scholarly journals Synthesis and evaluation of new thiazole-containing rhodanine-3-alkanoic acids as inhibitors of protein tyrosine phosphatases and glutathione S-transferases

2020 ◽  
Vol 15 (2) ◽  
pp. 33-40
Author(s):  
Oleksandr Kobzar ◽  
Vitaliy Sinenko ◽  
Yuriy Shulha ◽  
Vlasyslav Buldenko ◽  
Diana Hodyna ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Inhibitory Effect ◽  
Thiazole Ring ◽  
Binding Modes ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Alkanoic Acids ◽  
Ic50 Values ◽  
Glutathione S Transferases

Thiazole-containing derivatives of rhodanine-3-alkanoic acids with propanoic or undecanoic acid groups were synthesized and evaluated as inhibitors of some protein tyrosine phosphatases and glutathione S-transferases. The rhodanines bearing longer carboxylated N-alkyl chain were found to inhibit PTP1B, MEG1, MEG2, and VE-PTP as well as GST from equine liver and GSTA1-1 with IC50 values in the low micromolar range. The inhibitory effect on protein tyrosine phosphatase activity depends on substituent at position 2 of the thiazole ring. The best compound showed a competitive type of VE-PTP inhibition. In case of GST from equine liver, the inhibition was of mixed or non-competitive type with respect to glutathione or CDNB substrate, respectively. Possible binding modes of the inhibitors were discussed based on molecular docking calculations.

scholarly journals Inhibitory Effects of Secondary Metabolites from the Lichen Stereocaulon evolutum on Protein Tyrosine Phosphatase 1B

Planta Medica ◽  
2021 ◽  
Author(s):  
Birgit Waltenberger ◽  
Françoise Lohézic-Le Dévéhat ◽  
Thi Huyen Vu ◽  
Olivier Delalande ◽  
Claudia Lalli ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Tyrosine Phosphatase ◽  
Inhibitory Effect ◽  
Positive Control ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ic50 Values ◽  
A Cell

AbstractProtein tyrosine phosphatase 1B plays a significant role in type 2 diabetes mellitus and other diseases and is therefore considered a new drug target. Within this study, an acetone extract from the lichen Stereocaulon evolutum was identified to possess strong protein tyrosine phosphatase 1B inhibition in a cell-free assay (IC50 of 11.8 µg/mL). Fractionation of this bioactive extract led to the isolation of seven known molecules belonging to the depsidones and the related diphenylethers and one new natural product, i.e., 3-butyl-3,7-dihydroxy-5-methoxy-1(3H)-isobenzofurane. The isolated compounds were evaluated for their inhibition of protein tyrosine phosphatase 1B. Two depsidones, lobaric acid and norlobaric acid, and the diphenylether anhydrosakisacaulon A potently inhibited protein tyrosine phosphatase 1B with IC50 values of 12.9, 15.1, and 16.1 µM, respectively, which is in the range of the protein tyrosine phosphatase 1B inhibitory activity of the positive control ursolic acid (IC50 of 14.4 µM). Molecular simulations performed on the eight compounds showed that i) a contact between the molecule and the four main regions of the protein is required for inhibitory activity, ii) the relative rigidity of the depsidones lobaric acid and norlobaric acid and the reactivity related to hydrogen bond donors or acceptors, which interact with protein tyrosine phosphatase 1B key amino acids, are involved in the bioactivity on protein tyrosine phosphatase 1B, iii) the cycle opening observed for diphenylethers decreased the inhibition, except for anhydrosakisacaulon A where its double bond on C-8 offsets this loss of activity, iv) the function present at C-8 is a determinant for the inhibitory effect on protein tyrosine phosphatase 1B, and v) the more hydrogen bonds with Arg221 there are, the more anchorage is favored.

scholarly journals Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients

2019 ◽  
Vol 8 (7) ◽  
pp. 936 ◽  
Author(s):  
Faria ◽  
Andrade ◽  
Reijm ◽  
Spaander ◽  
de Maat ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cancer Patients ◽  
Gastrointestinal Cancer ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Cell Aggregation ◽  
Tyrosine Phosphatases ◽  
Indirect Contact ◽  
Protein Tyrosine

