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PTP1B

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https://www.readbyqxmd.com/read/28212750/conformational-rigidity-and-protein-dynamics-at-distinct-timescales-regulate-ptp1b-activity-and-allostery
#1
Meng S Choy, Yang Li, Luciana E S F Machado, Micha B A Kunze, Christopher R Connors, Xingyu Wei, Kresten Lindorff-Larsen, Rebecca Page, Wolfgang Peti
Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop...
February 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28209599/role-of-shp2-protein-tyrosine-phosphatase-in-sert-inhibition-by-enteropathogenic-e-coli-epec
#2
Megha Singhal, Christopher Manzella, Vinay Soni, Waddah A Alrefai, Seema Saksena, Gail A Hecht, Pradeep K Dudeja, Ravinder K Gill
Enteropathogenic E. coli (EPEC), one of the diarrheagenic E. coli pathotypes, is among the most important food-borne pathogens infecting children worldwide. Inhibition of serotonin transporter (SERT), that regulates extracellular availability of serotonin (5-HT), has been previously implicated in EPEC-associated diarrhea. EPEC was shown to inhibit SERT via activation of protein tyrosine phosphatases (PTPase), albeit the specific PTPase involved is not known. Current studies aimed to identify EPEC activated PTPase and its role in SERT inhibition...
February 16, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28202316/an-epigenetic-modifier-induces-production-of-10-s-verruculide-b-an-inhibitor-of-protein-tyrosine-phosphatases-by-phoma-sp-nov-lg0217-a-fungal-endophyte-of-parkinsonia-microphylla
#3
Juliana R Gubiani, E M Kithsiri Wijeratne, Taoda Shi, Angela R Araujo, A Elizabeth Arnold, Eli Chapman, A A Leslie Gunatilaka
Incorporation of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), to a culture broth of the endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla changed its metabolite profile and resulted in the production of (10'S)-verruculide B (1), vermistatin (2) and dihydrovermistatin (3). When cultured in the absence of the epigenetic modifier, it produced a new metabolite, (S,Z)-5-(3',4'-dihydroxybutyldiene)-3-propylfuran-2(5H)-one (4) together with nafuredin (5)...
February 3, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28199951/a-dioxidovanadium-v-complex-of-nno-donor-schiff-base-as-a-selective-inhibitor-of-protein-tyrosine-phosphatase-1b-synthesis-characterization-and-biological-activities
#4
Yuqi Jia, Liping Lu, Miaoli Zhu, Caixia Yuan, Shu Xing, Xueqi Fu
A new dioxidovanadium (V) complex, VO2(HPPCH) (1) (H2PPCH = N'-picolinoylpyridin-1-ium-2-carbohydrazonate) has been synthesized and characterized by elemental analysis, IR, X-ray diffraction analysis and electrospray ionization mass spectra. Complex 1 crystallized in the monoclinic system with space group P21/c. It potently inhibited PTP1B with IC50 of 0.13 μM, about 7, 15 and 125-fold stronger against PTP1B than over TCPTP, SHP-1 and SHP-2, displaying obvious selectivity against PTP1B. Western blotting analysis indicated that complex 1 effectively increased the phosphorylation of PTP1B substrates, especially the phosphorylation of IR/IGF 1R and IRS-1...
February 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28199837/an-endosomal-naadp-sensitive-two-pore-ca-2-channel-regulates-er-endosome-membrane-contact-sites-to-control-growth-factor-signaling
#5
Bethan S Kilpatrick, Emily R Eden, Leanne N Hockey, Elizabeth Yates, Clare E Futter, Sandip Patel
Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca(2+) derived from the endo-lysosomal system in maintaining contact between endosomes and the endoplasmic reticulum (ER). Antagonizing action of the Ca(2+)-mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca(2+) fluxes all clustered and enlarged late endosomes/lysosomes. We show that TPC1 localizes to ER-endosome contact sites and is required for their formation...
