scholarly journals Protein tyrosine phosphatase TbPTP1: a molecular switch controlling life cycle differentiation in trypanosomes

2006 ◽  
Vol 175 (2) ◽  
pp. 293-303 ◽  
Author(s):  
Balázs Szöőr ◽  
Jude Wilson ◽  
Helen McElhinney ◽  
Lydia Tabernero ◽  
Keith R. Matthews
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Tsetse Fly ◽  
Mammalian Host ◽  
African Trypanosomes ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
Stumpy Form

Differentiation in African trypanosomes (Trypanosoma brucei) entails passage between a mammalian host, where parasites exist as a proliferative slender form or a G0-arrested stumpy form, and the tsetse fly. Stumpy forms arise at the peak of each parasitaemia and are committed to differentiation to procyclic forms that inhabit the tsetse midgut. We have identified a protein tyrosine phosphatase (TbPTP1) that inhibits trypanosome differentiation. Consistent with a tyrosine phosphatase, recombinant TbPTP1 exhibits the anticipated substrate and inhibitor profile, and its activity is impaired by reversible oxidation. TbPTP1 inactivation in monomorphic bloodstream trypanosomes by RNA interference or pharmacological inhibition triggers spontaneous differentiation to procyclic forms in a subset of committed cells. Consistent with this observation, homogeneous populations of stumpy forms synchronously differentiate to procyclic forms when tyrosine phosphatase activity is inhibited. Our data invoke a new model for trypanosome development in which differentiation to procyclic forms is prevented in the bloodstream by tyrosine dephosphorylation. It may be possible to use PTP1B inhibitors to block trypanosomatid transmission.

scholarly journals Positional Dynamics and Glycosomal Recruitment of Developmental Regulators during Trypanosome Differentiation

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Balázs Szöőr ◽  
Dorina V. Simon ◽  
Federico Rojas ◽  
Julie Young ◽  
Derrick R. Robinson ◽  
...  
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Tyrosine Phosphatase ◽  
Tsetse Fly ◽  
Sub Saharan Africa ◽  
Metabolic Adaptation ◽  
Tsetse Flies ◽  
Content Type ◽  
African Trypanosomes ◽  
Sub Saharan

ABSTRACT Glycosomes are peroxisome-related organelles that compartmentalize the glycolytic enzymes in kinetoplastid parasites. These organelles are developmentally regulated in their number and composition, allowing metabolic adaptation to the parasite’s needs in the blood of mammalian hosts or within their arthropod vector. A protein phosphatase cascade regulates differentiation between parasite developmental forms, comprising a tyrosine phosphatase, Trypanosoma brucei PTP1 (TbPTP1), which dephosphorylates and inhibits a serine threonine phosphatase, TbPIP39, which promotes differentiation. When TbPTP1 is inactivated, TbPIP39 is activated and during differentiation becomes located in glycosomes. Here we have tracked TbPIP39 recruitment to glycosomes during differentiation from bloodstream “stumpy” forms to procyclic forms. Detailed microscopy and live-cell imaging during the synchronous transition between life cycle stages revealed that in stumpy forms, TbPIP39 is located at a periflagellar pocket site closely associated with TbVAP, which defines the flagellar pocket endoplasmic reticulum. TbPTP1 is also located at the same site in stumpy forms, as is REG9.1, a regulator of stumpy-enriched mRNAs. This site provides a molecular node for the interaction between TbPTP1 and TbPIP39. Within 30 min of the initiation of differentiation, TbPIP39 relocates to glycosomes, whereas TbPTP1 disperses to the cytosol. Overall, the study identifies a “stumpy regulatory nexus” (STuRN) that coordinates the molecular components of life cycle signaling and glycosomal development during transmission of Trypanosoma brucei. IMPORTANCE African trypanosomes are parasites of sub-Saharan Africa responsible for both human and animal disease. The parasites are transmitted by tsetse flies, and completion of their life cycle involves progression through several development steps. The initiation of differentiation between blood and tsetse fly forms is signaled by a phosphatase cascade, ultimately trafficked into peroxisome-related organelles called glycosomes that are unique to this group of organisms. Glycosomes undergo substantial remodeling of their composition and function during the differentiation step, but how this is regulated is not understood. Here we identify a cytological site where the signaling molecules controlling differentiation converge before the dispersal of one of them into glycosomes. In combination, the study provides the first insight into the spatial coordination of signaling pathway components in trypanosomes as they undergo cell-type differentiation.

