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Farnesylation

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https://www.readbyqxmd.com/read/28343347/bioanalysis-of-farnesyl-pyrophosphate-in-human-plasma-by-high-performance-liquid-chromatography-coupled-to-triple-quadrupole-tandem-mass-spectrometry-and-hybrid-quadrupole-orbitrap-high-resolution-mass-spectrometry
#1
Hiroshi Sugimoto, Mie Iguchi, Fumihiro Jinno
The isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are pivotal intermediates for cholesterol homeostasis and cell signaling in the mevalonate pathway. We developed a sensitive and selective high-performance liquid chromatography tandem triple quadrupole mass spectrometry (LC-QQQ-MS) method for FPP in human plasma without the need for a derivatization process. We optimized the sample preparation procedure to extract FPP and (13)C5-FPP (as internal standard) from sample fluids using methanol...
March 25, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28339090/inhibition-of-farnesyl-pyrophosphate-synthase-attenuates-high-glucose%C3%A2-induced-vascular-smooth-muscle-cells-proliferation
#2
Guo-Ping Chen, Xiao-Qin Zhang, Tao Wu, Jie Han, Dan Ye
The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis accelerated by hyperglycemia. Our previous studies found that farnesyl pyrophosphate synthase (FPPS, EC 2.5.1.10), an essential enzyme in the mevalonate pathway, was upregulated in aorta media from diabetic mice along with the process of atherosclerosis. However, the exact role of FPPS in high glucose‑induced proliferation of VSMCs is largely unclear. In our study, we found that alendronate (an FPPS inhibitor) attenuated diabetic accelerated atherosclerosis in vivo and suppressed high glucose‑induced VSMCs proliferation in vitro...
March 23, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28337806/the-pharmacological-profile-of-a-novel-highly-potent-bisphosphonate-ox14-1-fluoro-2-imidazo-1-2-%C3%AE-pyridin-3-yl-ethyl-bisphosphonate
#3
M A Lawson, F H Ebetino, A Mazur, A D Chantry, J Paton-Hough, H R Evans, D Lath, M K Tsoumpra, M W Lundy, R L M Dobson, M Quijano, A A Kwaasi, J E Dunford, X Duan, J T Triffitt, G Jeans, R G G Russell
Bisphosphonates are widely used in the treatment of clinical disorders characterized by increased bone resorption, including osteoporosis, Paget's disease and the skeletal complications of malignancy. The anti-resorptive potency of the nitrogen-containing bisphosphonates on bone in vivo is now recognised to depend upon two key properties, namely mineral binding affinity and inhibitory activity on farnesyl pyrophosphate synthase (FPPS), and these properties vary independently of each other in individual bisphosphonates...
March 24, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28330935/the-role-of-enhanced-responses-to-aba1-era1-in-arabidopsis-stomatal-responses-is-beyond-aba-signaling
#4
Pirko Jalakas, Yi-Chun Huang, Yu-Hung Yeh, Laurent Zimmerli, Ebe Merilo, Hannes Kollist, Mikael Brosche
Proper stomatal responses are essential for plant function in an altered environment. The core signaling pathway for abscisic acid (ABA)-induced stomatal closure involves perception of the hormone that leads to the activation of guard cell anion channels by the protein kinase OPEN STOMATA1 (OST1). Several other regulators are suggested to modulate the ABA signaling pathway, including the protein ENHANCED RESPONSE TO ABA 1 (ERA1), that encodes the farnesyl transferase beta subunit. The era1 mutant is hypersensitive to ABA during seed germination and shows a more closed stomata phenotype...
March 22, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28326143/posttranslational-isoprenylation-of-tryptophan-in-bacteria
#5
REVIEW
Masahiro Okada, Tomotoshi Sugita, Ikuro Abe
Posttranslational isoprenylation is generally recognized as a universal modification of the cysteine residues in peptides and the thiol groups of proteins in eukaryotes. In contrast, the Bacillus quorum sensing peptide pheromone, the ComX pheromone, possesses a posttranslationally modified tryptophan residue, and the tryptophan residue is isoprenylated with either a geranyl or farnesyl group at the gamma position to form a tricyclic skeleton that bears a newly formed pyrrolidine, similar to proline. The post-translational dimethylallylation of two tryptophan residues of a cyclic peptide, kawaguchipeptin A, from cyanobacteria has also been reported...
