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Takahide Matsui, Peidu Jiang, Saori Nakano, Yuriko Sakamaki, Hayashi Yamamoto, Noboru Mizushima
Macroautophagy is an evolutionarily conserved catabolic mechanism that delivers intracellular constituents to lysosomes using autophagosomes. To achieve degradation, lysosomes must fuse with closed autophagosomes. We previously reported that the soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin (STX) 17 translocates to autophagosomes to mediate fusion with lysosomes. In this study, we report an additional mechanism. We found that autophagosome-lysosome fusion is retained to some extent even in STX17 knockout (KO) HeLa cells...
May 22, 2018: Journal of Cell Biology
Xiu Tian, Ju-Xin Ruan, Jin-Quan Huang, Chang-Qing Yang, Xin Fang, Zhi-Wen Chen, Hui Hong, Ling-Jian Wang, Ying-Bo Mao, Shan Lu, Tian-Zhen Zhang, Xiao-Ya Chen
Gossypol and related sesquiterpene aldehydes in cotton function as defense compounds but are antinutritional in cottonseed products. By transcriptome comparison and coexpression analyses, we identified 146 candidates linked to gossypol biosynthesis. Analysis of metabolites accumulated in plants subjected to virus-induced gene silencing (VIGS) led to the identification of four enzymes and their supposed substrates. In vitro enzymatic assay and reconstitution in tobacco leaves elucidated a series of oxidative reactions of the gossypol biosynthesis pathway...
May 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jie-Qing Liu, Chen-Lei Lian, Tian-Yong Hu, Cui-Fang Wang, Ying Xu, Lei Xiao, Zhi-Qiang Liu, Shu-Qi Qiu, Bao-Hui Cheng
Ganoderma fungi have long been used as a famous traditional medicine and food in country of East Asia. In this work, two new farnesyl phenolic compounds, ganoduriporols A and B (1 and 2), were isolated from the fruiting bodies of Ganoderma duripora, and their structures were elucidated using various spectroscopic methods. Anti-inflammatory activities were assayed and evaluated for the two compounds. Ganoduriporols A and B exhibited dose-dependent anti-inflammatory effects in RAW 264.7 cells. Furthermore, ganoduriporol A was demonstrated to inhibit the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and prostaglandin E2 (PGE2 ) through the suppression of COX-2, MAPK and NF-κB signaling pathway in LPS-induced macrophage cells...
October 15, 2018: Food Chemistry
Jingjing Yan, Jingjing Guo, Wei Yuan, Wanying Mai, Kui Hong
Diverse and bioactive terpene compounds are produced by marine fungi. The biosynthesis of sesterterpene molecules containing a C25 skeleton is catalyzed by chimeric enzymes that carry out both chain elongation and terpene cyclization reactions. These bifunctional characteristics facilitate using different chain length polyisoprenoid diphosphates as precursors to yield the geranylfarnesyl diphosphate intermediate, which is then converted to a sesterterpene in one step. In this chapter, we describe the identification of sesterterpene synthase enzymes, together with other related enzymes such as diterpene and farnesyl diphosphate synthases, in a single fungal strain...
2018: Methods in Enzymology
Xi Zhang, Tianyang Guo, Tong Xiang, Yiyang Dong, Jichuan Zhang, Liqun Zhang
The natural rubber molecule is one of the end products of isoprenoids metabolism in the plant. Dimethylallyl diphosphate (DMAPP) and farnesyl pyrophosphate (FPP) are two typical isoprenoids which control the rate of biosynthesis and the molecular weight of natural rubber. A rapid, nonradioactive method for quantitation of DMAPP and FPP in natural rubber latex by liquid chromatography tandem with mass spectrometry (LC-MS/MS) was reported. DMAPP and FPP were determined in the multiple reaction monitoring mode(MRM)followed by separation with a silica-based C18 column...
May 3, 2018: Journal of Chromatography. A
Mehdi Dehghani, Zahra Samani, Hassan Abidi, Leila Manzouri, Reza Mahmoudi, Saeed Hosseini Teshnizi, Mohsen Nikseresht
Background and Purpose: The mevalonate pathway is one of the major metabolic pathways that use acetyl-CoA to produce sterols and isoprenoids. These compounds can be effective in the growth and development of tumors. One of the enzymes involved in the mevalonate pathway is FDFT1. Different variants of this gene are involved in the risk of suffering various diseases. The present study examined the relationship between FDFT1 rs2645429 polymorphism and the risk of nonsmall cell lung cancer (NSCLC) in a population from southern Iran...
2018: International Journal of Genomics
Ross A Carson, Anthony C Rudine, Serena J Tally, Alexis L Franks, Krystle A Frahm, Jacob K Waldman, Neerupma Silswal, Suban Burale, James V Phan, Uma R Chandran, A Paula Monaghan, Donald B DeFranco
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs)...