scholarly journals Genomic occupancy of the bromodomain protein Bdf3 is dynamic during differentiation of African trypanosomes from bloodstream to procyclic forms

2022 ◽  
Author(s):  
Ethan Ashby ◽  
Lucinda Paddock ◽  
Hannah L Betts ◽  
Geneva Miller ◽  
Anya Porter ◽  
...  
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
De Novo ◽  
Tsetse Fly ◽  
Mammalian Host ◽  
Interacting Proteins ◽  
Transcript Levels ◽  
African Trypanosomes ◽  
Bromodomain Proteins ◽  
Protein Occupancy

Trypanosoma brucei , the causative agent of Human and Animal African trypanosomiasis, cycles between a mammalian host and a tsetse fly vector. The parasite undergoes huge changes in morphology and metabolism as it adapts to each host environment. These changes are reflected in the differing transcriptomes of parasites living in each host. While changes in the transcriptome have been well catalogued for parasites differentiating from the mammalian bloodstream to the insect stage, it remains unclear whether chromatin interacting proteins mediate transcriptomic changes during life cycle adaptation. We and others have shown that chromatin interacting bromodomain proteins localize to transcription start sites in bloodstream parasites, but whether the localization of bromodomain proteins changes as parasites differentiate from bloodstream to insect stage parasites remains unknown. To address this question, we performed Cleavage Under Target and Release Using Nuclease (CUT&RUN) timecourse experiments using a tagged version of Bromodomain Protein 3 (Bdf3) in parasites differentiating from bloodstream to insect stage forms. We found that Bdf3 occupancy at most loci increased at 3 hours following onset of differentiation and decreased thereafter. A number of sites with increased bromodomain protein occupancy lie proximal to genes known to have altered transcript levels during differentiation, such as procyclins, procyclin associated genes, and invariant surface glycoproteins. While most Bdf3 occupied sites are observed throughout differentiation, a very small number appear de novo as differentiation progresses. Notably, one such site lies proximal to the procyclin gene locus, which contains genes essential for remodeling surface proteins following transition to the insect stage. Overall, these studies indicate that occupancy of chromatin interacting proteins is dynamic during life cycle stage transitions, and provides the groundwork for future studies aimed at uncovering whether changes in bromodomain protein occupancy affect transcript levels of neighboring genes. Additionally, the optimization of CUT&RUN for use in Trypanosoma brucei may prove helpful for other researchers as an alternative to Chromatin Immunoprecipitation (ChIP).

Potential Inhibitors of Protein Tyrosine Phosphatase (PTP1B) Enzyme: Promising Target for Type-II Diabetes Mellitus

2020 ◽  
Vol 20 (29) ◽  
pp. 2692-2707
Author(s):  
Sisir Nandi ◽  
Mridula Saxena
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Type Ii Diabetes ◽  
Tyrosine Phosphatase ◽  
Type Ii Diabetes Mellitus ◽  
Type Ii ◽  
Insulin Effect ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
Insulin Dependent Diabetic

