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https://www.readbyqxmd.com/read/28811501/characterisation-of-sterol-biosynthesis-and-validation-of-14%C3%AE-demethylase-as-a-drug-target-in-acanthamoeba
#1
Scott Thomson, Christopher A Rice, Tong Zhang, RuAngelie Edrada-Ebel, Fiona L Henriquez, Craig W Roberts
The soil amoebae Acanthamoeba causes Acanthamoeba keratitis, a severe sight-threatening infection of the eye and the almost universally fatal granulomatous amoebic encephalitis. More effective treatments are required. Sterol biosynthesis has been effectively targeted in numerous fungi using azole compounds that inhibit the cytochrome P450 enzyme sterol 14α-demethylase. Herein, using Gas Chromatography Mass Spectrometry (GCMS), we demonstrate that the major sterol of Acanthamoeba castellanii is ergosterol and identify novel putative precursors and intermediate sterols in its production...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28750236/development-validation-and-application-of-a-gc-ms-method-for-the-simultaneous-detection-and-quantification-of-neutral-lipid-species-in-trypanosoma-cruzi
#2
Mery Santivañez-Veliz, Elsa Moreno-Viguri, Silvia Pérez-Silanes, Javier Varela, Hugo Cerecetto, Mercedes González, Elena Lizarraga
The development and validation of an analytical method for the simultaneous analysis of five neutral lipids in Trypanosoma cruzi epimastigotes by GC-MS is presented in this study. The validated method meets all validation parameters for all components and the chromatographic conditions have been optimized during its development. This analytical method has demonstrated good selectivity, accuracy, within-day precision, recovery and linearity in each of the established ranges. In addition, detection and quantification limits for squalene, cholesterol, ergosterol and lanosterol have been improved and it is worth highlighting the fact that this is the first time that squalene-2,3-epoxide validation data have been reported...
July 19, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28713270/evaluation-of-selected-cyp51a1-polymorphisms-in-view-of-interactions-with-substrate-and-redox-partner
#3
Tadeja Režen, Iza Ogris, Marko Sever, Franci Merzel, Simona Golic Grdadolnik, Damjana Rozman
Cholesterol is essential for development, growth, and maintenance of organisms. Mutations in cholesterol biosynthetic genes are embryonic lethal and few polymorphisms have been so far associated with pathologies in humans. Previous analyses show that lanosterol 14α-demethylase (CYP51A1) from the late part of cholesterol biosynthesis has only a few missense mutations with low minor allele frequencies and low association with pathologies in humans. The aim of this study is to evaluate the role of amino acid changes in the natural missense mutations of the hCYP51A1 protein...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28698522/design-synthesis-and-biological-activity-of-new-triazole-and-nitro-triazole-derivatives-as-antifungal-agents
#4
Hossein Sadeghpour, Soghra Khabnadideh, Kamiar Zomorodian, Keyvan Pakshir, Khadijeh Hoseinpour, Nabiollah Javid, Ehsan Faghih-Mirzaei, Zahra Rezaei
In this study two series of fluconazole derivatives bearing nitrotriazole (series A) or piperazine ethanol (series B) side chain were designed and synthesized and then docked in the active site of lanosterol 14α-demethylase enzyme (1EA1) using the Autodock 4.2 program (The scripps research institute, La Jolla, CA, USA). The structures of synthesized compound were confirmed by various methods including elemental and spectral (NMR, CHN, and Mass) analyses. Then antifungal activities of the synthesized compound were tested against several natural and clinical strains of fungi using a broth microdilution assay against several standard and clinical fungi...
July 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28667115/cgmed3-changes-membrane-sterol-composition-to-help-candida-glabrata-tolerate-low-ph-stress
#5
Xiaobao Lin, Yanli Qi, Dongni Yan, Hui Liu, Xiulai Chen, Liming Liu
Candida glabrata is a promising microorganism for organic acid production. The present study aimed to investigate the role of Mediator complex subunit 3 (CgMed3p) in protecting C. glabrata at low pH conditions. To this end, the genes CgMED3A and CgMED3B were deleted, resulting in the double deletion Cgmed3ABΔ strain. Final biomass and cell viability of Cgmed3ABΔ decreased by 64.5% and 35.8%, respectively, compared to the wild-type at pH 2.0. In addition, lack of CgMed3ABp resulted in selective repression of a subset of genes in the lipid biosynthesis and metabolism pathways...
