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Farnesylation

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https://www.readbyqxmd.com/read/28102310/coordinated-cell-motility-is-regulated-by-a-combination-of-lkb1-farnesylation-and-kinase-activity
#1
S Wilkinson, Y Hou, J T Zoine, J Saltz, C Zhang, Z Chen, L A D Cooper, A I Marcus
Cell motility requires the precise coordination of cell polarization, lamellipodia formation, adhesion, and force generation. LKB1 is a multi-functional serine/threonine kinase that associates with actin at the cellular leading edge of motile cells and suppresses FAK. We sought to understand how LKB1 coordinates these multiple events by systematically dissecting LKB1 protein domain function in combination with live cell imaging and computational approaches. We show that LKB1-actin colocalization is dependent upon LKB1 farnesylation leading to RhoA-ROCK-mediated stress fiber formation, but membrane dynamics is reliant on LKB1 kinase activity...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28098152/human-farnesyl-pyrophosphate-synthase-is-allosterically-inhibited-by-its-own-product
#2
Jaeok Park, Michal Zielinski, Alexandr Magder, Youla S Tsantrizos, Albert M Berghuis
Farnesyl pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme's active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, farnesyl pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5-6 μM, within a catalytically relevant range...
January 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28059793/resveratrol-intervenes-in-the-cholesterol-and-isoprenoid-mediated-amyloidogenic-processing-of-a%C3%AE-pp-in-familial-alzheimer-s-disease
#3
Mohan Sathya, Ponnusamy Moorthi, Palanisamy Premkumar, Mahesh Kandasamy, Kesavan Swaminathan Jayachandran, Muthuswamy Anusuyadevi
Deterioration of cholesterol metabolism has recently been a frontier subject of investigation in the field of Alzheimer's disease (AD). Though amyloid-β protein precursor (AβPP) primes the pathological cascade, changes in cholesterol levels and its intermediates, geranyl geranyl pyrophosphate and farnesyl pyrophosphate, is expected to have a different consequence on AβPP processing and amyloid-β (Aβ) generation. However, the use of statins (HMG-COA reductase inhibitor) has been widely implicated in slowing down the pathogenic progression of AD, while the epidemiological reports on its biological effect remains controversial...
December 3, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28057800/olefin-isomers-of-a-triazole-bisphosphonate-synergistically-inhibit-geranylgeranyl-diphosphate-synthase
#4
Cheryl Allen, Sandhya Kortagere, Huaxiang Tong, Robert A Matthiesen, Joseph I Metzger, David F Wiemer, Sarah A Holstein
The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) which condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma as we have shown that targeting Rab GTPase geranylgeranylation impairs monoclonal protein trafficking, leading to endoplasmic reticulum stress and apoptosis. We have reported a series of triazole bisphosphonate GGDPS inhibitors of which the most potent was a 3:1 mixture of homogeranyl (HG) and homoneryl (HN) isomers...
January 5, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28054995/antiparasitic-activity-of-sulfur-and-fluorine-containing-bisphosphonates-against-trypanosomatids-and-apicomplexan-parasites
#5
Tamila Galaka, Mariana Ferrer Casal, Melissa Storey, Catherine Li, María N Chao, Sergio H Szajnman, Roberto Docampo, Silvia N J Moreno, Juan B Rodriguez
Based on crystallographic data of the complexes 2-alkyl(amino)ethyl-1,1-bisphosphonates-Trypanosoma cruzi farnesyl diphosphate synthase, some linear 1,1-bisphosphonic acids and other closely related derivatives were designed, synthesized and biologically evaluated against T. cruzi, the responsible agent of Chagas disease and against Toxoplasma gondii, the etiologic agent of toxoplasmosis and also towards the target enzymes farnesyl pyrophosphate synthase of T. cruzi (TcFPPS) and T gondii (TgFPPS), respectively...
January 4, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28050601/progeroid-syndrome-patients-with-zmpste24-deficiency-could-benefit-when-treated-with-rapamycin-and-dimethylsulfoxide
#6
Baris Akinci, Shireesha Sankella, Christopher Gilpin, Keiichi Ozono, Abhimanyu Garg, Anil K Agarwal
Patients with progeroid syndromes such as mandibuloacral dysplasia, type B (MADB) and restrictive dermopathy (RD) harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for posttranslational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation; however, the efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors...