Venous thromboembolism (VTE) is one of the most common causes of cancer related mortality. It has been speculated that hypercoagulation in cancer patients is triggered by direct or indirect contact of platelets with tumor cells, however the underlying molecular mechanisms involved are currently unknown. Unraveling these mechanisms may provide potential avenues for preventing platelet-tumor cell aggregation. Here, we investigated the role of protein tyrosine phosphatases in the functionality of platelets in both healthy individuals and patients with gastrointestinal cancer, and determined their use as a target to inhibit platelet hyperactivity. This is the first study to demonstrate that platelet agonists selectively activate low molecular weight protein tyrosine phosphatase (LMWPTP) and PTP1B, resulting in activation of Src, a tyrosine kinase known to contribute to several platelet functions. Furthermore, we demonstrate that these phosphatases are a target for 3-bromopyruvate (3-BP), a lactic acid analog currently investigated for its use in the treatment of various metabolic tumors. Our data indicate that 3-BP reduces Src activity, platelet aggregation, expression of platelet activation makers and platelet-tumor cell interaction. Thus, in addition to its anti-carcinogenic effects, 3-BP may also be effective in preventing platelet-tumor cell aggregationin cancer patients and therefore may reduce cancer mortality by limiting VTE in patients.

scholarly journals Multiple Functions of the Eya Phosphotyrosine Phosphatase

2015 ◽  
Vol 36 (5) ◽  
pp. 668-677 ◽  
Author(s):  
Ilaria Rebay
Keyword(s):  
Developmental Regulation ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Transcriptional Coactivator ◽  
Tyrosine Phosphatases ◽  
Phosphotyrosine Phosphatase ◽  
Eyes Absent ◽  
Multiple Functions ◽  
Protein Tyrosine ◽  
Cellular Events

Eyes absent (Eya), a protein conserved from plants to humans and best characterized as a transcriptional coactivator, is also the prototype for a novel class of eukaryotic aspartyl protein tyrosine phosphatases. This minireview discusses recent breakthroughs in elucidating the substrates and cellular events regulated by Eya's tyrosine phosphatase function and highlights some of the complexities, new questions, and surprises that have emerged from efforts to understand how Eya's unusual multifunctionality influences developmental regulation and signaling.

scholarly journals Podocyte Protein, Nephrin, Is a Substrate of Protein Tyrosine Phosphatase 1B

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Lamine Aoudjit ◽  
Ruihua Jiang ◽  
Tae Hoon Lee ◽  
Laura A. New ◽  
Nina Jones ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Phosphatase 1B ◽  
Tyrosine Phosphatases ◽  
Puromycin Aminonucleoside ◽  
Protein Tyrosine ◽  
Aminonucleoside Nephrosis ◽  
Puromycin Aminonucleoside Nephrosis

Glomerular podocytes are critical for the barrier function of the glomerulus in the kidney and their dysfunction causes protein leakage into the urine (proteinuria). Nephrin is a key podocyte protein, which regulates the actin cytoskeleton via tyrosine phosphorylation of its cytoplasmic domain. Here we report that two protein tyrosine phosphatases, PTP1B and PTP-PEST negatively regulate nephrin tyrosine phosphorylation. PTP1B directly binds to and dephosphorylates nephrin, while the action of PTP-PEST is indirect. The two phosphatases are also upregulated in the glomerulus in the rat model of puromycin aminonucleoside nephrosis. Both overexpression and inhibition of PTP1B deranged the actin cytoskeleton in cultured mouse podocytes. Thus, protein tyrosine phosphatases may affect podocyte function via regulating nephrin tyrosine phosphorylation.

scholarly journals Protein tyrosine phosphatase containing SH2 domains: characterization, preferential expression in hematopoietic cells, and localization to human chromosome 12p12-p13.