June 30, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28665796/contamination-of-pine-and-birch-wood-dust-with-microscopic-fungi-and-determination-of-its-sterol-contents
#6
Kinga Stuper-Szablewska, Tomasz Rogoziński, Juliusz Perkowski
Wood compounds, especially sterols, are connected with the level of contamination with microscopic fungi. Within this study, tests were conducted on wood dust samples collected at various work stations in a pine and birch timber conversion plant. Their contamination with mycobiota was measured as the concentration of ergosterol (ERG) by ultra performance liquid chromatography (UPLC). Another aim of this study was to assess the effect of contamination with microscopic fungi on the sterol contents in wood dusts...
June 27, 2017: Arhiv za Higijenu Rada i Toksikologiju
https://www.readbyqxmd.com/read/28658622/lanosterol-modulates-tlr4-mediated-innate-immune-responses-in-macrophages
#7
Elisa Araldi, Marta Fernández-Fuertes, Alberto Canfrán-Duque, Wenwen Tang, Gary W Cline, Julio Madrigal-Matute, Jordan S Pober, Miguel A Lasunción, Dianqing Wu, Carlos Fernández-Hernando, Yajaira Suárez
Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC1) transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNβ-mediated signal transducer and activator of transcription (STAT)1-STAT2 activation and IFNβ-stimulated gene expression...
June 27, 2017: Cell Reports
https://www.readbyqxmd.com/read/28637420/bioinformatics-insights-on-targets-receptors-of-amiodarone-in-human-and-acanthamoeba-castellanii
#8
Abdul Baig, Zohaib Rana, H R Ahmad
BACKGROUND: Amiodarone is prescribed for certain cardiac arrhythmias in medical practice. The drug targets and inhibits voltage dependent sodium (Na+v), calcium (Ca+2v), potassium (K+v) channels, and enzymes like cytochrome P450 and oxidosqualene cyclase. Past studies have shown that amiodarone exerts anti-amoebic effects against Trypanosoma cruzi and Acanthamoeba castellanii. OBJECTIVES: The presence of aforementioned targets and the type of cell death induced by amiodarone in these pathogenic eukaryotes like Acanthamoeba castellanii remain to be verified...
June 21, 2017: Infectious Disorders Drug Targets
https://www.readbyqxmd.com/read/28579986/hiv-aspartic-peptidase-inhibitors-modulate-surface-molecules-and-enzyme-activities-involved-with-physiopathological-events-in-fonsecaea-pedrosoi
#9
Vanila F Palmeira, Daniela S Alviano, Lys A Braga-Silva, Fátima R V Goulart, Marcela Q Granato, Sonia Rozental, Celuta S Alviano, André L S Santos, Lucimar F Kneipp
Fonsecaea pedrosoi is the main etiological agent of chromoblastomycosis, a recalcitrant disease that is extremely difficult to treat. Therefore, new chemotherapeutics to combat this fungal infection are urgently needed. Although aspartic peptidase inhibitors (PIs) currently used in the treatment of human immunodeficiency virus (HIV) have shown anti-F. pedrosoi activity their exact mechanisms of action have not been elucidated. In the present study, we have investigated the effects of four HIV-PIs on crucial virulence attributes expressed by F...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28530827/overexpression-of-the-squalene-epoxidase-gene-alone-and-in-combination-with-the-3-hydroxy-3-methylglutaryl-coenzyme-a-gene-increases-ganoderic-acid-production-in-ganoderma-lingzhi
#10
De-Huai Zhang, Lu-Xi Jiang, Na Li, Xuya Yu, Peng Zhao, Tao Li, Jun-Wei Xu
The squalene epoxidase (SE) gene from the biosynthetic pathway of ganoderic acid (GA) was cloned and overexpressed in Ganoderma lingzhi. The strain that overexpressed the SE produced approximately 2 times more GA molecules than the wild-type (WT) strain. Moreover, SE overexpression upregulated lanosterol synthase gene expression in the biosynthetic pathway. These results indicated that SE stimulates GA accumulation. Then, the SE and 3-hydroxy-3-methylglutaryl coenzyme A (HMGR) genes were simultaneously overexpressed in G...
