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Farnesylation

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https://www.readbyqxmd.com/read/28631130/new-insights-into-human-farnesyl-pyrophosphate-synthase-inhibition-by-second-generation-bisphosphonate-drugs
#1
D Fernández, R Ramis, J Ortega-Castro, R Casasnovas, B Vilanova, J Frau
Pamidronate, alendronate, APHBP and neridronate are a group of drugs, known as second-generation bisphosphonates (2G-BPs), commonly used in the treatment of bone-resorption disorders, and recently their use has been related to some collateral side effects. The therapeutic activity of 2G-BPs is related to the inhibition of the human Farnesyl Pyrophosphate Synthase (hFPPS). Available inhibitory activity values show that 2G-BPs act time-dependently, showing big differences in their initial inhibitory activities but similar final IC50 values...
June 19, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28630138/targeting-the-ras-palmitoylation-depalmitoylation-cycle-in-cancer
#2
REVIEW
David Tse Shen Lin, Nicholas G Davis, Elizabeth Conibear
The Ras proteins are well-known drivers of many cancers and thus represent attractive targets for the development of anticancer therapeutics. Inhibitors that disrupt the association of the Ras proteins with membranes by blocking the addition of the farnesyl lipid moiety to the Ras C-terminus failed in clinical trials. Here, we explore the possibility of targeting a second lipid modification, S-acylation, commonly referred to as palmitoylation, as a strategy to disrupt the membrane interaction of specific Ras isoforms...
June 19, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28623230/flexible-body-motions-of-calmodulin-and-the-farnesylated-hypervariable-region-yield-a-high-affinity-interaction-enabling-k-ras4b-membrane-extraction
#3
Hyunbum Jang, Avik Banerjee, Tanmay Chavan, Vadim Gaponenko, Ruth Nussinov
In calmodulin (CaM)-rich environments, oncogenic KRAS plays a critical role in adenocarcinomas by promoting PI3K/Akt signaling. We previously proposed that at elevated calcium levels in cancer, CaM recruits PI3Kα to the membrane and extracts K-Ras4B from the membrane, organizing a K-Ras4B/CaM/PI3Kα ternary complex. CaM can thereby replace a missing receptor tyrosine kinase signal to fully activate PI3Kα. Recent experimental data show that CaM selectively promotes K-Ras signaling, but not of N-Ras or H-Ras...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28620813/an-in-silico-insight-into-the-substrate-binding-characteristics-of-the-active-site-of-amorpha-4-11-diene-synthase-a-key-enzyme-in-artemisinin-biosynthesis
#4
Habib Eslami, Seyed Kaveh Mohtashami, Maryam Taghavi Basmanj, Maryam Rahati, Hamzeh Rahimi
The enzyme amorphadiene synthase (ADS) conducts the first committed step in the biosynthetic conversion of the substrate farnesyl pyrophosphate (FPP) to artemisinin, which is a highly effective natural product against multidrug-resistant strains of malaria. Due to the either low abundance or low turn-over rate of the enzyme, obtaining artemisinin from both natural and synthetic sources is costly and laborious. In this in silico study, we strived to elucidate the substrate binding site specificities of the ADS, with the rational that unraveling enzyme features paves the way for enzyme engineering to increase synthesis rate...
July 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28619714/the-g-protein-coupled-receptor-gpr31-promotes-membrane-association-of-kras
#5
Nicole Fehrenbacher, Israel Tojal da Silva, Craig Ramirez, Yong Zhou, Kwang-Jin Cho, Shafi Kuchay, Jie Shi, Susan Thomas, Michele Pagano, John F Hancock, Dafna Bar-Sagi, Mark R Philips
The product of the KRAS oncogene, KRAS4B, promotes tumor growth when associated with the plasma membrane (PM). PM association is mediated, in part, by farnesylation of KRAS4B, but trafficking of nascent KRAS4B to the PM is incompletely understood. We performed a genome-wide screen to identify genes required for KRAS4B membrane association and identified a G protein-coupled receptor, GPR31. GPR31 associated with KRAS4B on cellular membranes in a farnesylation-dependent fashion, and retention of GPR31 on the endoplasmic reticulum inhibited delivery of KRAS4B to the PM...
