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Farnesylation

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https://www.readbyqxmd.com/read/29352523/unilateral-incompatibility-is-linked-to-reduced-pollen-expression-of-a-farnesyl-pyrophosphate-synthase
#1
Sheila McCormick
No abstract text is available yet for this article.
February 2018: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/29349663/ibandronate-metal-complexes-solution-behavior-and-antiparasitic-activity
#2
Bruno Demoro, Santiago Rostán, Mauricio Moncada, Zhu-Hong Li, Roberto Docampo, Claudio Olea Azar, Juan Diego Maya, Julia Torres, Dinorah Gambino, Lucía Otero
To face the high costs of developing new drugs, researchers in both industry and academy are looking for ways to repurpose old drugs for new uses. In this sense, bisphosphonates that are clinically used for bone diseases have been studied as agents against Trypanosoma cruzi, causative parasite of Chagas disease. In this work, the development of first row transition metal complexes (M = Co2+, Mn2+, Ni2+) with the bisphosphonate ibandronate (iba, H4iba representing the neutral form) is presented. The in-solution behavior of the systems containing iba and the selected 3d metal ions was studied by potentiometry...
January 18, 2018: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/29346419/saxs-analysis-of-a-soluble-cytosolic-ngbr-construct-including-extracellular-and-transmembrane-domains
#3
Joshua Holcomb, Maysaa Doughan, Nicholas Spellmon, Brianne Lewis, Emerson Perry, Yingxue Zhang, Lindsey Nico, Junmei Wan, Srinivas Chakravarthy, Weifeng Shang, Qing Miao, Timothy Stemmler, Zhe Yang
The Nogo-B receptor (NgBR) is involved in oncogenic Ras signaling through directly binding to farnesylated Ras. It recruits farnesylated Ras to the non-lipid-raft membrane for interaction with downstream effectors. However, the cytosolic domain of NgBR itself is only partially folded. The lack of several conserved secondary structural elements makes this domain unlikely to form a complete farnesyl binding pocket. We find that inclusion of the extracellular and transmembrane domains that contain additional conserved residues to the cytosolic region results in a well folded protein with a similar size and shape to the E...
2018: PloS One
https://www.readbyqxmd.com/read/29342140/atomic-structure-of-the-eukaryotic-intramembrane-ras-methyltransferase-icmt
#4
Melinda M Diver, Leanne Pedi, Akiko Koide, Shohei Koide, Stephen B Long
The maturation of RAS GTPases and approximately 200 other cellular CAAX proteins involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CAAX motif, proteolytic cleavage of the AAX residues and methylation of the exposed prenylcysteine residue at its terminal carboxylate. This final step is catalysed by isoprenylcysteine carboxyl methyltransferase (ICMT), a eukaryote-specific integral membrane enzyme that resides in the endoplasmic reticulum...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29341437/phenotypic-heterogeneity-of-zmpste24-deficiency
#5
Thomas A Cassini, Amy K Robertson, Anna G Bican, Joy D Cogan, Vickie L Hannig, John H Newman, Rizwan Hamid, John A Phillips
A 4-year-old girl was referred to the Undiagnosed Diseases Network with a history of short stature, thin and translucent skin, macrocephaly, small hands, and camptodactyly. She had been diagnosed with possible Hallerman-Streiff syndrome. Her evaluation showed that she was mosaic for uniparental isodisomy of chromosome 1, which harbored a pathogenic c.1077dupT variant in ZMPSTE24 which predicts p.(Leu362fsX18). ZMPSTE24 is a zinc metalloproteinase that is involved in processing farnesylated proteins and pathogenic ZMPSTE24 variants cause accumulation of abnormal farnesylated forms of prelamin A...
January 17, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29340843/phytoene-production-utilizing-the-isoprenoid-biosynthesis-capacity-of-thermococcus-kodakarensis
#6
Tsubasa Fuke, Takaaki Sato, Savyasachee Jha, Myra L Tansengco, Haruyuki Atomi
Phytoene (C40H64) is an isoprenoid and a precursor of various carotenoids which are of industrial value. Archaea can be considered to exhibit a relatively large capacity to produce isoprenoids, as they are components of their membrane lipids. Here, we aimed to produce isoprenoids such as phytoene in the hyperthermophilic archaeon Thermococcus kodakarensis. T. kodakarensis harbors a prenyltransferase gene involved in the biosynthesis of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are precursors of squalene and phytoene, respectively...