February 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28197094/protein-tyrosine-phosphatase-1b-ptp1b-a-potential-target-for-alzheimer-s-therapy
#6
Marcelo N N Vieira, Natalia M Lyra E Silva, Sergio T Ferreira, Fernanda G De Felice
Despite significant advances in current understanding of mechanisms of pathogenesis in Alzheimer's disease (AD), attempts at drug development based on those discoveries have failed to translate into effective, disease-modifying therapies. AD is a complex and multifactorial disease comprising a range of aberrant cellular/molecular processes taking part in different cell types and brain regions. As a consequence, therapeutics for AD should be able to block or compensate multiple abnormal pathological events. Here, we examine recent evidence that inhibition of protein tyrosine phosphatase 1B (PTP1B) may represent a promising strategy to combat a variety of AD-related detrimental processes...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28189086/pterocarpan-scaffold-a-natural-lead-molecule-with-diverse-pharmacological-properties
#7
REVIEW
Chelliah Selvam, Brian C Jordan, Sandhya Prakash, Daniel Mutisya, Ramasamy Thilagavathi
Phytoalexins are substances produced by plants that act as potent inhibitors of pathogens. Pterocarpans are biologically active isoflavonoids most commonly found in the family Fabaceae that have the ability to act as phytoalexins. It is made up of a tetracyclic ring system possessing benzofuran-benzopyran. A very great number of pterocarpans have been isolated from natural sources and they are proved to have significant biological activities such as anti-microbial, anti-cancerous, anti-inflammatory and anti-malarial activities...
January 17, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28173704/structural-and-stereochemical-studies-of-laurokamurols-a-c-uncommon-bis-sesquiterpenoids-from-chinese-red-alga-laurencia-okamurai-yamada
#8
Xiao-Lu Li, Tibor Kurtán, Jun-Chi Hu, Attila Mándi, Jia Li, Xu-Wen Li, Yue-Wei Guo
Three novel heterodimeric laurane-type sesquiterpenoids, laurokamurols A-C (1-3), along with eight known related monomeric ones (4-11) were isolated from the East China Sea red alga Laurencia okamurai Yamada. The absolute configurations of the new bis-sesquitepenoids, especially their axial chirality, were determined by extensive spectroscopic analyses and TDDFT-ECD method. All the new compounds showed promising PTP1B inhibitory activities with IC50 values comparable to the positive control, indicating them as potential food additives or pharmaceutical drug leads towards obesity or diabetes...
February 7, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28140583/glycybridins-a-k-bioactive-phenolic-compounds-from-glycyrrhiza-glabra
#9
Kai Li, Shuai Ji, Wei Song, Yi Kuang, Yan Lin, Shunan Tang, Zexu Cui, Xue Qiao, Siwang Yu, Min Ye
In an attempt to discover bioactive agents from the herbal medicine Glycyrrhiza glabra (widely known as licorice), 11 new phenolic compounds, glycybridins A-K (1-11), along with 47 known phenolics (12-58) were isolated. Their structures were elucidated on the basis of extensive NMR and MS analyses as well as experimental and computed ECD data. According to the clinical therapeutic effects of licorice, enzyme or cell-based bioactivity screenings of 1-58 were conducted. A number of compounds significantly activate Nrf2, inhibit tyrosinase or PTP1B, inhibit LPS-induced NO production and NF-κB transcription, and inhibit the proliferation of human cancer cells (HepG2, SW480, A549, MCF7)...
January 31, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28126289/synthesis-biological-evaluation-and-in-silico-studies-of-5-3-methoxybenzylidene-thiazolidine-2-4-dione-analogues-as-ptp1b-inhibitors
#10
Manoj Kumar Mahapatra, Rajnish Kumar, Manoj Kumar
PTP1B (protein tyrosine phosphatase 1B) dephosphorylates the insulin receptor substrate and thus acts as a negative regulator of the insulin and leptin signalling pathway. Recently, it has been considered as a new therapeutic target of intervention for the treatment of type2 diabetes. A series of aryl/alkylsulfonyloxy-5-(3-methoxybenzylidene)thiazolidine-2,4-dione derivatives were synthesized, screened in vitro for their PTP1B inhibitory activity and in vivo for anti-hyperglycaemic activity. Docking results further helped in understanding the nature of interactions governing the binding mode of ligands inside the active site of PTP1B...