June 15, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28597297/intrinsic-protein-disorder-in-oncogenic-kras-signaling
#6
REVIEW
Ruth Nussinov, Hyunbum Jang, Chung-Jung Tsai, Tsung-Jen Liao, Shuai Li, David Fushman, Jian Zhang
How Ras, and in particular its most abundant oncogenic isoform K-Ras4B, is activated and signals in proliferating cells, poses some of the most challenging questions in cancer cell biology. In this paper, we ask how intrinsically disordered regions in K-Ras4B and its effectors help promote proliferative signaling. Conformational disorder allows spanning long distances, supports hinge motions, promotes anchoring in membranes, permits segments to fulfil multiple roles, and broadly is crucial for activation mechanisms and intensified oncogenic signaling...
June 8, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28587179/screening-of-deoxynivalenol-producing-strains-and-elucidation-of-possible-toxigenic-molecular-mechanism
#7
Xiangfeng Zheng, Xiaoli Zhang, Lina Zhao, Maurice T Apaliya, Qiya Yang, Wei Sun, Xiaoyun Zhang, Hongyin Zhang
In this study, seven strains of Fusarium graminearum were isolated from wheat, of which six were identified to produce deoxynivalenol and the production of deoxynivalenol was assessed. F. graminearum strain Fg1 was noted to produce 1.0 μg/g deoxynivalenol during the incubation period in the Czapek yeast broth, while none was detected in F. graminearum strain Fg2. Hence, the differences in proteomes and transcriptomes of Fg1 and Fg2 were compared to analyze the mechanism underlying deoxynivalenol production...
June 1, 2017: Toxins
https://www.readbyqxmd.com/read/28585042/characterizing-the-interactions-of-two-lipid-modifications-with-lipid-rafts-farnesyl-anchors-vs-palmitoyl-anchors
#8
Tao Zhang, Qichao Luo, Linlin Yang, Hualiang Jiang, Huaiyu Yang
Farnesyl (Far) and palmitoyl (Pal) anchors play important roles in the traffic of many lipidated proteins. Herein, we show the distinctive interactions and influences of the two lipid modifications on lipid rafts (LRs) and non-raft-like membranes using molecular dynamics simulations. Palmitoyl anchors behave in a more ordered fashion, pack tighter with the lipids of LRs and diffuse at a slower rate than farnesyl anchors in LRs. When interacting with non-raft-like membranes these two types of anchors become less ordered, pack more loosely with lipids, and diffuse at a higher rate...
June 5, 2017: European Biophysics Journal: EBJ
https://www.readbyqxmd.com/read/28559264/synergistic-activity-between-statins-and-bisphosphonates-against-acute-experimental-toxoplasmosis
#9
Zhu-Hong Li, Catherine Li, Sergio H Szajnman, Juan B Rodriguez, Silvia N J Moreno
Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit growth of a variety of protozoan parasites like Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfur-containing linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives (1-[(n-heptylthio)ethyl]-1,1-bisphosphonate, C7S, or compound 6) with statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG-CoA reductase)...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28556912/farnesyltransferase-inhibitor-fti-277-inhibits-pd-l1-expression-on-septic-spleen-lymphocytes-and-promotes-spleen-lymphocyte-activation
#10
Wentian Li, Ji Tu, Xianzhe Liu, Wen Yang
Farnesyltransferase inhibitors have been tested in clinical trials for the treatment of tumours. In sepsis, the binding of PD-1 to PD-L1 promotes lymphocyte apoptosis and decreases cytokine expression, thus affecting survival rates. The PD-1/PD-L1 pathway plays an important role in chronic viral infection, bacterial infection, and sepsis. However, the precise immunosuppressive and anti-inflammatory functions of this pathway remain poorly understood. In our previous study, the induction of sepsis by cecal ligation and puncture (CLP) resulted in increased farnesyltransferase activity and farnesylated protein levels in the spleen relative to sham treatment...
