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Ceramide synthases

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https://www.readbyqxmd.com/read/28336574/switching-head-group-selectivity-in-mammalian-sphingolipid-biosynthesis-by-active-site-engineering-of-sphingomyelin-synthases
#1
Matthijs Kol, Radhakrishnan Panatala, Mirjana Nordmann, Leoni Swart, Leonie Van Suijlekom, Birol Cabukusta, Angelika Hilderink, Tanja Gabrietz, John G M Mina, Pentti Somerharju, Sergei Korneev, Fikadu G Tafesse, Joost C M Holthuis
Sphingomyelin (SM) is a fundamental component of mammalian cell membranes that contributes to mechanical stability, signaling and sorting. Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, a reaction catalyzed by SM synthase SMS1 in the Golgi and SMS2 at the plasma membrane. Mammalian cells also synthesize trace amounts of the SM analog ceramide phosphoethanolamine (CPE), but the physiological relevance of CPE production is unclear. Previous work revealed that SMS2 is a bifunctional enzyme producing both SM and CPE whereas a closely related enzyme, SMSr/SAMD8, acts as a monofunctional CPE synthase in the ER...
March 23, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28322796/modulation-of-the-sphingolipid-rheostat-is-involved-in-paclitaxel-resistance-of-the-human-prostate-cancer-cell-line-pc3-pr
#2
Yuka Aoyama, Sayaka Sobue, Naoki Mizutani, Chisato Inoue, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Mamoru Kyogashima, Motoshi Suzuki, Yoshinoti Nozawa, Takashi Murate
Taxoids are anti-cancer drugs frequently used to treat solid tumors, but they are sometimes ineffective and tumors may become resistant to their action. Here, we examined the involvement of sphingolipid metabolic enzymes in paclitaxel (PTX) resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. PTX (20 nM) suppressed cell proliferation and increased various ceramide species in PC3, but not PC3-PR, cells. PC3-PR contained higher S1P levels than did PC3, regardless of PTX treatment...
March 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28320857/regulation-of-very-long-acyl-chain-ceramide-synthesis-by-acyl-coa-binding-protein
#3
Natalia Santos Ferreira, Hanne Engelsby, Ditte Neess, Samuel L Kelly, Giora Volpert, Alfred H Merrill, Anthony H Futerman, Nils J Faergeman
Ceramide and more complex sphingolipids constitute a diverse group of lipids, which serve important roles as structural entities of biological membranes and as regulators of cellular growth, differentiation, and development. Thus, ceramides are vital players in numerous diseases including metabolic and cardiovascular diseases as well as neurological disorders. Here we show that acyl coenzyme A binding protein (ACBP) potently facilitates very-long acyl chain ceramide synthesis. ACBP increases the activity of ceramide synthase 2 (CerS2) by more than 2-fold and CerS3 activity by 7-fold...
March 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28273483/ceramide-is-metabolized-to-acylceramide-and-stored-in-lipid-droplets
#4
Can E Senkal, Mohamed F Salama, Ashley J Snider, Janet J Allopenna, Nadia A Rana, Antonius Koller, Yusuf A Hannun, Lina M Obeid
In an approach aimed at defining interacting partners of ceramide synthases (CerSs), we found that fatty acyl-CoA synthase ACSL5 interacts with all CerSs. We demonstrate that ACSL5-generated FA-CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Functionally, inhibition of ceramide channeling to acylceramide enhanced accumulation of de novo ceramide and resulted in augmentation of ceramide-mediated apoptosis. Mechanistically, we show that acylceramide generation is catalyzed by diacylglycerol acyltransferase 2 (DGAT2) on lipid droplets...
March 7, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28223344/an-intestinal-farnesoid-x-receptor-ceramide-signaling-axis-modulates-hepatic-gluconeogenesis-in-mice
#5
Cen Xie, Changtao Jiang, Jingmin Shi, Xiaoxia Gao, Dongxue Sun, Lulu Sun, Ting Wang, Shogo Takahashi, Mallappa Anitha, Kristopher W Krausz, Andrew D Patterson, Frank J Gonzalez
Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota-FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-β-muricholic acid, which selectively suppresses intestinal FXR signaling...