January 17, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28125531/repeated-binge-like-alcohol-intoxication-depot-specific-adipose-tissue-immuno-metabolic-dysregulation
#11
Flavia M Souza-Smith, Stephen M Ford, Liz Simon, Patricia E Molina
Repeated binge-like alcohol intoxication (RBAI) induces whole-body insulin resistance, which is predicted to increase the risk for metabolic syndrome and type 2 diabetes. Previously we showed that acute alcohol intoxication increases mesenteric lymphatic permeability, perilymphatic adipose tissue (PLAT) inflammation, and circulating lipopolysaccharide (LPS) levels in rats. We hypothesize that mesenteric lymphatic hyperpermeability, adipose tissue inflammation and associated dysregulated adipokine expression and insulin signaling are central mechanisms underlying whole body metabolic dysregulation resulting from RBAI...
January 25, 2017: Shock
https://www.readbyqxmd.com/read/28111958/asymmetric-total-synthesis-of-distaminolyne-a-and-revision-of-its-absolute-configuration
#12
Dong-Yu Sun, Guan-Ying Han, Jing-Xu Gong, Bastien Nay, Xu-Wen Li, Yue-Wei Guo
The first total synthesis of a marine derived polyacetylene, distaminolyne A, and its enantiomer were achieved from the commercially available undec-10-en-1-ol. A key proline-catalyzed asymmetric α-aminooxylation of an aldehyde intermediate was used to introduce the chiral center en route to the enantiomerically pure 1,2-amino alcohols. The absolute configuration of both synthesized enantiomers of distaminolyne A was confirmed by using chiral derivatizing agents, leading to revision of the natural product absolute configuration from 2S to 2R...
January 23, 2017: Organic Letters
https://www.readbyqxmd.com/read/28111140/discovery-of-core-structurally-novel-ptp1b-inhibitors-with-specific-selectivity-containing-oxindole-fused-spirotetrahydrofurochroman-by-one-pot-reaction
#13
Suzhen Dong, Yubing Lei, Shikun Jia, Lixin Gao, Jia Li, Tong Zhu, Shunying Liu, Wenhao Hu
Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an ideal target for treatment of type II diabetes and obesity. However, no druggable PTP1B inhibitor has been established and there is still an urgent demand for the development of structurally novel PTPIB inhibitor. Herein, we reported core-structurally novel PTP1B inhibitors with low micromole-ranged inhibitory activity by one-pot reaction from simple starting materials. Further studies demonstrated some of these active compounds had a specific selectivity over other PTPs...
November 22, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28109786/a-tetramic-acid-derivative-with-protein-tyrosine-phosphatase-1b-inhibitory-activity-and-a-new-nortriterpene-glycoside-from-the-indonesian-marine-sponge-petrosia-sp
#14
Wilmar Maarisit, Hiroyuki Yamazaki, Syu-Ichi Kanno, Ayako Tomizawa, Henki Rotinsulu, Defny S Wewengkang, Deiske A Sumilat, Kazuyo Ukai, Magie M Kapojos, Michio Namikoshi
During the search for protein tyrosine phosphatase 1B (PTP1B) inhibitors from marine organisms, the known tetramic acid derivative, melophlin C (1), was isolated as an active component together with the new nortriterpenoid saponin, sarasinoside S (2), and three homologues: sarasinosides A1 (3), I1 (4), and J (5), from the Indonesian marine sponge Petrosia sp. The structure of 2 was elucidated on the basis of its spectroscopic data. Compound 1 inhibited PTP1B activity with an IC50 value of 14.6μM, while compounds 2-5 were not active at 15...
December 31, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28094236/deficiency-of-ptp1b-attenuates-hypothalamic-inflammation-via-activation-of-the-jak2-stat3-pathway-in-microglia
#15
Taku Tsunekawa, Ryoichi Banno, Akira Mizoguchi, Mariko Sugiyama, Takashi Tominaga, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Yoshihisa Sugimura, Hiroshi Arima
Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT)...