May 30, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28547322/metabolic-engineering-of-saccharomyces-cerevisiae-for-production-of-germacrene-a-a-precursor-of-beta-elemene
#11
Yating Hu, Yongjin J Zhou, Jichen Bao, Luqi Huang, Jens Nielsen, Anastasia Krivoruchko
Beta-elemene, a sesquiterpene and the major component of the medicinal herb Curcuma wenyujin, has antitumor activity against various types of cancer and could potentially serve as a potent antineoplastic drug. However, its current mode of production through extraction from plants has been inefficient and suffers from limited natural resources. Here, we engineered a yeast cell factory for the sustainable production of germacrene A, which can be transformed to beta-elemene by a one-step chemical reaction in vitro...
May 25, 2017: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28544034/knock-down-of-farnesyl-pyrophosphate-synthase-protects-heart-derived-h9c2-cells-against-hypoxia-reoxygenation-induced-injury
#12
Dong-Pu Dai, Huan-Dong Wu, Jian Yang, Shi-Zhen Shen, Chen-Ze Zhao, Jie Ding, Shen-Jiang Hu
Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. Our previous studies have indicated that cardiac-specific overexpression of FPPS induces cardiac hypertrophy and dysfunction in mice, and inhibition of FPPS prevents angiotensin (Ang) II-induced hypertrophy in cardiomyocytes. However, the role for FPPS in myocardial ischemia/reperfusion (MIR) injury is still not clear. The objective of this work was to investigate the effect of FPPS on MIR injury in H9c2 cells which were subjected to hypoxia/reoxygenation (HR) to mimic MIR...
May 24, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28540724/pde%C3%AE-binding-to-ras-isoforms-provides-a-route-to-proper-membrane-localization
#13
Serena Muratcioglu, Hyunbum Jang, Attila Gursoy, Ozlem Keskin, Ruth Nussinov
To signal, Ras isoforms must be enriched at the plasma membrane (PM). It was suggested that phosphodiesterase-δ (PDEδ) can bind and shuttle some farnesylated Ras isoforms to the PM, but not all. Among these, interest focused on K-Ras4B, the most abundant oncogenic Ras isoform. To study PDEδ/Ras interactions, we modeled and simulated the PDEδ/K-Ras4B complex. We obtained structures, which were similar to two subsequently determined crystal structures. We next modeled and simulated complexes of PDEδ with the farnesylated hypervariable regions of K-Ras4A and N-Ras...
June 7, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28527898/triterpenes-and-meroterpenes-from-ganoderma-lucidum-with-inhibitory-activity-against-hmgs-reductase-aldose-reductase-and-%C3%AE-glucosidase
#14
Baosong Chen, Jin Tian, Jinjin Zhang, Kai Wang, Li Liu, Bo Yang, Li Bao, Hongwei Liu
Seven new compounds including four lanostane triterpenoids, lucidenic acids Q-S (1-3) and methyl ganoderate P (4), and three triterpene-farnesyl hydroquinone conjugates, ganolucinins A-C (5-7), one new natural product ganomycin J (8), and 73 known compounds (9-81) were isolated from fruiting bodies of Ganoderma lucidum. The structures of the compounds 1-8 were determined by spectroscopic methods. Bioactivities of compounds isolated were assayed against HMG-CoA reductase, aldose reductase, α-glucosidase, and PTP1B...
May 17, 2017: Fitoterapia
https://www.readbyqxmd.com/read/28521569/exploring-the-biochemistry-of-the-prenylome-and-its-role-in-disease-through-proteomics-progress-and-potential
#15
Maura Brioschi, Alma Martinez Fernandez, Cristina Banfi
Protein prenylation is a ubiquitous covalent post-translational modification characterized by the addition of farnesyl or geranylgeranyl isoprenoid groups to a cysteine residue located near the carboxyl terminal of a protein. It is essential for the proper localization and cellular activity of numerous proteins, including Ras family GTPases and G-proteins. In addition to its roles in cellular physiology, the prenylation process has important implications in human diseases and in the recent years, it has become attractive target of inhibitors with therapeutic potential...
