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Farnesylation

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https://www.readbyqxmd.com/read/28208018/pharmacophore-mapping-of-thienopyrimidine-based-monophosphonate-thp-mp-inhibitors-of-the-human-farnesyl-pyrophosphate-synthase
#1
Jaeok Park, Chun Yuen Leung, Alexios N Matralis, Cyrus M Lacbay, Michail Tsakos, Guillermo Fernandez De Troconiz, Albert M Berghuis, Youla S Tsantrizos
The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into non-skeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating non-skeletal diseases...
February 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28195730/alternate-cyclization-cascade-initiated-by-substrate-isomer-in-multiproduct-terpene-synthase-from-medicago-truncatula
#2
Abith Vattekkatte, Stefan Garms, Wilhelm Boland
Promiscuity of terpene synthases results in the enormous diversity of terpenes found in nature. Multiproduct sesquiterpene synthase MtTPS5 isolated from Medicago truncatula generates 27 optically pure products from its natural substrate (2E,6E)-farnesyl diphosphate (FDP). In order to study the promiscuity of MtTPS5, (2Z,6E)-FDP an analogue of presumptive reaction intermediates from natural reaction cascade was utilized as a substrate. This stereoisomer induced a novel cyclization pathway leading to sesquiterpenes based on humulane, amorphene and himachalane skeletons...
February 14, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28188954/comparative-glandular-trichome-transcriptome-based-gene-characterization-reveals-reasons-for-differential-menthol-biosynthesis-in-mentha-species
#3
Md Qussen Akhtar, Nida Qamar, Pallavi Yadav, Pallavi Kulkarni, Ajay Kumar, Ajit Kumar Shasany
The genes involved in menthol biosynthesis are reported earlier in Mentha × piperita. But the information on these genes is not available in Mentha arvensis. To bridge the gap in knowledge on differential biosynthesis of monoterpenes leading to compositional variation in the essential oil of these species, a comparative transcriptome analysis of the glandular trichome was carried out. In addition to the MVA and MEP pathway genes, about 210 and 196 different terpene synthases (TPS) transcripts were identified from annotation in M...
February 11, 2017: Physiologia Plantarum
https://www.readbyqxmd.com/read/28185100/effects-of-acetoacetyl-coa-synthase-expression-on-production-of-farnesene-in-saccharomyces-cerevisiae
#4
Stefan Tippmann, Raphael Ferreira, Verena Siewers, Jens Nielsen, Yun Chen
Efficient production of sesquiterpenes in Saccharomyces cerevisiae requires a high flux through the mevalonate pathway. To achieve this, the supply of acetyl-CoA plays a crucial role, partially because nine moles of acetyl-CoA are necessary to produce one mole of farnesyl diphosphate, but also to overcome the thermodynamic constraint imposed on the first reaction, in which acetoacetyl-CoA is produced from two moles of acetyl-CoA by acetoacetyl-CoA thiolase. Recently, a novel acetoacetyl-CoA synthase (nphT7) has been identified from Streptomyces sp...
February 9, 2017: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28182779/o-prenylated-3-carboxycoumarins-as-a-novel-class-of-15-lox-1-inhibitors
#5
Atena Jabbari, Mina Mousavian, Seyed Mohamad Seyedi, Mehdi Bakavoli, Hamid Sadeghian
Allyloxy, Isopentenyloxy, geranyloxy and farnesyloxy derivatives of 3-carboxycoumarin, at position 5, 6, 7, and 8, were synthesized and their inhibitory potency against human 15-lipoxygenase-1 (human 15-LOX-1) were determined. Among the synthetic coumarins, O-allyl and O-isopentenyl derivatives demonstrated no considerable lipoxygenase inhibition while O-geranyl and O-farnesyl derivatives demonstrated potent inhibitory activity. 5-farnesyloxy-3-carboxycoumarin demonstrated the most potent inhibitory activity by IC50 = 0...
2017: PloS One
https://www.readbyqxmd.com/read/28167250/purification-and-characterization-of-human-dehydrodolychil-diphosphate-synthase-dhdds-overexpressed-in-e-coli
#6
Moshe Giladi, Ilan Edri, Michal Goldenberg, Hadas Newman, Roi Strulovich, Daniel Khananshvili, Yoni Haitin, Anat Loewenstein
Protein asparagine (N)-linked glycosylation is a post-translational modification that occurs in the endoplasmic reticulum; it plays an important role in protein folding, oligomerization, quality control, sorting, and transport. Accordingly, disorders of glycosylation may affect practically every organ system. Dehydrodolichyl diphosphate synthase (DHDDS) is an eukaryotic cis prenyltransferase (cis-PT) that catalyzes chain elongation of farnesyl diphosphate via multiple condensations with isopentenyl diphosphate to form dehydrodolichyl diphosphate, a precursor for the glycosyl carrier dolichylpyrophophate involved in N-linked glycosylation...