June 14, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28483956/the-tetrazole-vt-1161-is-a-potent-inhibitor-of-trichophyton-rubrum-through-its-inhibition-of-t-rubrum-cyp51
#11
Andrew G S Warrilow, Josie E Parker, Claire L Price, Edward P Garvey, William J Hoekstra, Robert J Schotzinger, Nathan P Wiederhold, W David Nes, Diane E Kelly, Steven L Kelly
Prior to characterization of antifungal inhibitors that target CYP51, Trichophyton rubrum CYP51 was expressed in Escherichia coli, purified, and characterized. T. rubrum CYP51 bound lanosterol, obtusifoliol, and eburicol with similar affinities (dissociation constant [Kd ] values, 22.7, 20.3, and 20.9 μM, respectively) but displayed substrate specificity, insofar as only eburicol was demethylated in CYP51 reconstitution assays (turnover number, 1.55 min(-1); Km value, 2 μM). The investigational agent VT-1161 bound tightly to T...
July 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28479228/design-strategies-of-oxidosqualene-cyclase-inhibitors-targeting-the-sterol-biosynthetic-pathway
#12
REVIEW
Vitor Won-Held Rabelo, Nelilma Correia Romeiro, Paula Alvarez Abreu
Targeting the sterol biosynthesis pathway has been explored for the development of new bioactive compounds. Among the enzymes of this pathway, oxidosqualene cyclase (OSC) which catalyzes lanosterol cyclization from 2,3-oxidosqualene has emerged as an attractive target. In this work, we reviewed the most promising OSC inhibitors from different organisms and their potential for the development of new antiparasitic, antifungal, hypocholesterolemic and anticancer drugs. Different strategies have been adopted for the discovery of new OSC inhibitors, such as structural modifications of the natural substrate or the reaction intermediates, the use of the enzyme's structural information to discover compounds with novel chemotypes, modifications of known inhibitors and the use of molecular modeling techniques such as docking and virtual screening to search for new inhibitors...
July 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28472585/real-time-imaging-of-the-azole-class-of-antifungal-drugs-in-live-candida-cells
#13
Raphael I Benhamou, Maayan Bibi, Kfir B Steinbuch, Hamutal Engel, Maayan Levin, Yael Roichman, Judith Berman, Micha Fridman
Azoles are the most commonly used class of antifungal drugs, yet where they localize within fungal cells and how they are imported remain poorly understood. Azole antifungals target lanosterol 14α-demethylase, a cytochrome P450, encoded by ERG11 in Candida albicans, the most prevalent fungal pathogen. We report the synthesis of fluorescent probes that permit visualization of antifungal azoles within live cells. Probe 1 is a dansyl dye-conjugated azole, and probe 2 is a Cy5-conjugated azole. Docking computations indicated that each of the probes can occupy the active site of the target cytochrome P450...
May 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28462697/insight-mechanism-of-the-selective-lanosterol-synthase-inhibitor-molecular-modeling-docking-and-density-functional-theory-approaches
#14
Suramanian Karunagaran, Chandrasekaran Meganathan, Rengarajan Kavitha, Muthu Vadivelu, Kuen Woo Lee
BACKGROUND: Lanosterol synthase (Oxidosqualene cyclase) is an enzyme, plays a central role in cholesterol and sterols biosynthesis. Lanosterol synthase drugs used to lower the level of cholesterol in the blood and treat wide variety of diseases like atherosclerosis, coronary heart diseases etc. OBJECTIVE: There is a great interest in the identification of drugs that target this enzyme for anticholesteraemic agent using insilico tools. METHODS: Ligand based pharmacophore model was developed using Discovery Studio 2...