January 9, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28049096/anti-diabetic-effect-of-three-new-norditerpenoid-alkaloids-in-vitro-and-potential-mechanism-via-pi3k-akt-signaling-pathway
#16
Dan Tang, Qi-Bin Chen, Xue-Lei Xin, Haji-Akber Aisa
Diabetes is a metabolic disease with the characteristic of high blood glucose (hyperglycemia). In our previous study, we found that nigelladines A-C (compounds A-C), three norditerpenoid alkaloids from the seeds of Nigella glandulifera Freyn (Ranunculaceae) exhibited protein of tyrosine phosphatase 1B (PTP1B) inhibitory activity in vitro. In the present study, we further investigated their anti-diabetes activities in L6 moytubes and illuminated the mechanisms of action of compounds A-C. Several parameters of glucose metabolism such as glucose consumption, glycogen content and hexokinase activity were increased by compounds A-C...
December 31, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28038441/visualization-of-exosome-mediated-mir-210-transfer-from-hypoxic-tumor-cells
#17
Kyung Oh Jung, Hyewon Youn, Chul-Hee Lee, Keon Wook Kang, June-Key Chung
Cancer cells actively release exosomes carrying specific cellular components, such as proteins, mRNA, and miRNA, to communicate with various cells in the tumor microenvironment. We visualized exosome-mediated transfer of miR-210 from hypoxic breast cancer cells to neighboring cells using a miR-210 specific reporter system. By in vitro and in vivo visualization, we found that exosomes with miR-210 were transferred to cells in the tumor microenvironment and that miR-210 was involved in expression of vascular remodeling related genes, such as Ephrin A3 and PTP1B, to promote angiogenesis...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28035984/promising-inhibitory-effects-of-anthraquinones-naphthopyrone-and-naphthalene-glycosides-from-cassia-obtusifolia-on-%C3%AE-glucosidase-and-human-protein-tyrosine-phosphatases-1b
#18
Hyun Ah Jung, Md Yousof Ali, Jae Sue Choi
The present work aims to evaluate the anti-diabetic potentials of 16 anthraquinones, two naphthopyrone glycosides, and one naphthalene glycoside from Cassia obtusifolia via inhibition against the protein tyrosine phosphatases 1B (PTP1B) and α-glucosidase. Among them, anthraquinones emodin and alaternin exhibited the highest inhibitory activities on PTP1B and α-glucosidase, respectively. Moreover, we examined the effects of alaternin and emodin on stimulation of glucose uptake by insulin-resistant human HepG2 cells...
December 27, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28031011/dephossitepred-a-high-accuracy-predictor-for-protein-dephosphorylation-sites
#19
Cangzhi Jia, Wenying He, Quan Zou
Many oncogenes encode proteins with a tyrosine kinase activity that appears to be directly involved in the process of transformation. Because these kinases are themselves activated for transformation by tyrosine phosphorylation, proteins that remove phosphate from tyrosine residues, protein tyrosine phosphatases (PTPs), are intuitive candidate transformation suppressors. In this study, we developed a novel PTP site prediction model, DephosSitePred, based on bi-profile sequence features. Weight parameters in the support vector machine were applied to improve the low sensitivity due to extremelyimbalanced datasets...
December 28, 2016: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28029177/discovery-of-bisindole-as-a-novel-scaffold-for-protein-tyrosine-phosphatase-1b-inhibitors
#20
Changcheng Jing, Ziyan Li, Kaili Jia, Chen Chen, Xiao Liu, Beibei Wang, Wenhao Hu, Jia Li, Tong Zhu, Suzhen Dong
Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an effective target for the treatment of both type II diabetes and obesity. However, no PTP1B inhibitor has come into clinic application. Herein, we report mixed 3,3'-bisindoles as novel PTP1B inhibitors with low micromole-ranged inhibitory activity. The best active compound 9f inhibited PTP1B activity with an IC50 of 2.79 µM. Meanwhile, it had low cytotoxicity and enhanced glucose uptake in vitro. Further studies demonstrated that some of these active compounds had a specific selectivity over other PTPs...
December 28, 2016: Archiv der Pharmazie
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