January 16, 2018: Extremophiles: Life Under Extreme Conditions
https://www.readbyqxmd.com/read/29339403/a-phase-1-study-of-azacitidine-combined-with-chemotherapy-in-childhood-leukemia-a-report-from-tacl-consortium
#7
Weili Sun, Timothy Triche, Jemily Malvar, Paul Gaynon, Richard Sposto, Xiaojing Yang, Henrique Bittencourt, Andrew E Place, Yoav Messinger, Chris Fraser, Luciano Dalla-Pozza, Bodour Salhia, Peter Jones, Alan S Wayne, Lia Gore, Todd M Cooper, Gangning Liang
Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemogenesis, chemotherapy resistance, and relapse. DNA methyltransferase inhibitors such as azacitidine and decitabine have been shown to reverse drug resistance and prime leukemia cells to cytotoxic agents in vitro. Here we report the first pediatric phase 1 study using azacitidine in sequence with chemotherapy in patients with relapsed/refractory leukemia. Fourteen patients were enrolled, twelve with acute myeloid leukemia (AML) and two with acute lymphoblastic leukemia (ALL)...
January 16, 2018: Blood
https://www.readbyqxmd.com/read/29337059/fpps-mediates-tgf-%C3%AE-1-induced-non-small-cell-lung-cancer-cell-invasion-and-the-emt-process-via-the-rhoa-rock1-pathway
#8
Lin Lin, Ming Li, Lei Lin, Xiaolin Xu, Gening Jiang, Liang Wu
Farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway, was recently shown to play a role in cancer progression. However, its role in non-small cell lung cancer (NSCLC) metastasis and the underlying mechanism remain unclear. In this study, FPPS expression was significantly correlated with TNM stage, and metastasis. Inhibition or knockdown of FPPS blocked TGF-β1-induced cell invasion and epithelial-to-mesenchymal transition (EMT) process. FPPS expression of FPPS was induced by TGF-β1 and FPPS promoted cell invasion and EMT via the RhoA/Rock1 pathway...
January 11, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29336441/a-high-pressure-study-of-calmodulin-ligand-interactions-using-small-angle-x-ray-and-elastic-incoherent-neutron-scattering
#9
Süleyman Cinar, Samy Al-Ayoubi, Christian Sternemann, Judith Peters, Roland Winter, Claus Czeslik
Calmodulin (CaM) is a Ca2+ sensor and mediates Ca2+ signaling through binding of numerous target ligands. The binding of ligands by Ca2+-saturated CaM (holo-CaM) is governed by attractive hydrophobic and electrostatic interactions that are weakened under high pressure in aqueous solutions. Moreover, the potential formation of void volumes upon ligand binding creates a further source of pressure sensitivity. Hence, high pressure is a suitable thermodynamic variable to probe protein-ligand interactions. In this study, we compare the binding of two different ligands to holo-CaM as a function of pressure by using X-ray and neutron scattering techniques...
January 16, 2018: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29320955/therapeutic-roles-of-statins-in-gynecology-and-obstetrics-the-current-evidence
#10
Burak Zeybek, Maged Costantine, Gokhan S Kilic, Mostafa A Borahay
INTRODUCTION: Statins are a class of drugs, which act by inhibiting the rate-limiting enzyme of cholesterol biosynthesis (3-hydroxy-3-methyl-glutaryl-CoA reductase). The inhibition of mevalonate synthesis leads to subsequent inhibition of downstream products of this pathway, which explains the pleiotropic effects of these agents in addition to their well-known lipid-lowering effects. Accumulating evidence suggests that statins might be beneficial in various obstetric and gynecologic conditions...
