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https://www.readbyqxmd.com/read/29140789/mechanism-and-dynamics-of-inpp5e-transport-into-and-inside-the-ciliary-compartment
#1
Stefanie Kristine Kösling, Eyad Kalawy Fansa, Stefano Maffini, Alfred Wittinghofer
The inositol polyphosphate 5´-phosphatase E (INPP5E) localizes to cilia. We showed that the carrier protein phosphodiesterase 6 delta subunit (PDE6δ) mediates the sorting of farnesylated INPP5E into cilia due to high affinity binding and release by Arl3 GTP. However, the dynamics of INPP5E transport into and inside the ciliary compartment are not fully understood. Here we first investigate the movement of INPP5E using live cell fluorescence microscopy and fluorescence recovery after photobleaching (FRAP) analysis...
August 28, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/29140585/timap-the-versatile-protein-phosphatase-1-regulator-in-endothelial-cells
#2
REVIEW
Anita Boratkó, Csilla Csortos
Transforming growth factor (TGF)-β inhibited membrane associated protein, TIMAP, is the member of the myosin phosphatase targeting protein (MYPT) family of protein phosphatase 1 (PP1) regulatory subunits. The N-terminal part of TIMAP has a typical MYPT family structure with a sequence element called MyPhone (myosin phosphatase N-terminal element), a putative bipartite nuclear localization signal, a PP1 catalytic subunit binding motif, and five ankyrin repeats. The C-terminal half of TIMAP is intrinsically disordered, but ends with a functional CAAX box for lipid modification which allows localization of TIMAP at the plasma membrane...
November 15, 2017: IUBMB Life
https://www.readbyqxmd.com/read/29130364/fluorescent-labeling-and-2-photon-imaging-of-mouse-tooth-pulp-nociceptors
#3
A Kadala, P Sotelo-Hitschfeld, Z Ahmad, P Tripal, B Schmid, A Mueller, L Bernal, Z Winter, S Brauchi, U Lohbauer, K Messlinger, J K Lennerz, K Zimmermann
Retrograde fluorescent labeling of dental primary afferent neurons (DPANs) has been described in rats through crystalline fluorescent DiI, while in the mouse, this technique was achieved with only Fluoro-Gold, a neurotoxic fluorescent dye with membrane penetration characteristics superior to the carbocyanine dyes. We reevaluated this technique in the rat with the aim to transfer it to the mouse because comprehensive physiologic studies require access to the mouse as a model organism. Using conventional immunohistochemistry, we assessed in rats and mice the speed of axonal dye transport from the application site to the trigeminal ganglion, the numbers of stained DPANs, and the fluorescence intensity via 1) conventional crystalline DiI and 2) a novel DiI formulation with improved penetration properties and staining efficiency...
November 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/29120102/deciphering-lipid-codes-k-ras-as-a-paradigm
#4
REVIEW
Yong Zhou, John F Hancock
The cell plasma membrane (PM) is a highly dynamic and heterogeneous lipid environment, driven by complex hydrophobic and electrostatic interactions among the hundreds of types of lipid species. Although the biophysical processes governing lipid lateral segregation in the cell PM have been established in vitro, biological implications of lipid heterogeneity are poorly understood. Of particular interest is how membrane proteins potentially utilize transient spatial clustering of PM lipids to regulate function...