2018: PloS One
Serena Fiorito, Francesco Epifano, Francesca Preziuso, Ivana Cacciatore, Antonio di Stefano, Vito Alessandro Taddeo, Philippe de Medina, Salvatore Genovese
Naturally occurring coumarins 7-isopentenyloxycoumarin, auraptene, and umbelliprenin are able to modulate the biosynthesis of melanin in murine Melan-a cells probably through the interaction with selected biological targets like estrogen receptor β and aryl hydrocarbon receptor. Such a modulation strictly depends on the individual structure of the coumarin: the presence of a 3,3-dimethylallyloxy side chain is a structural determinant for tanning activation whereas a farnesyl one leads to the opposite effect...
April 27, 2018: European Journal of Medicinal Chemistry
Xiaomin Deng, Dong Guo, Shuguang Yang, Minjing Shi, Jinquan Chao, Huiliang Li, Shiqing Peng, Wei-Min Tian
Rubber trees are the major source of worldwide natural rubber. Rubber-containing latex is obtained from the laticifer cells of rubber tree (Hevea brasiliensis Muell. Arg.) via regular tapping. However, little is known about the positive feedback regulation of rubber biosynthesis, a typical isoprenoid metabolic process in laticifer cells, by tapping-caused loss of latex. Here, we demonstrated the crucial role of jasmonate signalling in this feedback regulation. The endogenous jasmonate levels, the expression levels of rubber biosynthesis-related genes and the efficiency of in vitro rubber biosynthesis were significantly higher in laticifer cells of regularly tapped trees than those of virgin trees...
May 3, 2018: Journal of Experimental Botany
Minakshi Saikia, Archana P Retnakumari, Shabna Anwar, Nikhil P Anto, Rashmi Mittal, Shabna Shah, Kavya S Pillai, Vinod S Balachandran, Vidya Peter, Reeba Thomas, Ruby John Anto
Cytarabine is a conventionally used chemotherapeutic agent for treating acute myeloid leukemia (AML). However, chemoresistance, toxic side-effects and poor patient survival rates retard the efficacy of its performance. The current study deals with the chemosensitization of AML cells using heteronemin, a marine natural product towards cytarabine chemotherapy. Heteronemin could effectively sensitize HL-60 cells towards sub-toxic concentration of cytarabine resulting in synergistic toxicity as demonstrated by MTT assay and [3 H] thymidine incorporation studies, while being safe towards healthy blood cells...
April 6, 2018: Oncotarget
Angela Jeong, Kiall Francis Suazo, W Gibson Wood, Mark D Distefano, Ling Li
The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery that two major isoprenoids, farnesyl and geranylgeranyl pyrophosphate, are required to modify an array of proteins through a process known as protein prenylation, catalyzed by prenyltransferases. The lipophilic prenyl group facilitates the anchoring of proteins in cell membranes, mediating protein-protein interactions and signal transduction...
June 2018: Critical Reviews in Biochemistry and Molecular Biology
Tsuyoshi Ohishi, Yukihiro Matsuyama
Minodronate is a third-generation bisphosphonate that was developed and approved for clinical use in osteoporosis therapy in Japan. The mechanism of action for suppressing bone resorption is the inhibition of farnesyl pyrophosphate synthase, a key enzyme in the mevalonic acid metabolic pathway of osteoclasts, to induce apoptosis of the cells. Minodronate is the strongest inhibitor of bone resorption among the currently available oral bisphosphonates. Large randomized, placebo-controlled, double-blind clinical trials have revealed an increase in bone mineral density of both the lumbar spine and femoral neck over 3 years of daily minodronate therapy and risk reduction in vertebral fractures over 2 years of therapy...
2018: Therapeutics and Clinical Risk Management
Inmaculada Izquierdo-Bueno, Victoria E González-Rodríguez, Adeline Simon, Bérengère Dalmais, Jean-Marc Pradier, Pascal Le Pêcheur, Alex Mercier, Anne-Sophie Walker, Carlos Garrido, Isidro González Collado, Muriel Viaud
While abscisic acid (ABA) is known as a hormone produced by plants through the carotenoid pathway, a small number of phytopathogenic fungi are also able to produce this sesquiterpene but they use a distinct pathway that starts with the cyclization of farnesyl diphosphate (FPP) into 2Z,4E-α-ionylideneethane which is then subjected to several oxidation steps. To identify the sesquiterpene cyclase (STC) responsible for the biosynthesis of ABA in fungi, we conducted a genomic approach in Botrytis cinerea. The genome of the ABA-overproducing strain ATCC58025 was fully sequenced and five STC-coding genes were identified...