2017: Beilstein Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28320825/structure-of-the-rzz-complex-and-molecular-basis-of-its-interaction-with-spindly
#6
Shyamal Mosalaganti, Jenny Keller, Anika Altenfeld, Michael Winzker, Pascaline Rombaut, Michael Saur, Arsen Petrovic, Annemarie Wehenkel, Sabine Wohlgemuth, Franziska Müller, Stefano Maffini, Tanja Bange, Franz Herzog, Herbert Waldmann, Stefan Raunser, Andrea Musacchio
Kinetochores are macromolecular assemblies that connect chromosomes to spindle microtubules (MTs) during mitosis. The metazoan-specific ≈800-kD ROD-Zwilch-ZW10 (RZZ) complex builds a fibrous corona that assembles on mitotic kinetochores before MT attachment to promote chromosome alignment and robust spindle assembly checkpoint signaling. In this study, we combine biochemical reconstitutions, single-particle electron cryomicroscopy, cross-linking mass spectrometry, and structural modeling to build a complete model of human RZZ...
March 20, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28300835/geranylgeranyl-diphosphate-synthase-inhibition-induces-apoptosis-that-is-dependent-upon-ggpp-depletion-erk-phosphorylation-and-caspase-activation
#7
Sherry S Agabiti, Jin Li, Andrew J Wiemer
Bisphosphonates are diphosphate analogs that inhibit the intermediate enzymes of the mevalonate pathway. Here, we compared the effects of a farnesyl diphosphate synthase inhibitor, zoledronate, and a geranylgeranyl diphosphate synthase (GGDPS) inhibitor, digeranyl bisphosphonate (DGBP), on lymphocytic leukemia cell proliferation and apoptosis. Both zoledronate and DGBP inhibited proliferation with DGBP doing so more potently. DGBP was markedly less toxic than zoledronate toward the viability of healthy human peripheral blood mononuclear cells...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28294491/an-efficient-chemoenzymatic-synthesis-of-dihydroartemisinic-aldehyde
#8
Melodi Demiray, Xiaoping Tang, Thomas Wirth, Juan A Faraldos, Rudolf K Allemann
Artemisinin from the plant Artemisia annua is the most potent pharmaceutical for the treatment of malaria. In the plant, the sesquiterpene cyclase amorphadiene synthase, a cytochrome-dependent CYP450, and an aldehyde reductase convert farnesyl diphosphate (FDP) into dihydroartemisinic aldehyde (DHAAl), which is a key intermediate in the biosynthesis of artemisinin and a semisynthetic precursor for its chemical synthesis. Here, we report a chemoenzymatic process that is able to deliver DHAAl using only the sesquiterpene synthase from a carefully designed hydroxylated FDP derivative...
March 13, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28286413/optimising-terpene-synthesis-with-flow-biocatalysis
#9
Xiaoping Tang, Rudolf K Allemann, Thomas Wirth
Sesquiterpenes are an important family of natural products, many of which exhibit important pharmaceutical and agricultural properties. They are biosynthesised from farnesyl diphosphate in sesquiterpene synthase catalysed reactions. Here, we report the development of a highly efficient segmented flow system for the enzyme-catalysed continuous flow production of sesquiterpenes. Design of experiment (DoE) methods were used to optimise the performance of the flow biocatalysis, and quantitative yields were achieved by using an operationally simple but highly effective segmented flow system...
January 10, 2017: European Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28281558/allosteric-modulation-of-peroxisomal-membrane-protein-recognition-by-farnesylation-of-the-peroxisomal-import-receptor-pex19
#10
Leonidas Emmanouilidis, Ulrike Schütz, Konstantinos Tripsianes, Tobias Madl, Juliane Radke, Robert Rucktäschel, Matthias Wilmanns, Wolfgang Schliebs, Ralf Erdmann, Michael Sattler
The transport of peroxisomal membrane proteins (PMPs) requires the soluble PEX19 protein as chaperone and import receptor. Recognition of cargo PMPs by the C-terminal domain (CTD) of PEX19 is required for peroxisome biogenesis in vivo. Farnesylation at a C-terminal CaaX motif in PEX19 enhances the PMP interaction, but the underlying molecular mechanisms are unknown. Here, we report the NMR-derived structure of the farnesylated human PEX19 CTD, which reveals that the farnesyl moiety is buried in an internal hydrophobic cavity...