March 2017: Diabetes
https://www.readbyqxmd.com/read/28198542/ceramide-synthase-2-facilitates-s1p-dependent-egress-of-thymocytes-into-the-circulation-in-mice
#6
Michael Rieck, Christiane Kremser, Katarzyna Jobin, Elisabeth Mettke, Christian Kurts, Markus Gräler, Klaus Willecke, Waldemar Kolanus
Well-defined gradients of the lipid mediator sphingosine-1-phosphate (S1P) direct chemotactic egress of mature thymocytes from the thymus into the circulation. Although it is known that these gradients result from low S1P levels in the thymic parenchyma and high S1P concentrations at the exit sites and in the plasma, the biochemical mechanisms that regulate these differential S1P levels remain unclear. Several studies demonstrated that ceramide synthase 2 (Cers2) regulates the levels of the S1P precursor sphingosine...
February 15, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28179290/fumonisin-b1-inhibits-endoplasmic-reticulum-stress-associated-apoptosis-after-foscanpdt-combined-with-c6-pyridinium-ceramide-or-fenretinide
#7
Nithin B Boppana, Jacqueline M Kraveka, Mehrdad Rahmaniyan, L I Li, Alicja Bielawska, Jacek Bielawski, Jason S Pierce, Jeremy S Delor, Kezhong Zhang, Mladen Korbelik, Duska Separovic
BACKGROUND/AIM: Combining an anticancer agent fenretinide (HPR) or C6-pyridinium ceramide (LCL29) with Foscan-mediated photodynamic therapy (FoscanPDT) is expected to augment anticancer benefits of each substance. We showed that treatment with FoscanPDT+HPR enhanced accumulation of C16-dihydroceramide, and that fumonisin B1 (FB), an inhibitor of ceramide synthase, counteracted caspase-3 activation and colony-forming ability of head and neck squamous cell carcinoma (HNSCC) cells. Because cancer cells appear to be more susceptible to increased levels of the endoplasmic reticulum (ER) stress than normal cells, herein we tested the hypothesis that FoscanPDT combined with HPR or LCL29 induces FB-sensitive ER stress-associated apoptosis that affects cell survival...
2017: Anticancer Research
https://www.readbyqxmd.com/read/28123341/downregulation-of-lipin-1-induces-insulin-resistance-by-increasing-intracellular-ceramide-accumulation-in-c2c12-myotubes
#8
Shujuan Huang, Suling Huang, Xi Wang, Qingli Zhang, Jia Liu, Ying Leng
Dysregulation of lipid metabolism in skeletal muscle is involved in the development of insulin resistance. Mutations in lipin-1, a key lipid metabolism regulator leads to significant systemic insulin resistance in fld mice. However, the function of lipin-1 on lipid metabolism and insulin sensitivity in skeletal muscle is still unclear. Herein we demonstrated that downregulation of lipin-1 in C2C12 myotubes by siRNA transfection suppressed insulin action, characterized by reduced insulin stimulated Akt phosphorylation and glucose uptake...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28120887/er-residency-of-the-ceramide-phosphoethanolamine-synthase-smsr-relies-on-homotypic-oligomerization-mediated-by-its-sam-domain
#9
Birol Cabukusta, Matthijs Kol, Laura Kneller, Angelika Hilderink, Andreas Bickert, John G M Mina, Sergei Korneev, Joost C M Holthuis
SMSr/SAMD8 is an ER-resident ceramide phosphoethanolamine synthase with a critical role in controlling ER ceramides and suppressing ceramide-induced apoptosis in cultured cells. SMSr-mediated ceramide homeostasis relies on the enzyme's catalytic activity as well as on its N-terminal sterile α-motif or SAM domain. Here we report that SMSr-SAM is structurally and functionally related to the SAM domain of diacylglycerol kinase DGKδ, a central regulator of lipid signaling at the plasma membrane. Native gel electrophoresis indicates that both SAM domains form homotypic oligomers...