January 1, 2018: Reproductive Sciences
https://www.readbyqxmd.com/read/29320680/k-ras4b-remains-monomeric-on-membranes-over-a%C3%A2-wide-range-of%C3%A2-surface-densities-and-lipid-compositions
#11
Jean K Chung, Young Kwang Lee, John-Paul Denson, William K Gillette, Steven Alvarez, Andrew G Stephen, Jay T Groves
Ras is a membrane-anchored signaling protein that serves as a hub for many signaling pathways and also plays a prominent role in cancer. The intrinsic behavior of Ras on the membrane has captivated the biophysics community in recent years, especially the possibility that it may form dimers. In this article, we describe results from a comprehensive series of experiments using fluorescence correlation spectroscopy and single-molecule tracking to probe the possible dimerization of natively expressed and fully processed K-Ras4B in supported lipid bilayer membranes...
January 9, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29319354/inhibition-of-the-rhoa-rho-associated-coiled-coil-containing-protein-kinase-1-pathway-is-involved-in-the-therapeutic-effects-of-simvastatin-on-pulmonary-arterial-hypertension
#12
Wei-Hua Liu, Xiao-Hong Xu, Qin Luo, Hong-Liang Zhang, Yong Wang, Qun-Ying Xi, Zhi-Hui Zhao, Zhi-Hong Liu
BACKGROUND: Recent research has shown that statins improve pulmonary arterial hypertension (PAH), but their mechanisms of action are not fully understood. This study aimed to investigate the role of RhoA/ROCK1 regulation in the therapeutic effects of simvastatin on PAH. METHODS: For in vivo experiments, rats (N = 40) were randomly assigned to four groups: control, simvastatin, monocrotaline (MCT), and MCT + simvastatin. The MCT group and MCT + simvastatin groups received proline dithiocarbamate (50 mg/kg, i...
January 10, 2018: Clinical and Experimental Hypertension: CHE
https://www.readbyqxmd.com/read/29311076/crystal-structure-of-nisi-in-a-lipid-free-form-the-nisin-immunity-protein-from-lactococcus-lactis
#13
Jin Hee Jeong, Sung Chul Ha
Nisin is a lantibiotic, a family of polypeptides containing lanthionine with antimicrobial activity. Nisin-producing microorganisms require immunity proteins for self-protection from nisin itself. Lactococcus lactis, a microorganism that synthesizes nisin, has an integral NisFEG ABC transporter and NisI lipoprotein that function in the nisin immunity. Here, we present the crystal structure of the full length of NisI22-C, a lipid-free form of NisI, determined at 1.9 Å resolution. Similar to the NMR structures of N- and C-terminal domain of NisI, NisI22-C is composed of N- and C-terminal domains, both of which display a fold similar to that found in SpaI, a lipoprotein with immunity against subtilin in Bacillus subtilis The full length structure of NisI22-c reveals a large and deep cleft by the interdomain association, one side of which is occupied by the residues important for immunity...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29303071/prenylated-coumarins-of-the-genus-citrus-an-overview-of-the-2006-2016-literature-data
#14
Salvatore Genovese, Vito Alessandro Taddeo, Francesco Epifano, Serena Fiorito
O-Prenyl coumarins (3,3-dimethylallyl, geranyl-, farnesyl- and related biosynthetic derivatives) represent a class of rarely occurring natural products. In the last two decades such secondary metabolites have been found to possess promising and effective pharmacological properties, mainly in terms of anti-cancer and anti-inflammatory properties. To date about 160 oxyprenylated coumarins have been extracted from plants, fungi, and bacteria. The genus Citrus have been demonstrated to be among the richest source of the title products...