1992 ◽  
Vol 12 (2) ◽  
pp. 836-846 ◽  
Author(s):  
T L Yi ◽  
J L Cleveland ◽  
J N Ihle
Keyword(s):  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Human Gene ◽  
Tyrosine Phosphatase ◽  
Hematopoietic Cells ◽  
Protein Tyrosine Phosphatases ◽  
Hematopoietic Cell ◽  
Protein Tyrosine Phosphorylation ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine

Protein tyrosine phosphorylation has been implicated in the growth and functional responses of hematopoietic cells. Recently, approaches have been developed to characterize the protein tyrosine phosphatases that may contribute to regulation of protein tyrosine phosphorylation. One novel protein tyrosine phosphatase was expressed predominantly in hematopoietic cells. Hematopoietic cell phosphatase encodes a 68-kDa protein that contains a single phosphatase conserved domain. Unlike other known protein tyrosine phosphatases, hematopoietic cell phosphatase contains two src homology 2 domains. We also cloned the human homolog, which has 95% amino acid sequence identity. Both the murine and human gene products have tyrosine-specific phosphatase activity, and both are expressed predominantly in hematopoietic cells. Importantly, the human gene maps to chromosome 12 region p12-p13. This region is associated with rearrangements in approximately 10% of cases of acute lymphocytic leukemia in children.

Evolutionarily Conserved Allosteric Communication in Protein Tyrosine Phosphatases

2018 ◽  
Author(s):  
Michael K. Hjortness ◽  
Laura Riccardi ◽  
Akarawin Hongdusit ◽  
Peter H. Zwart ◽  
Banumathi Sankaran ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Kinetic Studies ◽  
Structural Basis ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Allosteric Communication ◽  
Wide Range ◽  
Evolutionarily Conserved ◽  
Dynamics Simulations

Protein tyrosine phosphatases (PTPs) are an important class of regulatory enzymes that exhibit aberrant activities in a wide range of diseases. A detailed mapping of allosteric communication in these enzymes could, thus, reveal the structural basis of physiologically relevant—and, perhaps, therapeutically informative—perturbations (i.e., mutations, post-translational modifications, or binding events) that influence their catalytic states. This study combines detailed biophysical studies of protein tyrosine phosphatase 1B (PTP1B) with bioinformatic analyses of the PTP family to examine allosteric communication in PTPs. Results of X-ray crystallography, molecular dynamics simulations, and sequence-based statistical analyses indicate that PTP1B possesses a broadly distributed allosteric network that is evolutionarily conserved across the PTP family, and findings from kinetic studies and mutational analyses show that this network is functionally intact in sequence-diverse PTPs. The allosteric network resolved in this study reveals new sites for targeting allosteric inhibitors of PTPs and helps explain the functional influence of a diverse set of disease-associated mutations.

scholarly journals Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases

2020 ◽  
Author(s):  
Rory Crean ◽  
Michal Biler ◽  
Marc van der Kamp ◽  
Alvan C. Hengge ◽  
Shina Caroline Lynn Kamerlin
Keyword(s):  
Environmental Changes ◽  
Tyrosine Phosphatase ◽  
Conformational Dynamics ◽  
Rare Event ◽  
Protein Tyrosine Phosphatases ◽  
Structural Features ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Critical Residue ◽  
Loop Dynamics

<p>Protein tyrosine phosphatases (PTPs) play an important role in cellular signalling and have been implicated in human cancers, diabetes, and obesity. Despite shared catalytic mechanisms and transition states for the chemical steps of catalysis, catalytic rates within the PTP family vary over several orders of magnitude. These rate differences have been implied to arise from differing conformational dynamics of the closure of a protein loop, the WPD-loop, which carries a catalytically critical residue. The present work reports computational studies of the human protein tyrosine phosphatase 1B (PTP1B), and YopH from <i>Yersinia pestis</i>, for which NMR has demonstrated a link between both their respective rates of WPD-loop motion and catalysis rates, which differ by an order of magnitude. We have performed detailed structural analysis, both conventional and enhanced sampling simulations of their loop dynamics, as well as empirical valence bond simulations of the chemical step of catalysis. These analyses revealed the key residues and structural features responsible for these differences, as well as the residues and pathways that facilitate allosteric communication in these enzymes. Curiously, our wild-type YopH simulations also identify a catalytically incompetent hyper-open conformation of its WPD-loop, sampled as a rare event, previously only experimentally observed in YopH-based chimeras. The effect of differences within the WPD-loop and its neighbouring loops on the modulation of loop dynamics, as revealed in this work, may provide a facile means for the family of PTP enzymes to respond to environmental changes and regulate their catalytic activities. </p>