March 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28272514/transcriptomic-insight-into-terpenoid-and-carbazole-alkaloid-biosynthesis-and-functional-characterization-of-two-terpene-synthases-in-curry-tree-murraya-koenigii
#11
Seema Meena, Sarma Rajeev Kumar, Varun Dwivedi, Anup Kumar Singh, Chandan S Chanotiya, Md Qussen Akhtar, Krishna Kumar, Ajit Kumar Shasany, Dinesh A Nagegowda
Curry tree (Murraya koenigii L.) is a rich source of aromatic terpenes and pharmacologically important carbazole alkaloids. Here, M. koenigii leaf transcriptome was generated to gain insight into terpenoid and alkaloid biosynthesis. Analysis of de novo assembled contigs yielded genes for terpene backbone biosynthesis and terpene synthases. Also, gene families possibly involved in carbazole alkaloid formation were identified that included polyketide synthases, prenyltransferases, methyltransferases and cytochrome P450s...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28265494/purification-and-biochemical-characterization-of-recombinant-persicaria-minor%C3%A2-%C3%AE-sesquiphellandrene-synthase
#12
De-Sheng Ker, Sze Lei Pang, Noor Farhan Othman, Sekar Kumaran, Ee Fun Tan, Thiba Krishnan, Kok Gan Chan, Roohaida Othman, Maizom Hassan, Chyan Leong Ng
BACKGROUND: Sesquiterpenes are 15-carbon terpenes synthesized by sesquiterpene synthases using farnesyl diphosphate (FPP) as a substrate. Recently, a sesquiterpene synthase gene that encodes a 65 kDa protein was isolated from the aromatic plant Persicaria minor. Here, we report the expression, purification and characterization of recombinant P. minor sesquiterpene synthase protein (PmSTS). Insights into the catalytic active site were further provided by structural analysis guided by multiple sequence alignment...
2017: PeerJ
https://www.readbyqxmd.com/read/28262489/compartmentalization-of-er-bound-chaperone-confines-protein-deposit-formation-to-the-aging-yeast-cell
#13
Juha Saarikangas, Fabrice Caudron, Rupali Prasad, David F Moreno, Alessio Bolognesi, Martí Aldea, Yves Barral
In order to produce rejuvenated daughters, dividing budding yeast cells confine aging factors, including protein aggregates, to the aging mother cell. The asymmetric inheritance of these protein deposits is mediated by organelle and cytoskeletal attachment and by cell geometry. Yet it remains unclear how deposit formation is restricted to the aging lineage. Here, we show that selective membrane anchoring and the compartmentalization of the endoplasmic reticulum (ER) membrane confine protein deposit formation to aging cells during division...
March 20, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28258968/identification-of-a-drimenol-synthase-and-drimenol-oxidase-from-persicaria-hydropiper-involved-in-the-biosynthesis-of-insect-deterrent-drimanes
#14
Maurice Henquet, Neli Prota, Justin J J van der Hooft, Marina Varbanova-Herde, Raymond J M Hulzink, Martin de Vos, Marcel Prins, Michiel T J de Both, Maurice C R Franssen, Harro Bouwmeester, Maarten Jongsma
The sesquiterpenoid polygodial, belonging to the drimane family, has been shown to be an antifeedant for a number of herbivorous insects. It is presumed to be synthesized from farnesyl diphosphate via drimenol, subsequent C-12 hydroxylation, and further oxidations at both C-11 and C-12 to form a dialdehyde. Here, we have identified a drimenol synthase (PhDS) and a cytochrome P450 drimenol oxidase (PhDOX1) from Persicaria hydropiper. Expression of PhDS in yeast and plants resulted in production of drimenol only...
