keyword
MENU ▼
Read by QxMD icon Read
search

Farnesylation

keyword
https://www.readbyqxmd.com/read/27935847/structure-based-development-of-pde%C3%AE-inhibitors
#1
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...
November 17, 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
#2
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
#3
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...
December 8, 2016: Nucleus
https://www.readbyqxmd.com/read/27921136/penicillium-roqueforti-pr-toxin-gene-cluster-characterization
#4
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
#5
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
https://www.readbyqxmd.com/read/27909058/secreted-glioblastoma-nanovesicles-contain-intracellular-signaling-proteins-and-active-ras-incorporated-in-a-farnesylation-dependent-manner
#6
Natalie Luhtala, Aaron Aslanian, John R Yates, Tony Hunter
Glioblastomas (GBMs) are malignant brain tumors with a median survival of less than 18 months. Redundancy of signaling pathways represented within GBMs contributes to their therapeutic resistance. Exosomes are extracellular nanovesicles released from cells and present in human biofluids that represent a possible biomarker of tumor signaling state that could aid in personalized treatment. Herein, we demonstrate that mouse GBM cell-derived extracellular nanovesicles resembling exosomes from an H-RasV12 myr-Akt mouse model for GBM are enriched for intracellular signaling cascade proteins (GO: 0007242) and Ras protein signal transduction (GO: 0007265), and contain active Ras...
December 1, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27905068/inhibition-of-mevalonate-pathway-and-synthesis-of-the-storage-lipids-in-human-liver-derived-and-non-liver-cell-lines-by-lippia-alba-essential-oils
#7
Sandra Montero-Villegas, Mónica Polo, Marianela Galle, Boris Rodenak-Kladniew, María Castro, Ana Ves-Losada, Rosana Crespo, Margarita García de Bravo
The essential oils (EOs) of Lippia alba, an herb extensively used as a folk medicine in Latin America, are today promoted as an effective means of eliminating problems caused by hyperlipemia. We hypothesized that L.alba EOs inhibited cholesterol and triacylglycerols synthesis and decreased the intracellular depots of those lipids (lipid droplets), mechanisms involving the induction of a hypolipidemic response. Our aim was, therefore, to evaluate the hypolipogenic capability of the EOs of four L. alba chemotypes on liver-derived (HepG2) and non-liver (A549) human cell lines and to identify the potential biochemical targets of those chemotypes, particularly within the mevalonate pathway (MP)...
November 30, 2016: Lipids
https://www.readbyqxmd.com/read/27895021/1-in-vitro-and-in-vivo-activity-of-sulfur-containing-linear-bisphosphonates-against-apicomplexan-parasites
#8
Sergio H Szajnman, Tamila Galaka, Zhu-Hong Li, Catherine Li, Nathan M Howell, María N Chao, Boris Striepen, Vasant Muralidharan, Silvia N J Moreno, Juan B Rodriguez
We tested a series of sulfur-containing linear bisphosphonates against Toxoplasma gondii, the etiologic agent of toxoplasmosis. The most potent compound ( 22: , 1-[(n-decylsulfonyl)ethyl]-1,1-biphosphonic acid) is a sulfone-containing compound, which had an EC50 of 0.11 ± 0.02 μM against intracellular tachyzoites. The compound showed low toxicity when tested in tissue culture with a selectivity index of >2,000. 22: also showed high activity in vivo in a toxoplasmosis mouse model. The compound inhibited the Toxoplasma farnesyl diphosphate synthase (TgFPPS) but the concentration needed to inhibit 50% of the enzymatic activity (IC50) was higher than the concentration that inhibited 50% of growth...
November 28, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27883036/the-mevalonate-pathway-regulates-primitive-streak-formation-via-protein-farnesylation
#9
Yoshimi Okamoto-Uchida, Ruoxing Yu, Norio Miyamura, Norie Arima, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Suguru Yoshida, Takamitsu Hosoya, Makiko Nawa, Takeshi Kasama, Yoichi Asaoka, Reiner Wimmer Alois, Ulrich Elling, Josef M Penninger, Sachiko Nishina, Noriyuki Azuma, Hiroshi Nishina
The primitive streak in peri-implantation embryos forms the mesoderm and endoderm and controls cell differentiation. The metabolic cues regulating primitive streak formation remain largely unknown. Here we utilised a mouse embryonic stem (ES) cell differentiation system and a library of well-characterised drugs to identify these metabolic factors. We found that statins, which inhibit the mevalonate metabolic pathway, suppressed primitive streak formation in vitro and in vivo. Using metabolomics and pharmacologic approaches we identified the downstream signalling pathway of mevalonate and revealed that primitive streak formation requires protein farnesylation but not cholesterol synthesis...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27874871/mass-spectrometry-captures-off-target-drug-binding-and-provides-mechanistic-insights-into-the-human-metalloprotease-zmpste24
#10
Shahid Mehmood, Julien Marcoux, Joseph Gault, Andrew Quigley, Susan Michaelis, Stephen G Young, Elisabeth P Carpenter, Carol V Robinson
Off-target binding of hydrophobic drugs can lead to unwanted side effects, either through specific or non-specific binding to unintended membrane protein targets. However, distinguishing the binding of drugs to membrane proteins from that of detergents, lipids and cofactors is challenging. Here, we use high-resolution mass spectrometry to study the effects of HIV protease inhibitors on the human zinc metalloprotease ZMPSTE24. This intramembrane protease plays a major role in converting prelamin A to mature lamin A...