January 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28112248/mechanistic-interplay-between-ceramide-and-insulin-resistance
#10
Federico Reali, Melissa J Morine, Ozan Kahramanoğulları, Suryaprakash Raichur, Hans-Christoph Schneider, Daniel Crowther, Corrado Priami
Recent research adds to a growing body of literature on the essential role of ceramides in glucose homeostasis and insulin signaling, while the mechanistic interplay between various components of ceramide metabolism remains to be quantified. We present an extended model of C16:0 ceramide production through both the de novo synthesis and the salvage pathways. We verify our model with a combination of published models and independent experimental data. In silico experiments of the behavior of ceramide and related bioactive lipids in accordance with the observed transcriptomic changes in obese/diabetic murine macrophages at 5 and 16 weeks support the observation of insulin resistance only at the later phase...
January 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28088541/secretory-pathway-optimization-of-cho-producer-cells-by-co-engineering-of-the-mitosrna-1978-target-genes-cers2-and-tbc1d20
#11
Lisa A Pieper, Michaela Strotbek, Till Wenger, Martin Gamer, Monilola A Olayioye, Angelika Hausser
Chinese Hamster Ovary (CHO) cells are the most commonly used host for the production of biopharmaceuticals. Although transcription and translation engineering strategies have been employed to generate high-producer cell clones, the secretory pathway still remains a bottleneck in cellular productivity. In this study we show that ectopic expression of a human mitochondrial genome-encoded small RNA (mitosRNA-1978) in an IgG expressing CHO cell line strongly improved specific productivity by functioning in a microRNA-like fashion...
January 11, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28087695/novel-interconnections-in-lipid-metabolism-revealed-by-overexpression-of-sphingomyelin-synthase-1
#12
Gergana M Deevska, Patrick P Dotson, Alexander A Karakashian, Giorgis Isaac, Mark Wrona, Samuel B Kelly, Alfred H Merrill, Mariana N Nikolova-Karakashian
This study investigates the consequences of elevating sphingomyelin synthase 1 (SMS1) activity, which generates the main mammalian sphingolipid, sphingomyelin. HepG2 cells stably transfected with SMS1 (HepG2-SMS1), exhibit elevated enzyme activity in vitro and increased sphingomyelin content (mainly C22:0- and C24:0-sphingomyelin), but lower hexosylceramide (Hex-Cer) levels. HepG2-SMS1 cells have less triacylglycerols than controls but similar diacylglycerol acyltransferase activity, triacylglycerol secretion, and mitochondrial function...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28081222/at7867-inhibits-human-colorectal-cancer-cells-via-akt-dependent-and-akt-independent-mechanisms
#13
Shihu Zhang, Zhengming Deng, Chen Yao, Ping Huang, Yi Zhang, Shibing Cao, Xiangcheng Li
AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death...
2017: PloS One
https://www.readbyqxmd.com/read/28078595/method-to-measure-sphingomyelin-synthase-activity-changes-in-response-to-cd95l
#14
Fatima Bilal, Michaël Pérès, Nathalie Andrieu-Abadie, Thierry Levade, Bassam Badran, Ahmad Daher, Bruno Ségui
Sphingomyelin synthases 1 and 2 convert the anti-oncometabolite ceramide to sphingomyelin, the most abundant sphingolipid in plasma membrane. CD95L-induced ceramide increase is associated with the caspase-dependent inhibition of sphingomyelin synthesis, which enhances the mitochondrial route to apoptosis. Knocking down sphingomyelin synthase 1 or inhibiting sphingomyelin synthesis facilitates ceramide accumulation, cytochrome c release from mitochondria, and caspase-9 activation in cancer cell upon CD95L treatment...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28035926/pleiotropic-effect-of-human-apoe4-on-cerebral-ceramide-and-saturated-fatty-acid-levels
#15
Sandra den Hoedt, Carola I F Janssen, Guiseppe Astarita, Daniele Piomelli, Frank P J Leijten, Simone M Crivelli, Adrie J M Verhoeven, Helga E de Vries, Jochen Walter, Pilar Martinez-Martinez, Eric J G Sijbrands, Amanda J Kiliaan, Monique T Mulder
BACKGROUND: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the ɛ4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD. OBJECTIVE: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet. METHODS: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28035360/hepatic-inflammatory-cytokine-production-can-be-regulated-by-modulating-sphingomyelinase-and-ceramide-synthase-6
#16
Min Hee Kim, Hee Kyung Ahn, Eun-Ji Lee, Su-Jeong Kim, Ye-Ryung Kim, Joo-Won Park, Woo-Jae Park
Chronic inflammation is associated with the pathogenesis of type 2 diabetes and diabetic complications, and palmitate has been nominated as a candidate for the molecular link between these disorders. Recently, a crucial role of ceramide in inflammation and metabolic diseases has been reported. Therefore, in this study, we investigated whether ceramide formation is involved in palmitate‑induced hepatic inflammation in vitro and in vivo. Ceramide can be generated either by the de novo pathway or by sphingomyelin degradation, and six different ceramide synthases (CerS) determine the specific acyl chain length of ceramide in mammals...