scholarly journals Sulfonyl-bridged Calix[4]arene as an Inhibitor of Protein Tyrosine Phosphatases

2017 ◽  
Vol 5 (2) ◽  
pp. 144-151 ◽  
Author(s):  
Vladyslav Buldenko ◽  
Oleksandr Kobzar ◽  
Viacheslav Trush ◽  
Andriy Drapailo ◽  
Vitaly Kalchenko ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Ic50 Value ◽  
Potential Inhibitors ◽  
Derivatives Of ◽  
Active Site Region ◽  
Micromolar Range

Previously, phosphonic acid derivatives of calix[4]arene and thiacalix[4]arene were found to be potential inhibitors of protein tyrosine phosphatase 1B. In the present paper, the inhibitory activity of unsubstituted sulfonyl-bridget calix[4]arene towards some of the therapeutically important protein tyrosine phosphatases has been established. The obtained results showed that the sulfonylcalix[4]arene is able to inhibit protein tyrosine phosphatase MEG2 with IC50 value in the micromolar range. At the same time, the inhibitor demonstrated lower activity in case of other protein tyrosine phosphatases such as PTP1B, MEG1, TC-PTP, SHP2, and PTPβ. The performed molecular docking indicated that the inhibitor binds to the active site region of MEG2 and PTP1B with WPD-loop in the open conformation.

SRC binding to the cytoskeleton, triggered by growth cone attachment to laminin, is protein tyrosine phosphatase-dependent

1998 ◽  
Vol 111 (16) ◽  
pp. 2465-2475 ◽  
Author(s):  
S. Helmke ◽  
K. Lohse ◽  
K. Mikule ◽  
M.R. Wood ◽  
K.H. Pfenninger
Keyword(s):  
Phosphatase Activity ◽  
Growth Cone ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Growth Cones ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Adhesion Sites ◽  
Adhesion Site

The interaction of the non-receptor tyrosine kinase, Src, with the cytoskeleton of adhesion sites was studied in nerve growth cones isolated from fetal rat brain. Of particular interest was the role of protein tyrosine phosphatases in the regulation of Src-cytoskeleton binding. Growth cones were found to contain a high level of protein tryrosine phosphatase activity, most of it membrane-associated and forming large, multimeric and wheat germ agglutinin-binding complexes. The receptor tyrosine phosphatase PTPalpha seems to be the most prevalent species among the membrane-associated enzymes. As seen by immunofluorescence, PTPalpha is present throughout the plasmalemma of the growth cone including filopodia, and it forms a punctate pattern consistent with that of integrin beta1. For adhesion site analysis, isolated growth cones were either plated onto the neurite growth substratum, laminin, or kept in suspension. Plating growth cones on laminin triggered an 8-fold increase in Src binding to the adherent cytoskeleton. This effect was blocked completely with the protein tyrosine phosphatase inhibitor, vanadate. Growth cone plating also increased the association with adhesion sites of tyrosine phosphatase activity (14-fold) and of PTPalpha immunoreactivity (6-fold). Vanadate blocked the enzyme activity but not the recruitment of PTPalpha to the adhesion sites. In conjunction with our previous results on growth cones, these data suggest that integrin binding to laminin triggers the recruitment of PTPalpha (and perhaps other protein tyrosine phosphatases) to adhesion sites, resulting in de-phosphorylation of Src's tyr 527. As a result Src unfolds, becomes kinase-active, and its SH2 domain can bind to an adhesion site protein. This implies a critical role for protein tyrosine phosphatase activity in the earliest phases of adhesion site assembly.

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