November 9, 2017: Traffic
https://www.readbyqxmd.com/read/29118758/combining-v%C3%AE-9v%C3%AE-2-t-cells-with-a-lipophilic-bisphosphonate-efficiently-kills-activated-hepatic-stellate-cells
#5
Xiaoying Zhou, Yanzheng Gu, Hongying Xiao, Ning Kang, Yonghua Xie, Guangbo Zhang, Yan Shi, Xiaoyu Hu, Eric Oldfield, Xueguang Zhang, Yonghui Zhang
Activated hepatic stellate cells (aHSCs) are now established as a central driver of fibrosis in human liver injury. In the presence of chronic or repeated injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) can occur, so there is interest in down-regulating aHSCs activity in order to treat these diseases. Here, we report that Vγ9Vδ2 T cells are reduced in patients with liver cirrhosis, stimulating us to investigate possible interactions between Vγ9Vδ2 T cells and aHSCs. We find that Vγ9Vδ2 T cells kill aHSCs and killing is enhanced when aHSCs are pretreated with BPH-1236, a lipophilic analog of the bone resorption drug zoledronate...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29118396/engineering-saccharomyces-cerevisiae-for-geranylgeraniol-overproduction-by-combinatorial-design
#6
Tian-Qing Song, Ming-Zhu Ding, Fang Zhai, Duo Liu, Hong Liu, Wen-Hai Xiao, Ying-Jin Yuan
Combinatorial design is an effective strategy to acquire the optimal solution in complex systems. In this study, the combined effects of pathway combination, promoters' strength fine-tuning, copy numbers and integration locus variations caused by δ-integration were explored in Saccharomyces cerevisiae using geranylgeraniol (GGOH) production as an example. Two GGOH biosynthetic pathway branches were constructed. In branch 1, GGOH was converted from isopentenyl pyrophosphate (IPP) and farnesyl diphosphate (FPP)...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29115742/nucleophilic-water-capture-or-proton-loss-single-amino-acid-switch-converts-delta-cadinene-synthase-to-germacradien-4-ol-synthase
#7
Rudolf K Allemann, Marianna Loizzi, Veronica Gonzalez, David Miller
Delta-Cadinene synthase is a sesquiterpene cyclase that utilizes the universal achiral precursor farnesyl diphosphate (FDP) to generate predominantly the bicyclic sesquiterpene -cadinene and ~2% germacradien-4-ol, which is also generated from FDP by the cyclase germacradien-4-ol synthase. Here, the mechanism, by which sesquiterpene synthases discriminate between deprotonation and reaction with a nucleophilic water molecule was investigated by site directed mutagenesis of -cadinene synthase. When W279 in -cadinene synthase was replaced with various smaller amino acids the ratio of alcohol versus hydrocarbon product was directly proportional to the van der Waals volume of the amino acid side chain...
November 8, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29102787/identification-and-characterization-of-a-novel-sesquiterpene-synthase-from-aquilaria-sinensis-an-important-gene-for-agarwood-formation
#8
Wei Ye, Xin He, Hongqing Wu, Lei Wang, Weimin Zhang, Yunfei Fan, Haohua Li, Taomei Liu, Xiaoxia Gao
Sesquiterpene synthases are key enzymes for biosynthesis of sesquiterpene compounds and are important for agarwood formation in Aquilaria sinensis.The As-sesTPS gene encoding a novel sesquiterpene synthase was expressed in Escherichia coli strain BL21 (DE3) as an inclusion body and purified by Ni affinity chromatography. The molecular weight of the protein was lower than the theoretical value. Amino acid sequencing results indicated that the 27.2 kDa-recombinant protein was a truncated sesquiterpene synthase from chemically induced A...
November 1, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29100957/implications-of-farnesyltransferase-and-its-inhibitors-as-a-promising-strategy-for-cancer-therapy
#9
REVIEW
Sergey G Klochkov, Margarita E Neganova, Nagendra Sastry Yarla, Madhukiran Parvathaneni, Bechan Sharma, Vadim V Tarasov, George Barreto, Sergey O Bachurin, Ghulam Md Ashraf, Gjumrakch Aliev
Ras proteins have been reported to play key role in oncologic diseases. Ras proteins are associated with cellular membranes for its carcinogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase is responsible for a type of Ras membrane targeting, which leads to cancer origin and progression. Inhibitors of farnesyltransferase have been developed as novel anticancer agents for several cancers. In this review, role of farnesyltransferase in cancer progression and development has been discussed...
October 31, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29083151/a-red-algal-bourbonane-sesquiterpene-synthase-defined-by-microgram-scale-nmr-coupled-crystalline-sponge-x-ray-diffraction-analysis
#10
Roland D Kersten, Shoukou Lee, Daishi Fujita, Tomáš Pluskal, Susan Kram, Jennifer E Smith, Takahiro Iwai, Joseph P Noel, Makoto Fujita, Jing-Ke Weng
Sesquiterpene scaffolds are the core backbones of many medicinally and industrially important natural products. A plethora of sesquiterpene synthases, widely present in bacteria, fungi, and plants, catalyze the formation of these intricate structures often with multiple stereocenters starting from linear farnesyl diphosphate substrates. Recent advances in next-generation sequencing and metabolomics technologies have greatly facilitated gene discovery for sesquiterpene synthases. However, a major bottleneck limits biochemical characterization of recombinant sesquiterpene synthases: the absolute structural elucidation of the derived sesquiterpene products...