February 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28031787/lac-1-and-lag-1-with-ras-1-affect-aging-and-the-biological-clock-in-neurospora-crassa
#17
John K Brunson, James Griffith, Daneisha Bowles, Mary E Case, Jonathan Arnold
Using an automated cell counting technique developed previously (Case et al., Ecology and Evolution 2014; 4: 3494), we explore the lifespan effects of lac-1, a ceramide synthase gene paralogous to lag-1 in Neurospora crassa in conjunction with the band bd (ras-1) gene. We find that the replicative lifespan of a lac-1(KO)bd double mutants is short, about one race tube cycle, and this double mutant lacks a strong ~21-hr clock cycle as shown by race tube and fluorometer analysis of fluorescent strains including lac-1(KO) ...
December 2016: Ecology and Evolution
https://www.readbyqxmd.com/read/27881717/localization-of-1-deoxysphingolipids-to-mitochondria-induces-mitochondrial-dysfunction
#18
Irina Alecu, Andrea Tedeschi, Natascha Behler, Klaus Wunderling, Christian Lamberz, Mario A R Lauterbach, Anne Gaebler, Daniela Ernst, Paul P Van Veldhoven, Ashraf Al-Amoudi, Eicke Latz, Alaa Othman, Lars Kuerschner, Thorsten Hornemann, Frank Bradke, Christoph Thiele, Anke Penno
1-Deoxysphingolipids (deoxySLs) are atypical sphingolipids that are elevated in the plasma of patients with type 2 diabetes and hereditary sensory and autonomic neuropathy type 1 (HSAN1). Clinically, diabetic neuropathy and HSAN1 are very similar, suggesting the involvement of deoxySLs in the pathology of both diseases. However, very little is known about the biology of these lipids and the underlying pathomechanism. We synthesized an alkyne analog of 1-deoxysphinganine (doxSA), the metabolic precursor of all deoxySLs, to trace the metabolism and localization of deoxySLs...
January 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/27853511/molecular-docking-and-molecular-dynamics-simulation-study-of-inositol-phosphorylceramide-synthase-inhibitor-complex-in-leishmaniasis-insight-into-the-structure-based-drug-design
#19
Vineetha Mandlik, Shailza Singh
Inositol phosphorylceramide synthase (IPCS) has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis...
2016: F1000Research
https://www.readbyqxmd.com/read/27842800/anti-candida-albicans-natural-products-sources-of-new-antifungal-drugs-a-review
#20
REVIEW
A Zida, S Bamba, A Yacouba, R Ouedraogo-Traore, R T Guiguemdé
INTRODUCTION: Candida albicans is the most prevalent fungal pathogen in humans. Due to the development of drug resistance, there is today a need for new antifungal agents for the efficient management of C. albicans infections. Therefore, we reviewed antifungal activity, mechanisms of action, possible synergism with antifungal drugs of all natural substances experimented to be efficient against C. albicans for future. METHODS: An extensive and systematic review of the literature was undertaken and all relevant abstracts and full-text articles analyzed and included in the review...
November 11, 2016: Journal de Mycologie Médicale
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