December 2016: Nature Chemistry
https://www.readbyqxmd.com/read/27867276/ursolic-acid-a-natural-pentacylcic-triterpene-from-ochrosia-elliptica-and-its-role-in-the-management-of-certain-neglected-tropical-diseases
#11
Rola M Labib, Sherif S Ebada, Fadia S Youssef, Mohamed L Ashour, Samir A Ross
BACKGROUND: Leishmaniasis and African trypanosomiasis are recognized as the leading causes of mortality and morbidity with the greatest prevalence in the developing countries. They affect more than one billion of the poorest people on the globe. OBJECTIVE: To find a cheap, affordable, safe, and efficacious antileshmanial and antitrypanosomal natural drug and to elucidate its probable mode of action. MATERIALS AND METHODS: Phytochemical investigation of the non-polar fraction of the methanol extract of leaves of Ochrosia elliptica Labill...
October 2016: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/27862766/terpene-cyclases-from-social-amoebae
#12
Patrick Rabe, Jan Rinkel, Britta Nubbemeyer, Tobias G Köllner, Feng Chen, Jeroen S Dickschat
Genome sequences of social amoebae reveal the presence of terpene cyclases (TCs) in these organisms. Two TCs from Dictyostelium discoideum converted farnesyl diphosphate into (2S,3R,6S,9S)-(-)-protoillud-7-ene and (3S)-(+)-asterisca-2(9),6-diene. The enzyme mechanisms and EI-MS fragmentations of the products were studied by labeling experiments.
November 10, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27853760/enzymatic-synthesis-of-natural-aristolochene-from-a-non-natural-substrate
#13
Juan A Faraldos, Daniel J Grundy, Oscar Cascon, Stefano Leoni, Marc W van der Kamp, Rudolf K Allemann
The sesquiterpene cyclase aristolochene synthase from Penicillium roquefortii (PR-AS) has evolved to catalyse with high specificity (92%) the conversion of farnesyl diphosphate (FDP) to the bicyclic hydrocarbon (+)-aristolochene, the natural precursor of several fungal toxins. Here we report that PR-AS converts the unnatural FDP isomer 7-methylene farnesyl diphosphate to (+)-aristolochene via the intermediate 7-methylene germacrene A. Within the confined space of the enzyme's active site, PR-AS stabilises the reactive conformers of germacrene A and 7-methylene germacrene A, respectively, which are protonated by the same active site acid (most likely HOPPi) to yield the shared natural bicyclic intermediate eudesmane cation, from which (+)-aristolochene is then generated...
November 17, 2016: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/27834682/does-viperin-function-as-a-radical-s-adenosyl-l-methionine-dependent-enzyme-in-regulating-farnesylpyrophosphate-synthase-expression-and-activity
#14
Caitlyn Makins, Soumi Ghosh, Gabriel D Román-Meléndez, Paige A Malec, Robert T Kennedy, E Neil G Marsh
Viperin is an endoplasmic reticulum-associated antiviral responsive protein, which is highly up regulated in eukaryotic cells upon viral infection through both interferon-dependent and independent pathways. Viperin is predicted to be a radical S-adenosyl-L-methionine (SAM) enzyme, but it is unknown if viperin actually exploits radical SAM chemistry to exert its antiviral activity. We have investigated the interaction of viperin with its most firmly established cellular target, farnesyl pyrophosphate synthase (FPPS)...
November 10, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27829890/mechanistic-investigations-on-six-bacterial-terpene-cyclases
#15
Patrick Rabe, Thomas Schmitz, Jeroen S Dickschat
The products obtained by incubation of farnesyl diphosphate (FPP) with six purified bacterial terpene cyclases were characterised by one- and two-dimensional NMR spectroscopic methods, allowing for a full structure elucidation. The absolute configurations of four terpenes were determined based on their optical rotary powers. Incubation experiments with (13)C-labelled isotopomers of FPP in buffers containing water or deuterium oxide allowed for detailed insights into the cyclisation mechanisms of the bacterial terpene cyclases...