April 30, 2018: Environmental Microbiology
Tingting Chen, Ya Wang, Tingting Zhang, Baofeng Zhang, Lei Chen, Liandong Zhao, Ling Chen
Simvastatin (SV) enhances glutamate release and synaptic plasticity in hippocampal CA1 region upon activation of α7 nicotinic acetylcholine receptor (α7nAChR). In this study, we examined the effects of SV on the functional activity of α7nAChR on CA1 pyramidal cells using patch-clamp recording and explored the underlying mechanisms. We found that the treatment of hippocampal slices with SV for 2 h induced a dose-dependent increase in the amplitude of ACh-evoked inward currents ( I ACh ) and the level of α7nAChR protein on the cell membrane without change in the level of α7nAChR phosphorylation...
2018: Frontiers in Pharmacology
Gabriel Balmus, Delphine Larrieu, Ana C Barros, Casey Collins, Monica Abrudan, Mukerrem Demir, Nicola J Geisler, Christopher J Lelliott, Jacqueline K White, Natasha A Karp, James Atkinson, Andrea Kirton, Matt Jacobsen, Dean Clift, Raphael Rodriguez, David J Adams, Stephen P Jackson
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements...
April 27, 2018: Nature Communications
Jennifer M Bratt, Kevin Y Chang, Michelle Rabowsky, Lisa M Franzi, Sean P Ott, Simone Filosto, Tzipora Goldkorn, Muhammad Arif, Jerold A Last, Nicholas J Kenyon, Amir A Zeki
Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI)-277 would attenuate allergic asthma by depleting membrane-associated Ras. We used the OVA mouse model of allergic inflammation and human airway epithelial (HBE1) cells to determine the role of FTase in inflammatory cell recruitment...
April 27, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Jan Rinkel, Martin Litzenburger, Rita Bernhardt, Jeroen Sidney Dickschat
The cytochrome P450 monooxygenase CYP267B1 from Sorangium cellulosum was applied for enzymatic oxidation of the sesquiterpene alcohols T-muurolol and isodauc-8-en-11-ol. Various isotopically labelled geranyl and farnesyl diphosphates were used for product identification from micro-scale reactions, for determination of the absolute configurations of unknown compounds, to follow the stereochemical course of a cytochrome P450-catalysed hydroxylation step, and to investigate kinetic isotope effects. Overall, this study demonstrates that isotopically labelled terpene precursors are highly useful to follow cytochrome P450 dependent oxidations of terpenes...
April 26, 2018: Chembiochem: a European Journal of Chemical Biology
Szabolcs Takáts, Gábor Glatz, Győző Szenci, Attila Boda, Gábor V Horváth, Krisztina Hegedűs, Attila L Kovács, Gábor Juhász
The autophagosomal SNARE Syntaxin17 (Syx17) forms a complex with Snap29 and Vamp7/8 to promote autophagosome-lysosome fusion via multiple interactions with the tethering complex HOPS. Here we demonstrate that, unexpectedly, one more SNARE (Ykt6) is also required for autophagosome clearance in Drosophila. We find that loss of Ykt6 leads to large-scale accumulation of autophagosomes that are unable to fuse with lysosomes to form autolysosomes. Of note, loss of Syx5, the partner of Ykt6 in ER-Golgi trafficking does not prevent autolysosome formation, pointing to a more direct role of Ykt6 in fusion...
April 25, 2018: PLoS Genetics
Jin-Ping Liu, Jin Hu, Yan-Hui Liu, Cui-Ping Yang, Yu-Fen Zhuang, Xiu-Li Guo, Yi-Jian Li, Liangsheng Zhang
The phytohomorne methyl jasmonate (MeJA) is known to trigger extensive reprogramming of gene expression leading to transcriptional activation of many secondary metabolic pathways. However, natural rubber is a commercially important secondary metabolite and little is known about the genetic and genomic basis of jasmonate-elicited rubber biosynthesis in rubber tree ( Hevea brasiliensis ). RNA sequencing (RNA-seq) of H. brasiliensis bark treated with 1 g lanolin paste containing 0.02% w/w MeJA for 24 h (M2) and 0...
May 2018: Physiology and Molecular Biology of Plants: An International Journal of Functional Plant Biology
Xiang Lu, Karima Djabali
The mammalian nuclear lamina proteins—prelamin A- and B-type lamins—are post-translationally modified by farnesylation, endoproteolysis, and carboxymethylation at a carboxy-terminal CAAX (C, cysteine; a, aliphatic amino acid; X, any amino acid) motif. However, prelamin A processing into mature lamin A is a unique process because it results in the production of farnesylated and carboxymethylated peptides. In cells from patients with Hutchinson⁻Gilford progeria syndrome, the mutant prelamin A protein, progerin, cannot release its prenylated carboxyl-terminal moiety and therefore remains permanently associated with the nuclear envelope (NE), causing severe nuclear alterations and a dysmorphic morphology...
April 23, 2018: Cells
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