January 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28045196/mechanistic-studies-of-sesquiterpene-cyclases-based-on-their-carbon-isotope-ratios-at-natural-abundance
#7
Wenhua Tan, Stefan Bartram, Wilhelm Boland
During the process of terpene biosynthesis, C-C bond breaking and forming steps are subjected to kinetic carbon isotope effects, leading to distinct carbon isotopic signatures of the products. Accordingly, carbon isotopic signatures could be used to reveal the "biosynthetic history" of the produced terpenoids. Five known sesquiterpene cyclases, regulating three different pathways, representing simple to complex biosynthetic sequences, were heterologously expressed and used for in vitro assays with farnesyl diphosphate as substrate...
January 3, 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/28043124/improved-micellar-formulation-for-enhanced-delivery-for-paclitaxel
#8
Jieni Xu, Xiaolan Zhang, Yichao Chen, Yixian Huang, Pengcheng Wang, Yuan Wei, Xiaochao Ma, Song Li
We have previously improved the bioactivity of PEG5k-FTS2 system by incorporating disulfide bond (PEG5k-S-S-FTS2) to facilitate the release of farnesyl thiosalicylic acid (FTS).1 Later, fluorenylmethyloxycarbonyl (Fmoc) moiety has been introduced to PEG5k-FTS2 system (PEG5k-Fmoc-FTS2) in order to enhance drug loading capacity (DLC) and formulation stability.2 In this study, we have brought in both disulfide linkage and Fmoc group to PEG5k-FTS2 to form a simple PEG5k-Fmoc-S-S-FTS2 micellar system. PEG5k-Fmoc-S-S-FTS2 conjugate formed filamentous micelles with a ∼10-fold decrease in critical micellar concentration (CMC)...
January 3, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28041850/lipid-sorting-specificity-encoded-in-k-ras-membrane-anchor-regulates-signal-output
#9
Yong Zhou, Priyanka Prakash, Hong Liang, Kwang-Jin Cho, Alemayehu A Gorfe, John F Hancock
K-Ras is targeted to the plasma membrane by a C-terminal membrane anchor that comprises a farnesyl-cysteine-methyl-ester and a polybasic domain. We used quantitative spatial imaging and atomistic molecular dynamics simulations to examine molecular details of K-Ras plasma membrane binding. We found that the K-Ras anchor binds selected plasma membrane anionic lipids with defined head groups and lipid side chains. The precise amino acid sequence and prenyl group define a combinatorial code for lipid binding that extends beyond simple electrostatics; within this code lysine and arginine residues are non-equivalent and prenyl chain length modifies nascent polybasic domain lipid preferences...
January 12, 2017: Cell
https://www.readbyqxmd.com/read/28040698/the-prenylated-proteome-of-plasmodium-falciparum-reveals-pathogen-specific-prenylation-activity-and-drug-mechanism-of-action
#10
Jolyn E Gisselberg, Lichao Zhang, Joshua E Elias, Ellen Yeh
Plasmodium parasites contain several unique membrane compartments in which prenylated proteins may play important roles in pathogenesis. Protein prenylation has also been proposed as an antimalarial drug target since farnesyltransferase inhibitors cause potent growth inhibition of blood-stage Plasmodium However, the specific prenylated proteins that mediate antimalarial activity have yet to be identified. Given the potential for new parasite biology and elucidating drug mechanism-of-action, we performed a large-scale identification of the prenylated proteome in blood-stage P...
December 31, 2016: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28008986/inhibition-of-farnesyl-pyrophosphate-synthase-improves-pressure-overload-induced-chronic-cardiac-remodeling
#11
Chen-Ze Zhao, Xu-Ming Zhao, Jian Yang, Yun Mou, Bin Chen, Huan-Dong Wu, Dong-Pu Dai, Jie Ding, Shen-Jiang Hu
Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous studies, we find that inhibition of FPPS attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats. In this study, we evaluate the effects and mechanisms of FPPS inhibition in pressure overload mice. Male FPPS-small interfering RNA (SiRNA) transgenic (Tg) mice and non-transgenic littermate control (NLC) were randomly divided into suprarenal abdominal aortic constriction (AAC) group and sham operation group...