2016: Beilstein Journal of Organic Chemistry
https://www.readbyqxmd.com/read/27825357/fermentative-production-and-direct-extraction-of-%C3%AE-bisabolol-in-metabolically-engineered-escherichia-coli
#16
Gui Hwan Han, Seong Keun Kim, Paul Kyung-Seok Yoon, Younghwan Kang, Byoung Su Kim, Yaoyao Fu, Bong Hyun Sung, Heung Chae Jung, Dae-Hee Lee, Seon-Won Kim, Seung-Goo Lee
BACKGROUND: (-)-α-Bisabolol, also known as levomenol, is an unsaturated sesquiterpene alcohol that has mainly been used in pharmaceutical and cosmetic products due to its anti-inflammatory and skin-soothing properties. (-)-α-Bisabolol is currently manufactured mainly by steam-distillation of the essential oils extracted from the Brazilian candeia tree that is under threat because its natural habitat is constantly shrinking. Therefore, microbial production of (-)-α-bisabolol plays a key role in the development of its sustainable production from renewable feedstock...
November 8, 2016: Microbial Cell Factories
https://www.readbyqxmd.com/read/27809506/annulative-methods-enable-a-total-synthesis-of-the-complex-meroterpene-berkeleyone-a
#17
Chi P Ting, Gong Xu, Xianhuang Zeng, Thomas J Maimone
Synthetic pathways to complex meroterpenes derived from 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate have not been reported despite heavy biosynthetic and medicinal interest. Herein we report a concise, 13-step total synthesis of berkeleyone A, a potential gateway compound to a plethora of fungal-derived meroterpenes. In addition, we have developed a novel annulation reaction for the assembly of hydroxylated 1,3-cyclohexadiones in a single step.
November 3, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27809361/development-of-pyridazinone-chemotypes-targeting-the-pde%C3%AE-prenyl-binding-site
#18
Sandip Murarka, Pablo Martín-Gago, Carsten Schultz-Fademrecht, Alaa Al Saabi, Matthias Baumann, Eyad Fansa, Shehab Ismail, Peter Nussbaumer, Alfred Wittinghofer, Herbert Waldmann
The K-Ras GTPase is a major target in anticancer drug discovery. However, direct interference with signaling by K-Ras has not led to clinically useful drugs yet. Correct localization and signaling by farnesylated K-Ras is regulated by the prenyl binding protein PDEδ. Interfering with binding of PDEδ to K-Ras by means of small molecules provides a novel opportunity to suppress oncogenic signaling. Here we describe the identification and structure-guided development of novel K-Ras-PDEδ inhibitor chemotypes based on pyrrolopyridazinones and pyrazolopyridazinones that bind to the farnesyl binding pocket of PDEδ with low nanomolar affinity...
November 3, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27802439/metabolic-stress-induces-caspase-3-mediated-degradation-and-inactivation-of-farnesyl-and-geranylgeranyl-transferase-activities-in-pancreatic-%C3%AE-cells
#19
Rajakrishnan Veluthakal, Daleep K Arora, Marc L Goalstone, Renu A Kowluru, Anjaneyulu Kowluru
BACKGROUND/AIMS: At least 300 prenylated proteins are identified in the human genome; the majority of which partake in a variety of cellular processes including growth, differentiation, cytoskeletal organization/dynamics and vesicle trafficking. Aberrant prenylation of proteins is implicated in human pathologies including cancer; neurodegenerative diseases, retinitis pigmentosa, and premature ageing syndromes. Original observations from our laboratory have demonstrated that prenylation of proteins [small G-proteins and γ-subunits of trimeric G-proteins] is requisite for physiological insulin secretion...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27791178/structural-basis-of-recognition-of-farnesylated-and-methylated-kras4b-by-pde%C3%AE
#20
Srisathiyanarayanan Dharmaiah, Lakshman Bindu, Timothy H Tran, William K Gillette, Peter H Frank, Rodolfo Ghirlando, Dwight V Nissley, Dominic Esposito, Frank McCormick, Andrew G Stephen, Dhirendra K Simanshu
Farnesylation and carboxymethylation of KRAS4b (Kirsten rat sarcoma isoform 4b) are essential for its interaction with the plasma membrane where KRAS-mediated signaling events occur. Phosphodiesterase-δ (PDEδ) binds to KRAS4b and plays an important role in targeting it to cellular membranes. We solved structures of human farnesylated-methylated KRAS4b in complex with PDEδ in two different crystal forms. In these structures, the interaction is driven by the C-terminal amino acids together with the farnesylated and methylated C185 of KRAS4b that binds tightly in the central hydrophobic pocket present in PDEδ...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
keyword
keyword
71267
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"