,Mahatsekake, Clement,Gobeaux, Frédéric,Peramo, Arnaud,Brusini, Romain,Calet, Serge,Testard, Fabienne,Lepetre-Mouelhi, Sinda,Desma?le, Didier,Varna, Mariana,Couvreur, Patrick
, p. 302 - 314 (2019/07/12)
A large variety of nanoparticle-based delivery systems have become increasingly important for diagnostic and/or therapeutic applications. Yet, the numerous physical and chemical parameters that influence both the biological and colloidal properties of nanoparticles remain poorly understood. This complicates the ability to reliably produce and deliver well-defined nanocarriers which often leads to inconsistencies, conflicts in the published literature and, ultimately, poor translation to the clinics. A critical issue lies in the challenge of scaling-up nanomaterial synthesis and formulation from the lab to industrial scale while maintaining control over their diverse properties. Studying these phenomena early on in the development of a therapeutic agent often requires partnerships between the public and private sectors which are hard to establish. In this study, through the particular case of squalene-adenosine nanoparticles, we reported on the challenges encountered in the process of scaling-up nanomedicines synthesis. Here, squalene (the carrier) was functionalized and conjugated to adenosine (the active drug moiety) at an industrial scale in order to obtain large quantities of biocompatible and biodegradable nanoparticles. After assessing nanoparticle batch-to-batch consistency, we demonstrated that the presence of squalene analogs resulting from industrial scale-up may influence several features such as size, surface charge, protein adsorption, cytotoxicity and crystal structure. These analogs were isolated, characterized by multiple stage mass spectrometry, and their influence on nanoparticle properties further evaluated. We showed that slight variations in the chemical profile of the nanocarrier's constitutive material can have a tremendous impact on the reproducibility of nanoparticle properties. In a context where several generics of approved nanoformulated drugs are set to enter the market in the coming years, characterizing and solving these issues is an important step in the pharmaceutical development of nanomedicines.
Squalene-Hopene Cyclase: On the Polycyclization Reactions of Squalene Analogues Bearing Ethyl Groups at Positions C-6, C-10, C-15, and C-19
Takahashi, Kazunari,Sasaki, Yusuke,Hoshino, Tsutomu
supporting information, p. 1477 - 1490 (2018/04/06)
Squalene-hopene cyclase (SHC) has been found to convert acyclic squalene into 6,6,6,6,5-fused pentacyclic triterpenes hopene and hopanol. The enzymatic reactions of squalene analogues bearing ethyl groups in lieu of methyl groups at positions C-6, C-10, C-15, and C-19 have been examined to investigate whether the larger ethyl substituents (a C1 unit increment) are accepted as substrates and to investigate how these substitutions affect polycyclization cascades. Analogue 6-ethylsqualene 19a did not cyclize, which indicates that substitution with the bulky group at C-6 completely inhibited the polycyclization reaction. In contrast, 19-ethylsqualene 19b afforded a wide spectrum of cyclization products, including mono-, bi-, tetra-, and pentacyclic products in a ratio of 6:6:1:2. The production of tetra- and pentacyclic scaffolds suggests that the reaction cavity for D-ring formation site is somewhat loosely packed and can accept the 19-ethyl group, and that a robust hydrophobic interaction exists between the 19-ethyl group and the binding site. In contrast to 19b, 10-ethylsqualene 20a and 15-ethylsqualene 20b afforded mainly mono- and bicyclic products, that is, the polycyclization cascade terminated prematurely at the bicyclic reaction stage. Therefore, the catalytic domains for the 10- and 15-methyl binding sites are tightly packed and cannot fully accommodate the Et substituents. The cyclization pathways followed by the ethyl-substituted substrates in the presence of SHC and lanosterol and β-amyrin synthases are compared.
OLIGONUCLEOTIDE COMPOSITIONS AND METHODS THEREOF
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Paragraph 001394, (2017/04/23)
Among other things, the present disclosure relates to designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide altered splicing of a transcript. In some embodiments, provided oligonucleotide compositions have low toxicity. In some embodiments, provided oligonucleotide compositions provide improved protein binding profiles. In some embodiments, provided oligonucleotide compositions have improved delivery. In some embodiments, provided oligonucleotide compositions have improved uptake. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions.