January 4, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29290764/aminoacylase-3-is-a-new-potential-marker-and-therapeutic-target-in-hepatocellular-carcinoma
#15
Kirill Tsirulnikov, Sergio Duarte, Anamika Ray, Nakul Datta, Ali Zarrinpar, Lin Hwang, Kym Faull, Alexander Pushkin, Ira Kurtz
Ras proteins (HRas, KRas and NRas) are common oncogenes that require membrane association for activation. Previous approaches to block/inhibit Ras membrane association were unsuccessful for cancer treatment in human clinical studies. In the present study we utilized a new approach to decrease Ras membrane association in hepatocellular carcinoma (HCC) cell lines via inhibition of an enzyme aminoacylase 3 (AA3; EC 3.5.1.114). AA3 expression was significantly elevated in the livers of HCC patients and HCC cell lines...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29285232/synergistic-effect-of-farnesyl-transferase-inhibitor-lonafarnib-combined-with-chemotherapeutic-agents-against-the-growth-of-hepatocellular-carcinoma-cells
#16
Jialiang Wang, Yifan Lian, Yurong Gu, Hongbo Wang, Lin Gu, Yanlin Huang, Liang Zhou, Yuehua Huang
Hepatocellular carcinoma (HCC) is a common and deadly cancer worldwide and is often refractory to chemotherapy due to the development of multidrug resistance. Lonafarnib is an orally active and potent non-peptidomimetic inhibitor of farnesyl transferase. Here, using in vitro HCC cell models, we demonstrated that lonafarnib inhibited tumor proliferation and reduced the activity of mitogen-activated protein kinases pathways. In addition, lonafarnib caused G1 to S phase arrest through the downregulation of Cyclin D1, CDK6 and SKP2, while it induced cellular apoptosis by promoting the cleavage and activation of Caspase-3 and PARP...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29282592/systematic-exploration-of-multiple-drug-binding-sites
#17
Mónika Bálint, Norbert Jeszenői, István Horváth, David van der Spoel, Csaba Hetényi
BACKGROUND: Targets with multiple (prerequisite or allosteric) binding sites have an increasing importance in drug design. Experimental determination of atomic resolution structures of ligands weakly bound to multiple binding sites is often challenging. Blind docking has been widely used for fast mapping of the entire target surface for multiple binding sites. Reliability of blind docking is limited by approximations of hydration models, simplified handling of molecular flexibility, and imperfect search algorithms...
December 28, 2017: Journal of Cheminformatics
https://www.readbyqxmd.com/read/29282289/efficient-farnesylation-of-an-extended-c-terminal-c-x-3x-sequence-motif-expands-the-scope-of-the-prenylated-proteome
#18
Melanie J Blanden, Kiall F Suazo, Emily R Hildebrandt, Daniel S Hardgrove, Meet Patel, William P Saunders, Mark D Distefano, Walter K Schmidt, James L Hougland
Protein prenylation is a post-translational modification that has been most commonly associated with enabling protein trafficking to and interaction with cellular membranes. In this process, an isoprenoid group is attached to a cysteine near the C-terminus of a substrate protein by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I or II (GGTase-I and GGTase-II). FTase and GGTase-I have long been proposed to specifically recognize a four amino acid CaaX C-terminal sequence within their substrates...
December 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29276048/specific-inhibition-of-the-bifunctional-farnesyl-geranylgeranyl-diphosphate-synthase-in-malaria-parasites-via-a-new-small-molecule-binding-site
#19
Jolyn E Gisselberg, Zachary Herrera, Lindsey M Orchard, Manuel Llinás, Ellen Yeh
The bifunctional farnesyl/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key branchpoint enzyme in isoprenoid biosynthesis in Plasmodium falciparum (malaria) parasites. PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit FPPS and GGPPS enzymes by acting as a diphosphate substrate analog show poor bioavailability and selectivity for PfFPPS/GGPPS. We identified a new non-bisphosphonate compound, MMV019313, which is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS...
December 15, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29239694/a-novel-prenyl-polybasic-domain-code-determines-lipid-binding-specificity-of-the-k-ras-membrane-anchor
#20
Yong Zhou, John F Hancock
Ras proteins must localize to the plasma membrane (PM) for biological function. The membrane anchor of the K-Ras4B isoform comprises a farnesylated and methylated C-terminal cysteine together with an adjacent hexa-lysine polybasic domain (PBD). Traditionally, polybasic sequences have been thought to interact electrostatically with negatively charged membranes showing no specificity for anionic lipid head groups. By contrast we recently showed that the K-Ras membrane anchor actually exhibits a very high degree of specificity for phosphatidylserine (PtdSer)...
December 14, 2017: Small GTPases
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