December 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28001060/biosynthesis-of-antroquinonol-and-4-acetylantroquinonol-b-via-a-polyketide-pathway-using-orsellinic-acid-as-a-ring-precursor-in-antrodia-cinnamomea
#12
Kevin Chi-Chung Chou, Shang-Han Yang, Hsiang-Lin Wu, Pei-Yin Lin, Tsu-Liang Chang, Fuu Sheu, Kai-Hsien Chen, Been-Huang Chiang
Antroquinonol (AQ) and 4-acetylantroquinonol B (4-AAQB), isolated from the mycelium of Antrodia cinnamomea, have a similar chemical backbone to coenzyme Q (CoQ). Based on the postulation that biosynthesis of both AQ and 4-AAQB in A. cinnamomea starts from the polyketide pathway, we cultivated this fungus in a culture medium containing [U-(13)C]oleic acid, and then we analyzed the crude extracts of the mycelium using UHPLC-MS. We found that AQ and 4-AAQB follow similar biosynthetic sequences as CoQ. Obvious [(13)C2] fragments on the ring backbone were detected in the mass spectrum for [(13)C2]AQ, [(13)C2]4-AAQB, and their [(13)C2] intermediates found in this study...
December 21, 2016: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/27988893/n-acetylglutaminoyl-s-farnesyl-l-cysteine-sig-1191-an-anti-inflammatory-molecule-that-increases-the-expression-of-the-aquaglyceroporin-aquaporin-3-in-human-keratinocytes
#13
José R Fernández, Corey Webb, Karl Rouzard, Michael Voronkov, Kristen L Huber, Jeffry B Stock, Maxwell Stock, Joel S Gordon, Eduardo Perez
Isoprenylcysteine (IPC) small molecules were discovered as signal transduction modulating compounds ~25 years ago. More recently, IPC molecules have demonstrated antioxidant and anti-inflammatory properties in a variety of dermal cells as well as antimicrobial activity, representing a novel class of compounds to ameliorate skin conditions and disease. Here, we demonstrate a new IPC compound, N-acetylglutaminoyl-S-farnesyl-L-cysteine (SIG-1191), which inhibits UVB-induced inflammation blocking pro-inflammatory cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) production...
December 17, 2016: Archives of Dermatological Research
https://www.readbyqxmd.com/read/27987234/deciphering-fungal-dimorphism-farnesol-s-unanswered-questions
#14
Kenneth W Nickerson, Audrey L Atkin
Candida albicans excretes E,E-farnesol as a virulence factor and quorum sensing molecule that prevents the yeast to hyphal conversion. Polke et al. (2016) identified eed1Δ/Δ as the first farnesol hypersensitive mutant of C. albicans. eed1Δ/Δ also excretes 10X more farnesol and while able to form hyphae, it cannot maintain hyphae. This mutant enables new research into unanswered questions, including the existence of potential farnesol receptors and transporters, regulation of farnesol synthesis, and relationships among farnesol, germ tube formation and hyphal maintenance...
December 17, 2016: Molecular Microbiology
https://www.readbyqxmd.com/read/27939849/a-squalene-synthase-protein-degradation-method-for-improved-sesquiterpene-production-in-saccharomyces-cerevisiae
#15
Bingyin Peng, Manuel R Plan, Panagiotis Chrysanthopoulos, Mark P Hodson, Lars K Nielsen, Claudia E Vickers
Sesquiterpenes are C15 isoprenoids with utility as fragrances, flavours, pharmaceuticals, and potential biofuels. Microbial fermentation is being examined as a competitive approach for bulk production of these compounds. Competition for carbon allocation between synthesis of endogenous sterols and production of the introduced sesquiterpene limits yields. Achieving balance between endogenous sterols and heterologous sesquiterpenes is therefore required to achieve economical yields. In the current study, the yeast Saccharomyces cerevisiae was used to produce the acyclic sesquiterpene alcohol, trans-nerolidol...
January 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/27935847/structure-based-development-of-pde%C3%AE-inhibitors
#16
Pablo Martín-Gago, Eyad Kalawy Fansa, Alfred Wittinghofer, Herbert Waldmann
The prenyl binding protein PDEδ enhances the diffusion of farnesylated Ras proteins in the cytosol, ultimately affecting their correct localization and signaling. This has turned PDEδ into a promising target to prevent oncogenic KRas signaling. In this review we summarize and describe the structure-guided-development of the three different PDEδ inhibitor chemotypes that have been documented so far. We also compare both their potency for binding to the PDEδ pocket and their in vivo efficiency in suppressing oncogenic KRas signaling, as a result of the inhibition of the PDEδ/KRas interaction...