November 14, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29080272/3d-qsar-molecular-docking-and-oniom-studies-on-the-structure-activity-relationships-and-action-mechanism-of-nitrogen-containing-bisphosphonates
#11
Qing-Zhu Liu, Shan-Shan Wang, Xi Li, Xue-Yu Zhao, Ke Li, Gao-Chao Lv, Ling Qiu, Jian-Guo Lin
Nitrogen-containing bisphosphonates (N-BPs) have been used widely to treat various bone diseases by inhibiting the key enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway. Understanding the structure-activity relationships and the action mechanisms of these bisphosphonates is instructive for the design and development of novel potent inhibitors. Here, a series of N-BPs inhibitors of human FPPS (hFPPS) were investigated by using a combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and three-layer ONIOM studies...
October 27, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29075041/deregulated-expression-and-activity-of-farnesyl-diphosphate-synthase-fdps-in-glioblastoma
#12
Mario Abate, Chiara Laezza, Simona Pisanti, Giovanni Torelli, Vincenzo Seneca, Giuseppe Catapano, Francesco Montella, Roberta Ranieri, Maria Notarnicola, Patrizia Gazzerro, Maurizio Bifulco, Elena Ciaglia
Glioblastoma (GBM), the most aggressive brain cancer, is highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical for cell proliferation but the function and regulation of key intermediate enzymes like farnesyl-diphosphate synthase (FDPS), up to now, remained unknown. A deregulated expression and activity of FDPS was the central research idea of the present study. FDPS mRNA, protein and enzyme activity were analyzed in a cohort of stage III-IV glioma patients (N = 49) and primary derived cells...
October 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29069775/drug-repositioning-of-mevalonate-pathway-inhibitors-as-antitumor-agents-for-ovarian-cancer
#13
Yusuke Kobayashi, Hiroyasu Kashima, Yohan Suryo Rahmanto, Kouji Banno, Yu Yu, Yusuke Matoba, Keiko Watanabe, Moito Iijima, Takashi Takeda, Haruko Kunitomi, Miho Iida, Masataka Adachi, Kanako Nakamura, Kosuke Tsuji, Kenta Masuda, Hiroyuki Nomura, Eiichiro Tominaga, Daisuke Aoki
Drug repositioning is an alternative strategy redirecting existing drugs for new disease. We have previously reported an antitumor effect of statins, antidyslipidemic drugs, on ovarian cancer in vitro and in vivo. In this study, we investigated the antitumor effects of other mevalonate pathway inhibitors and the mechanism of the antitumor effect from a metabolic perspective. The effects of inhibitors of the mevalonate pathway on tumor cell growth were evaluated in vitro. Bisphosphonates that inhibit this pathway are commonly used as antiosteoporotic drugs, and antitumor effects of the bisphosphonate were examined in vitro and in vivo...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29068210/direct-conversion-of-co2-to-%C3%AE-farnesene-using-metabolically-engineered-synechococcus-elongatus-pcc-7942
#14
Hyun Jeong Lee, Jiwon Lee, Sun-Mi Lee, Youngsoon Um, Yunje Kim, Sang Jun Sim, Jong-Il Choi, Han Min Woo
Direct conversion of carbon dioxide (CO2) to value-added chemicals by engineering of cyanobacteria has received attention as a sustainable strategy in food and chemical industries. Herein, Synechococcus elongatus PCC 7942, a model cyanobacterium, was engineered to produce α-farnesene from CO2. Due to the lack of farnesene synthase (FS) activity in the wild-type cyanobacterium, we metabolically engineered S. elongatus PCC 7942 to express heterologous FS from either Norway spruce or apple fruit, resulting in detectable peaks of α-farnesene...
October 25, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29056891/polygala-tenuifolia-extract-inhibits-lipid-accumulation-in-3t3-l1-adipocytes-and-high-fat-diet-induced-obese-mouse-model-and-affects-hepatic-transcriptome-and-gut-microbiota-profiles
#15
Chun-Chung Wang, Jui-Hung Yen, Yi-Cheng Cheng, Chia-Yu Lin, Cheng-Ta Hsieh, Rung-Jiun Gau, Shu-Jiau Chiou, Hwan-You Chang
Obesity, the excessive accumulation of lipids in the body, is closely associated with many prevalent human disorders. Continued efforts to identify plant extracts that exhibit anti-obesity effects have drawn much attention. This study investigated whether a Polygala tenuifolia extract (PTE) possesses anti-obesity activity and how PTE may affect liver gene expression and gut microbiota. We used 3T3-L1 adipocytes and a high-fat diet-induced obese mouse model to determine the effects of PTE on lipid accumulation...
