Roles of Aspartic Acid-181 and Serine-222 in Intermediate Formation and Hydrolysis of the Mammalian Protein-Tyrosine-Phosphatase PTP1†

Biochemistry ◽  
1997 ◽  
Vol 36 (15) ◽  
pp. 4568-4575 ◽  
Author(s):  
Daniel L. Lohse ◽  
John M. Denu ◽  
Nicholas Santoro ◽  
Jack E. Dixon
Keyword(s):  
Aspartic Acid ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Intermediate Formation ◽  
Protein Tyrosine ◽  
Hydrolysis Of ◽  
Mammalian Protein

scholarly journals Molecular Determinants of Substrate Recognition in Hematopoietic Protein-tyrosine Phosphatase

2004 ◽  
Vol 279 (50) ◽  
pp. 52150-52159 ◽  
Author(s):  
Zhonghui Huang ◽  
Bo Zhou ◽  
Zhong-Yin Zhang
Keyword(s):  
Substrate Specificity ◽  
Protein Tyrosine Phosphatase ◽  
Cellular Proliferation ◽  
High Efficiency ◽  
Tyrosine Phosphatase ◽  
Substrate Recognition ◽  
Fold Increase ◽  
Phosphoryl Transfer ◽  
Protein Tyrosine ◽  
Hydrolysis Of

The extracellular signal-regulated protein kinase 2 (ERK2) plays a central role in cellular proliferation and differentiation. Full activation of ERK2 requires dual phosphorylation of Thr183and Tyr185in the activation loop. Tyr185dephosphorylation by the hematopoietic protein-tyrosine phosphatase (HePTP) represents an important mechanism for down-regulating ERK2 activity. The bisphosphorylated ERK2 is a highly efficient substrate for HePTP with akcat/Kmof 2.6 × 106m–1s–1. In contrast, thekcatK/mvalues for the HePTP-catalyzed hydrolysis of Tyr(P) peptides are 3 orders of magnitude lower. To gain insight into the molecular basis for HePTP substrate specificity, we analyzed the effects of altering structural features unique to HePTP on the HePTP-catalyzed hydrolysis ofp-nitrophenyl phosphate, Tyr(P) peptides, and its physiological substrate ERK2. Our results suggest that substrate specificity is conferred upon HePTP by both negative and positive selections. To avoid nonspecific tyrosine dephosphorylation, HePTP employs Thr106in the substrate recognition loop as a key negative determinant to restrain its protein-tyrosine phosphatase activity. The extremely high efficiency and fidelity of ERK2 dephosphorylation by HePTP is achieved by a bipartite protein-protein interaction mechanism, in which docking interactions between the kinase interaction motif in HePTP and the common docking site in ERK2 promote the HePTP-catalyzed ERK2 dephosphorylation (∼20-fold increase inkcat/Km) by increasing the local substrate concentration, and second site interactions between the HePTP catalytic site and the ERK2 substrate-binding region enhance catalysis (∼20-fold increase inkcat/Km) by organizing the catalytic residues with respect to Tyr(P)185for optimal phosphoryl transfer.

scholarly journals Heterologous expression of a mammalian protein tyrosine phosphatase gene in Leishmania: effect on differentiation

2003 ◽  
Vol 50 (5) ◽  
pp. 1517-1526 ◽  
Author(s):  
Mirna Nascimento ◽  
Nay Abourjeily ◽  
Anirban Ghosh ◽  
Wen Wei Zhang ◽  
Greg Matlashewski
Keyword(s):  
Heterologous Expression ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Mammalian Protein

1742-P: Targeting the Low Molecular Weight Protein Tyrosine Phosphatase for Obesity-Associated Diabetes Therapy

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1742-P
Author(s):  
STEPHANIE M. STANFORD ◽  
MICHAEL A. DIAZ ◽  
JIWEN J. ZOU ◽  
ROBERT J. ARDECKY ◽  
ANTHONY PINKERTON ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Low Molecular Weight ◽  
Molecular Weight Protein ◽  
Diabetes Therapy ◽  
Protein Tyrosine ◽  
Weight Protein ◽  
Low Molecular Weight Protein

Inhibition of Protein Tyrosine Phosphatase 1B by Lutein Derivatives isolated from Mexican Oregano (Lippia graveolens)

2018 ◽  
Vol 17 (3) ◽  
pp. 134-139
Author(s):  
R.M. Perez-Gutierrez
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Spectroscopic Data ◽  
Methanol Extract ◽  
Tyrosine Phosphatase ◽  
Positive Control ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ic50 Value ◽  
Ic50 Values

Methanol extract from Lippia graveolens (Mexican oregano) was studied in order to identify inhibitory bioactives for protein tyrosine phosphatase 1B (PTP1B). Known flavone as lutein (1), and another flavone glycoside such as lutein-7-o-glucoside (2), 6-hydroxy-lutein-7-ohexoside (3) and lutein-7-o-ramnoide (4) were isolated from methanol extract of aerial parts of the Lippia graveolens. All isolates were identified based on extensive spectroscopic data analysis, including UV, IR, NMR, MS and compared with spectroscopic data previously reported. These flavones were evaluated for PTP1B inhibitory activity. Among them, compounds 1 and 3 displayed potential inhibitory activity against PTP1B with IC50 values of 7.01 ± 1.25 μg/ml and 18.4 μg/ml, respectively. In addition, compound 2 and 4 showed moderate inhibitory activity with an IC50 value of 23.8 ± 6.21 and 67.8 ± 5.80 μg/ml respectively. Among the four compounds, luteolin was found to be the most potent PTP1B inhibitor compared to the positive control ursolic acid, with an IC50 value of 8.12 ± 1.06 μg/ml. These results indicate that flavonoids constituents contained in Lippia graveolens can be considered as a natural source for the treatment of type 2 diabetes.

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