December 21, 2016: Biological Chemistry
https://www.readbyqxmd.com/read/27933789/the-t296v-mutant-of-amorpha-4-11-diene-synthase-is-defective-in-allylic-diphosphate-isomerization-but-retains-the-ability-to-cyclize-the-intermediate-3r-nerolidyl-diphosphate-to-amorpha-4-11-diene
#17
Zhenqiu Li, Ruiping Gao, Qinggang Hao, Huifang Zhao, Longbin Cheng, Fang He, Li Liu, Xiuhua Liu, Wayne K W Chou, Huajie Zhu, David E Cane
The T296V mutant of amorpha-4,11-diene synthase catalyzes the abortive conversion of the natural substrate (E,E)-farnesyl diphosphate mainly into the acyclic product (E)-β-farnesene (88%) instead of the natural bicyclic sesquiterpene amorphadiene (7%). Incubation of the T296V mutant with (3R,6E)-nerolidyl diphosphate resulted in cyclization to amorphadiene. Analysis of additional mutants of amino acid residue 296 and in vitro assays with the intermediate analogue (2Z,6E)-farnesyl diphosphate as well as (3S,6E)-nerolidyl diphosphate demonstrated that the T296V mutant can no longer catalyze the allylic rearrangement of farnesyl diphosphate to the normal intermediate (3R,6E)-nerolidyl diphosphate, while retaining the ability to cyclize (3R,6E)-nerolidyl diphosphate to amorphadiene...
December 6, 2016: Biochemistry
https://www.readbyqxmd.com/read/27929926/comparing-lamin-proteins-post-translational-relative-stability-using-a-2a-peptide-based-system-reveals-elevated-resistance-of-progerin-to-cellular-degradation
#18
Di Wu, Phillip A Yates, Haoyue Zhang, Kan Cao
Nuclear lamins are the major components of the nuclear lamina at the periphery of the nucleus, supporting the nuclear envelope and participating in many nuclear processes, including DNA replication, transcription and chromatin organization. A group of diseases, the laminopathies, is associated with mutations in lamin genes. One of the most striking cases is Hutchinson-Gilford progeria syndrome (HGPS) which is the consequence of a lamin A dominant negative mutant named progerin. Due to the abnormal presence of a permanent C-terminal farnesyl tail, progerin gradually accumulates on the nuclear membrane, perturbing a diversity of signalings and transcriptional events...
November 2016: Nucleus
https://www.readbyqxmd.com/read/27921136/penicillium-roqueforti-pr-toxin-gene-cluster-characterization
#19
Pedro I Hidalgo, Elisabeth Poirier, Ricardo V Ullán, Justine Piqueras, Laurence Meslet-Cladière, Emmanuel Coton, Monika Coton
PR toxin is a well-known isoprenoid mycotoxin almost solely produced by Penicillium roqueforti after growth on food or animal feed. This mycotoxin has been described as the most toxic produced by this species. In this study, an in silico analysis allowed identifying for the first time a 22.4-kb biosynthetic gene cluster involved in PR toxin biosynthesis in P. roqueforti. The pathway contains 11 open reading frames encoding for ten putative proteins including the major fungal terpene cyclase, aristolochene synthase, involved in the first farnesyl-diphosphate cyclization step as well as an oxidoreductase, an oxidase, two P450 monooxygenases, a transferase, and two dehydrogenase enzymes...
December 5, 2016: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27915173/effect-of-prolonged-water-stress-on-essential-oil-content-compositions-and-gene-expression-patterns-of-mono-and-sesquiterpene-synthesis-in-two-oregano-origanum-vulgare-l-subspecies
#20
Mohammad Reza Morshedloo, Lyle E Craker, Alireza Salami, Vahideh Nazeri, Hyunkyu Sang, Filippo Maggi
Origanum vulgare L., recognized throughout the world as a popular medicinal and flavoring herb, contains a wide array of medicinally active components, including phenolic glucosides, flavonoids, tannins, sterols and high amounts of terpenoids. Especially the latter are often extracted by hydrodistillation resulting in the so-called essential oil that is rich in monoterpenes (e.g. carvacrol, thymol, linalyl acetate) and/or sesquiterpenes (e.g. (E)-β-caryophyllene, germacrene D, bicyclogermacrene, β-caryophyllene oxide)...
November 28, 2016: Plant Physiology and Biochemistry: PPB
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