2017: Food & Nutrition Research
https://www.readbyqxmd.com/read/29039527/simvastatin-inhibits-the-expression-of-stemness%C3%A2-related-genes-and-the-metastatic-invasion-of-human-cancer-cells-via-destruction-of-the-cytoskeleton
#16
Rosarita Tatè, Enrica Zona, Rosanna De Cicco, Veronica Trotta, Maria Urciuoli, Alessandro Morelli, Salvatore Baiano, Rosa Carnuccio, Maria Pia Fuggetta, Franco Morelli
Statins are a class of drugs that inhibit the rate-limiting steps in the cholesterol biosynthesis pathway. They act by inhibiting 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate. Blocking of mevalonate synthesis leads to inhibition of the farnesylation and geranylgeranylation of several functional proteins, such as RhoA and other small guanosine triphosphate-binding proteins, that are important in maintaining the undifferentiated status of the cells...
October 13, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29036218/crystallographic-and-thermodynamic-characterization-of-phenylaminopyridine-bisphosphonates-binding-to-human-farnesyl-pyrophosphate-synthase
#17
Jaeok Park, Dmitry Rodionov, Joris W De Schutter, Yih-Shyan Lin, Youla S Tsantrizos, Albert M Berghuis
Human farnesyl pyrophosphate synthase (hFPPS) catalyzes the production of the 15-carbon isoprenoid farnesyl pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (PNP-BPs) that have bulky hydrophobic side chains through a structure-based approach...
2017: PloS One
https://www.readbyqxmd.com/read/29032332/long-term-treatment-with-chaethomellic-acid-a-reduces-glomerulosclerosis-and-arteriolosclerosis-in-a-rat-model-of-chronic-kidney-disease
#18
António Nogueira, Helena Vala, Carmen Vasconcelos-Nóbrega, Ana Isabel Faustino-Rocha, Carlos André Pires, Aura Colaço, Paula Alexandra Oliveira, Maria João Pires
The high prevalence of end-stage renal disease emphasizes the failure to provide therapies to effectively prevent and/or reverse renal fibrosis. Therefore, the aim of this study was to evaluate the effect of long-term treatment with chaethomellic acid A (CAA), which selectively blocks Ha-Ras farnesylation, on renal mass reduction-induced renal fibrosis. Male Wistar rats were sham-operated (SO) or subjected to 5/6 renal mass reduction (RMR). One week after surgery, rats were placed in four experimental groups: SO:SO rats without treatment (n=13); SO+CAA: SO rats treated with CAA (n=13); RMR:RMR rats without treatment (n=14); and RMR+CAA:RMR rats treated with CAA (n=13)...
October 12, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29030460/hmg-coa-reductase-inhibition-delays-dna-repair-and-promotes-senescence-after-tumor-irradiation
#19
Elena V Efimova, Natalia Ricco, Edwardine Labay, Helena J Mauceri, Amy C Flor, Aishwarya Ramamurthy, Harold G Sutton, Ralph R Weichselbaum, Stephen J Kron
Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSBs) can enhance radiation effects in the tumor and overcome therapeutic resistance without incurring off-target toxicities. Unrepaired DSBs can block cancer cell proliferation, promote cancer cell death and induce cellular senescence. Given the slow progress to date translating novel DSB repair inhibitors as radiosensitizers, we have explored drug repurposing, a proven route to improving speed, costs and success rates of drug development...
October 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29029393/intermittent-treatment-with-farnesyltransferase-inhibitor-and-sulforaphane-improves-cellular-homeostasis-in-hutchinson-gilford-progeria-fibroblasts
#20
Diana Gabriel, Dinah Dorith Shafry, Leslie B Gordon, Karima Djabali
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic condition associated with mutations in the LMNA gene. This disease recapitulates some aspects of normal aging, such as hair loss, thin skin, joint stiffness, and atherosclerosis. The latter leads to heart attack or stroke that causes death at an average age of 14.6 years in children with HGPS. The typical LMNA mutation results in the production of a truncated prelamin A protein, progerin, that remains permanently farnesylated and abnormally associated with the nuclear envelope...
September 12, 2017: Oncotarget
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