April 26, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28336949/induction-of-apoptosis-and-ganoderic-acid-biosynthesis-by-camp-signaling-in-ganoderma-lucidum
#15
Bang-Jau You, Ni Tien, Miin-Huey Lee, Bo-Ying Bao, Yih-Shyuan Wu, Tsung-Chi Hu, Hong-Zin Lee
Apoptosis is an essential physiological process that controls many important biological functions. However, apoptosis signaling in relation to secondary metabolite biosynthesis in plants and fungi remains a mystery. The fungus Ganoderma lucidum is a popular herbal medicine worldwide, but the biosynthetic regulation of its active ingredients (ganoderic acids, GAs) is poorly understood. We investigated the role of 3',5'-cyclic adenosine monophosphate (cAMP) signaling in fungal apoptosis and GA biosynthesis in G...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28322148/effects-of-exogenous-salicylic-acid-on-ganoderic-acid-biosynthesis-and-the-expression-of-key-genes-in-the-ganoderic-acid-biosynthesis-pathway-in-the-lingzhi-or-reishi-medicinal-mushroom-ganoderma-lucidum-agaricomycetes
#16
Peng-Fei Cao, Chen-Gao Wu, Zhi-Hao Dang, Liang Shi, Ai-Liang Jiang, Ang Ren, Ming-Wen Zhao
We demonstrate herein that salicylic acid (SA) can enhance ganoderic acid (GA) accumulation in the lingzhi or reishi medicinal mushroom Ganoderma lucidum. Following treatment with different concentrations of SA, the GA content was increased 22.72% to 43.04% compared with the control group. When the fungi were treated with 200 μmol/L SA at different times, the GA content was improved 10.21% to 35.24% compared with the control group. By choosing the optimum point based on response surface methodology, the GA content could be increased up to 229...
2017: International Journal of Medicinal Mushrooms
https://www.readbyqxmd.com/read/28314390/oxysterols-in-cosmetics-determination-by-planar-solid-phase-extraction-and-gas-chromatography-mass-spectrometry
#17
S Schrack, C Hohl, W Schwack
Sterol oxidation products (SOPs) are linked to several toxicological effects. Therefore, investigation of potential dietary uptake sources particularly food of animal origin has been a key issue for these compounds. For the simultaneous determination of oxysterols from cholesterol, phytosterols, dihydrolanosterol and lanosterol in complex cosmetic matrices, planar solid phase extraction (pSPE) was applied as clean-up tool. SOPs were first separated from more non-polar and polar matrix constituents by normal phase thin-layer chromatography and then focussed into one target zone...
November 18, 2016: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28303159/antifungal-activity-of-the-ethanol-extract-from-flos-rosae-chinensis-with-activity-against-fluconazole-resistant-clinical-candida
#18
Lulu Zhang, Hui Lin, Wei Liu, Baodi Dai, Lan Yan, YongBing Cao, Yuan-Ying Jiang
This study was designed to investigate the antifungal activity of a hydroalcoholic extract from Flos Rosae Chinensis (FRC) combined with fluconazole (FCZ) against clinical isolates of Candida albicans resistant to FCZ. The minimum inhibitory concentration (MIC) of FRC was determined using a checkerboard microdilution assay. The synergistic effects of the combination of FRC and FCZ against clinical isolates of C. albicans resistant to FCZ were further confirmed by constructing time-growth curves and performing an agar diffusion test...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28294269/%C3%AE-amyrin-biosynthesis-catalytic-mechanism-and-substrate-recognition
#19
REVIEW
Tsutomu Hoshino
The enzymatic polycyclization reactions catalyzed by oxidosqualene (OXSQ) cyclases (OSCs) proceed with complete regio- and stereospecificity, leading to the formation of new C-C bonds and chiral centers and to the generation of diverse polycyclic sterols and triterpenoids. The diverse structural array is remarkable, and approximately 150 different carbon frameworks have been found. Detailed investigations on squalene-hopene cyclase (SHC) and lanosterol synthase (LaS) have been reported, but progress in the study of β-amyrin synthase, which is ubiquitously found in plants, has lagged in comparison...
March 15, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28264842/contributions-of-both-atp-binding-cassette-transporter-and-cyp51a-proteins-are-essential-for-azole-resistance-in-aspergillus-fumigatus
#20
Sanjoy Paul, Daniel Diekema, W Scott Moye-Rowley
While azole drugs targeting the biosynthesis of ergosterol are effective antifungal agents, their extensive use has led to the development of resistant organisms. Infections involving azole-resistant forms of the filamentous fungus Aspergillus fumigatus are often associated with genetic changes in the cyp51A gene encoding the lanosterol α14 demethylase target enzyme. Both a sequence duplication in the cyp51A promoter (TR34) and a substitution mutation in the coding sequence (L98H) are required for the full expression of azole resistance...
May 2017: Antimicrobial Agents and Chemotherapy
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