February 3, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28160774/positive-selection-and-functional-divergence-of-farnesyl-pyrophosphate-synthase-genes-in-plants
#7
Jieying Qian, Yong Liu, Naixia Chao, Chengtong Ma, Qicong Chen, Jian Sun, Yaosheng Wu
BACKGROUND: Farnesyl pyrophosphate synthase (FPS) belongs to the short-chain prenyltransferase family, and it performs a conserved and essential role in the terpenoid biosynthesis pathway. However, its classification, evolutionary history, and the forces driving the evolution of FPS genes in plants remain poorly understood. RESULTS: Phylogeny and positive selection analysis was used to identify the evolutionary forces that led to the functional divergence of FPS in plants, and recombinant detection was undertaken using the Genetic Algorithm for Recombination Detection (GARD) method...
February 4, 2017: BMC Molecular Biology
https://www.readbyqxmd.com/read/28128232/functional-characterization-of-nes-and-ges-responsible-for-the-biosynthesis-of-e-nerolidol-and-e-e-geranyllinalool-in-tripterygium-wilfordii
#8
Ping Su, Tianyuan Hu, Yujia Liu, Yuru Tong, Hongyu Guan, Yifeng Zhang, Jiawei Zhou, Luqi Huang, Wei Gao
Triptolide and celastrol, two principal bioactive compounds in Tripterygium wilfordii, are produced from geranylgeranyl diphosphate (GGPP) and farnesyl diphosphate ((E,E)-FPP) through terpenoid biosynthesis pathway. However, little is known about T. wilfordii terpene synthases which could competitively utilize GGPP and (E,E)-FPP as substrates, producing C15 and C20 tertiary alcohols. Here we firstly cloned the genes encoding nerolidol synthase (NES) and geranyllinalool synthases (GES1, GES2), which are responsible for the biosynthesis of (E)-nerolidol and (E,E)-geranyllinalool...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28123123/-acute-phase-reaction-following-bisphosphonates
#9
Hiroshi Tsurukami
Bisphosphonates are effective in decreasing bone resorption, the incidence of fragility fracure, and pain from bone metastases. Although relatively well tolerated, the initial dose(s)of intravenous or oral monthly aminobisphosphonates can be associated with an acute phase response, a nonspecific physiologic reaction associated with increased levels of inflammatory cytokines, fever, and flu like symptoms including fatigue, nausea, and myalgia within 3 days of dosing and lasting 7 days or less. Nitrogen-BPs(N-BPs)inhibit osteoclast function by acting as potent inhibitors of the enzyme farnesyl diphosphate(FPP)synthase in the mevalonate biosynthetic pathway...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/28116998/exploration-of-new-and-potent-lead-molecules-against-caax-prenyl-protease-i-of-leishmania-donovani-through-pharmacophore-based-virtual-screening-approach
#10
Sitrarasu Vijaya Prabhu, Kartikeya Tiwari, Venkatesan Suryanarayanan, Vikash Kumar Dubey, Sanjeev Kumar Singh
AIM AND OBJECTIVE: Visceral leishmaniasis is a deadly disease left untreated in over 95% of cases. It is characterized by irregular bouts of fever, weight loss, enlargement of the spleen and liver, and anemia. It is highly endemic in the Indian subcontinent. CAAX prenyl proteaseI of Leishmania donovani is one of the important targets regulating the post translational modification process. Hence identifying potent drug candidate against the target is essential. This study mainly focuses on developing new and potent inhibitors against CAXX prenyl protease I of Leishmania donovani...
January 20, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28102310/coordinated-cell-motility-is-regulated-by-a-combination-of-lkb1-farnesylation-and-kinase-activity
#11
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
#12
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
#13
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
#14
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) that condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma because we have shown that targeting Rab GTPase geranylgeranylation impairs monoclonal protein trafficking, leading to endoplasmic reticulum stress and apoptosis. We 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...
March 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28054995/antiparasitic-activity-of-sulfur-and-fluorine-containing-bisphosphonates-against-trypanosomatids-and-apicomplexan-parasites
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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