May 26, 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/28520394/in-vitro-metabolic-engineering-of-amorpha-4-11-diene-biosynthesis-at-enhanced-rate-and-specific-yield-of-production
#16
Xixian Chen, Congqiang Zhang, Ruiyang Zou, Gregory Stephanopoulos, Heng-Phon Too
In vitro metabolic engineering is an alternative approach to cell-based biosynthesis. It offers unprecedented flexibility for the study of biochemical pathways, thus providing useful information for the rational design and assembly of reaction modules. Herein, we took the advantage of in vitro metabolic engineering to initially gain insight into the regulatory network of a reconstituted amorpha-4,11-diene (AD) synthetic pathway. Guided by lin-log approximation, we rapidly identified the hitherto unrecognized inhibition of adenosine triphosphate (ATP) on both farnesyl pyrophosphate synthase (FPPS) and amorpha-4,11-diene synthase (ADS)...
May 25, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28515154/progerin-sequestration-of-pcna-promotes-replication-fork-collapse-and-mislocalization-of-xpa-in-laminopathy-related-progeroid-syndromes
#17
Benjamin A Hilton, Ji Liu, Brian M Cartwright, Yiyong Liu, Maya Breitman, Youjie Wang, Rowdy Jones, Hui Tang, Antonio Rusinol, Phillip R Musich, Yue Zou
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene resulting in production of a truncated farnesylated-prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin...
May 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28508733/synthesis-of-aurachins-b-and-h
#18
Kazuki Takahashi, Shigefumi Kuwahara, Masaru Enomoto
The synthesis of aurachin B, an antibiotic that features a C3-oxygen-substituted quinoline N-oxide nucleus bearing a farnesyl side chain at C4, was accomplished in 60% overall yield from o-nitrotoluene by a concise five-step sequence. An enantioselective synthesis of aurachin H was also achieved for the first time in only two steps from an optically active epoxy iodide.
May 16, 2017: Bioscience, Biotechnology, and Biochemistry
https://www.readbyqxmd.com/read/28489963/the-aspergillus-fumigatus-farnesyltransferase-%C3%AE-subunit-rama-mediates-growth-virulence-and-antifungal-susceptibility
#19
Tiffany S Norton, Qusai Al Abdallah, Amy M Hill, Rachel V Lovingood, Jarrod R Fortwendel
Post-translational prenylation mechanisms, including farnesylation and geranylgeranylation, mediate both subcellular localization and protein-protein interaction in eukaryotes. The prenyltransferase complex is an αβ heterodimer in which the essential α-subunit is common to both the farnesyltransferase and the geranylgeranyltransferase type-I enzymes. The β-subunit is unique to each enzyme. Farnesyltransferase activity is an important mediator of protein localization and subsequent signaling for multiple proteins, including Ras GTPases...
May 10, 2017: Virulence
https://www.readbyqxmd.com/read/28484475/de-novo-sequencing-and-transcriptome-analysis-reveal-key-genes-regulating-steroid-metabolism-in-leaves-roots-adventitious-roots-and-calli-of-periploca-sepium-bunge
#20
Jian Zhang, Xinglin Li, Fuping Lu, Shanying Wang, Yunhe An, Xiaoxing Su, Xiankuan Li, Lin Ma, Guangjian Han
Periploca sepium Bunge is a traditional medicinal plant, whose root bark is important for Chinese herbal medicine. Its major bioactive compounds are C21 steroids and periplocin, a kind of cardiac glycoside, which are derived from the steroid synthesis pathway. However, research on P. sepium genome or transcriptomes and their related genes has been lacking for a long time. In this study we estimated this species nuclear genome size at 170 Mb (using flow cytometry). Then, RNA sequencing of four different tissue samples of P...
2017: Frontiers in Plant Science
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