Background: There has been growing interest in the development of highly potent and selective protein tyrosine phosphatase (PTP1B) inhibitors for the past 2-3 decades. Though most PTPs share a common active site motif, the interest in selective inhibitors, particularly against PTP1B is increasing to discover new chemical entities as antidiabetic agents. In the current paradigm to find potent and selective PTP1B inhibitors, which is currently considered as one of the best validated biological targets for non-insulin-dependent diabetic and obese individuals, resistance to insulin due to decreased sensitivity of the insulin receptor is a pathological factor and is also genetically linked, causing type II diabetes. Objectives: Insulin receptor sensitization is performed by a signal transduction mechanism via a selective protein tyrosine phosphatase (PTP1B). After the interaction of insulin with its receptor, autophosphorylation of the intracellular part of the receptor takes place, turning it into an active kinase (sensitization). PTP1B is involved in the desensitization of the receptor by dephosphorylation. PTP1b inhibitors delay the receptor desensitization, prolonging insulin effect and making PTP1B as a drug target for the treatment of diabetes II. Therefore, it has become a major target for the discovery of potent drugs for the treatment of type II diabetes and obesity. An attempt has been made in the present study to discuss the latest design and discovery of protein tyrosine phosphatase (PTP1B) inhibitors. Methods: Many PTP1B inhibitors such as diaminopyrroloquinazoline, triazines, pyrimido triazine derivatives, 2-(benzylamino)-1-phenylethanol, urea, acetamides and piperazinylpropanols, phenylsulphonamides and phenylcarboxamide, benzamido, arylcarboxylic acid derivatives, arylsupfonyl derivatives, thiazoles, isothiozolidiones and thiazolodinones have been discussed, citing the disease mechanisms. Results: The reader will gain an overview of the structure and biological activity of recently developed PTPs inhibitors. Conclusion: The co-crystallized ligands and the screened inhibitors could be used as a template for the further design of potent congeners.

scholarly journals Metabolic reprogramming during the Trypanosoma brucei life cycle

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 683 ◽  
Author(s):  
Terry K. Smith ◽  
Frédéric Bringaud ◽  
Derek P. Nolan ◽  
Luisa M. Figueiredo
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Model Organism ◽  
Protozoan Parasite ◽  
Tsetse Fly ◽  
Metabolic Reprogramming ◽  
Mammalian Host ◽  
Insect Vector ◽  
Environmental Signals ◽  
Cellular Metabolic Activity

Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism.

Enantiomeric 3-arylcoumarins and 2-arylcoumarones from the roots of Glycyrrhiza uralensis as protein tyrosine phosphatase 1B (PTP1B) inhibitors

RSC Advances ◽  
2015 ◽  
Vol 5 (56) ◽  
pp. 45258-45265 ◽  
Author(s):  
Shuai Ji ◽  
Xue Qiao ◽  
Zi-wei Li ◽  
Yong-rui Wang ◽  
Si-wang Yu ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Glycyrrhiza Uralensis ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
The Absolute

Four new PTP1B inhibitors were isolated from Glycyrrhiza uralensis, and the absolute configuration of 2,3-dihydro-2,3,3-trimethylbenzofurans was first unambiguously established.

scholarly journals Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Xiangyu Zhang ◽  
Hailun Jiang ◽  
Wei Li ◽  
Jian Wang ◽  
Maosheng Cheng
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Active Sites ◽  
Tyrosine Phosphatase ◽  
Pharmacophore Model ◽  
Protein Tyrosine Phosphatase 1B ◽  
Binding Modes ◽  
Protein Tyrosine ◽  
R Region ◽  
Ptp1b Inhibitors ◽  
Autodock 4.0

Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for treating cancer, obesity, and type 2 diabetes. In our work, the way of combined ligand- and structure-based approach was applied to analyze the characteristics of PTP1B enzyme and its interaction with competitive inhibitors. Firstly, the pharmacophore model of PTP1B inhibitors was built based on the common feature of sixteen compounds. It was found that the pharmacophore model consisted of five chemical features: one aromatic ring (R) region, two hydrophobic (H) groups, and two hydrogen bond acceptors (A). To further elucidate the binding modes of these inhibitors with PTP1B active sites, four docking programs (AutoDock 4.0, AutoDock Vina 1.0, standard precision (SP) Glide 9.7, and extra precision (XP) Glide 9.7) were used. The characteristics of the active sites were then described by the conformations of the docking results. In conclusion, a combination of various pharmacophore features and the integration information of structure activity relationship (SAR) can be used to design novel potent PTP1B inhibitors.

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