March 4, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28245611/de-novo-transcriptome-analysis-of-plant-pathogenic-fungus-myrothecium-roridum-and-identification-of-genes-associated-with-trichothecene-mycotoxin-biosynthesis
#15
Wei Ye, Taomei Liu, Muzi Zhu, Weimin Zhang, Haohua Li, Zilei Huang, Saini Li
Myrothecium roridum is a plant pathogenic fungus that infects different crops and decreases the yield of economical crops, including soybean, cotton, corn, pepper, and tomato. Until now, the pathogenic mechanism of M. roridum has remained unclear. Different types of trichothecene mycotoxins were isolated from M. roridum, and trichothecene was considered as a plant pathogenic factor of M. roridum. In this study, the transcriptome of M. roridum in different incubation durations was sequenced using an Illumina Hiseq 2000...
February 25, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28242621/a-farnesylated-coxiella-burnetii-effector-forms-a-multimeric-complex-at-the-mitochondrial-outer-membrane-during-infection
#16
Laura F Fielden, Jennifer H Moffatt, Yilin Kang, Michael James Baker, Chen Ai Khoo, Craig R Roy, Diana Stojanovski, Hayley J Newton
Coxiella burnetii, the causative agent of Q fever, establishes a unique lysosome-derived intracellular niche termed the Coxiella-containing vacuole (CCV). The Dot/Icm type IVB secretion system is essential for biogenesis of the CCV and intracellular replication of Coxiella. Effector proteins, translocated into the host cell through this apparatus, act to modulate host trafficking and signaling processes to facilitate CCV development. Here we investigated the role of CBU0077, a conserved Coxiella effector that had previously been observed to localize to lysosomal membranes...
February 27, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28239463/enhancing-adoptive-cancer-immunotherapy-with-v%C3%AE-2v%C3%AE-2-t-cells-through-pulse-zoledronate-stimulation
#17
Mohanad H Nada, Hong Wang, Grefachew Workalemahu, Yoshimasa Tanaka, Craig T Morita
BACKGROUND: Human γδ T cells expressing Vγ2Vδ2 T cell receptors monitor foreign- and self-prenyl pyrophosphate metabolites in isoprenoid biosynthesis to mediate immunity to microbes and tumors. Adoptive immunotherapy with Vγ2Vδ2 T cells has been used to treat cancer patients with partial and complete remissions. Most clinical trials and preclinical studies have used continuous zoledronate exposure to expand Vγ2Vδ2 cells where zoledronate is slowly diluted over the course of the culture...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28236226/nmr-resonance-assignments-of-the-fkbp-domain-of-human-aryl-hydrocarbon-receptor-interacting-protein-like-1-aipl1-in-complex-with-a-farnesyl-ligand
#18
Liping Yu, Ravi P Yadav, Nikolai O Artemyev
Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a specialized chaperone of phosphodiesterase 6, a key effector enzyme in the phototransduction cascade. The FKBP domain of AIPL1 is known to bind the farnesyl moiety of PDE6. Mutations in AIPL1, including many missense mutations in the FKBP domain, have been associated with Leber congenital amaurosis, a severe blinding disease. Here, we report the backbone and sidechain assignments of the N-terminal FKBP(Δloop) (with a loop deletion) of AIPL1 in complex with a farnesyl ligand...
February 24, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28223871/new-acyclic-secondary-metabolites-from-the-biologically-active-fraction-of-albizia-lebbeck-flowers
#19
Shaza M Al-Massarani, Ali A El Gamal, Mohamed F Abd El Halim, Mansour S Al-Said, Maged S Abdel-Kader, Omer A Basudan, Saleh I Alqasoumi
The total extract of Albizia lebbeck flowers was examined in vivo for its possible hepatoprotective activity in comparison with the standard drug silymarin at two doses. The higher dose expressed promising activity especially in reducing the levels of AST, ALT and bilirubin. Fractionation via liquid-liquid partition and reexamination of the fractions revealed that the n-butanol fraction was the best in improving liver biochemical parameters followed by the n-hexane fraction. However, serum lipid parameters were best improved with CHCl3 fraction...
January 2017: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
https://www.readbyqxmd.com/read/28208018/pharmacophore-mapping-of-thienopyrimidine-based-monophosphonate-thp-mp-inhibitors-of-the-human-farnesyl-pyrophosphate-synthase
#20
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 nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases...
February 28, 2017: Journal of Medicinal Chemistry
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