Computational study of the effects of protein tyrosine nitrations on the catalytic activity of human thymidylate synthase

2012 ◽  
Vol 27 (1) ◽  
pp. 45-66 ◽  
Author(s):  
Adam Jarmuła ◽  
Wojciech Rode
Keyword(s):  
Catalytic Activity ◽  
Thymidylate Synthase ◽  
Computational Study ◽  
Protein Tyrosine

Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase

2001 ◽  
Vol 281 (6) ◽  
pp. H2289-H2294 ◽  
Author(s):  
Illarion V. Turko ◽  
Sisi Marcondes ◽  
Ferid Murad
Keyword(s):  
Catalytic Activity ◽  
Matrix Protein ◽  
Ketone Bodies ◽  
Tyrosine Nitration ◽  
Alternative Source ◽  
In Vivo Models ◽  
Protein Tyrosine ◽  
Protein Tyrosine Nitration ◽  
Coa Transferase

High levels of reactive species of nitrogen and oxygen in diabetes may cause modifications of proteins. Recently, an increase in protein tyrosine nitration was found in several diabetic tissues. To understand whether protein tyrosine nitration is the cause or the result of the associated diabetic complications, it is essential to identify specific proteins vulnerable to nitration with in vivo models of diabetes. In the present study, we have demonstrated that succinyl-CoA:3-oxoacid CoA-transferase (SCOT; EC 2.8.3.5 ) is susceptible to tyrosine nitration in hearts from streptozotocin-treated rats. After 4 and 8 wk of streptozotocin administration and diabetes progression, SCOT from rat hearts had a 24% and 39% decrease in catalytic activity, respectively. The decrease in SCOT catalytic activity is accompanied by an accumulation of nitrotyrosine in SCOT protein. SCOT is a mitochondrial matrix protein responsible for ketone body utilization. Ketone bodies provide an alternative source of energy during periods of glucose deficiency. Because diabetes results in profound derangements in myocardial substrate utilization, we suggest that SCOT tyrosine nitration is a contributing factor to this impairment in the diabetic heart.

scholarly journals Regulation of CO production in cerebral microvessels of newborn pigs

2003 ◽  
Vol 285 (1) ◽  
pp. H292-H297 ◽  
Author(s):  
Charles W. Leffler ◽  
Liliya Balabanova ◽  
C. Dale Sullivan ◽  
Xiaohu Wang ◽  
Alexander L. Fedinec ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Protein Tyrosine Kinase ◽  
Protein Tyrosine Phosphatases ◽  
Gas Chromatography Mass Spectrometry ◽  
Cerebral Blood Vessels ◽  
Cerebral Microvessels ◽  
Protein Tyrosine ◽  
Kinase C ◽  
Protein Kinase C Inhibitor ◽  
Newborn Pigs

Carbon monoxide (CO) is produced from heme by heme oxygenase-2 (HO-2) in cerebral blood vessels. Gas chromatography-mass spectrometry was used on piglet cerebral microvessels to address the hypothesis that CO production is regulated by heme delivery and HO-2 catalytic activity. CO production appears to be substrate limited because heme and its precursor aminolevulinate increase CO production. Ionomycin also increases CO production. However, CO production from exogenous heme was the same in Ca-replete medium, Ca-free medium with ionomycin, and Ca-replete medium with ionomycin. Phorbol myristate acetate increases CO production but does not change the catalytic activity of HO-2. Also, the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine has no effect on the HO-2 catalytic activity. Protein tyrosine kinase inhibition reduces HO-2 catalytic activity. Inhibition of protein tyrosine phosphatases increased HO-2 catalytic activity. Therefore, regulation of CO production by cerebral microvessels can include changing heme availability and HO-2 catalytic activity. HO-2 catalytic activity is stimulated by tyrosine phosphorylation.

scholarly journals Distinct Functions of the Two Protein Tyrosine Phosphatase Domains of LAR (Leukocyte Common Antigen-Related) on Tyrosine Dephosphorylation of Insulin Receptor

2001 ◽  
Vol 15 (2) ◽  
pp. 271-280 ◽  
Author(s):  
Kazutake Tsujikawa ◽  
Naoto Kawakami ◽  
Yukiko Uchino ◽  
Tomoko Ichijo ◽  
Tatsuhiko Furukawa ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Insulin Receptor ◽  
Transmembrane Protein ◽  
Mutant Protein ◽  
Common Antigen ◽  
Insulin Receptor Tyrosine Kinase ◽  
Leukocyte Common Antigen ◽  
Protein Tyrosine ◽  
Ptpase Activity

Abstract Most receptor-like, transmembrane protein tyrosine phosphatases (PTPases), such as CD45 and the leukocyte common antigen-related (LAR) molecule, have two tandemly repeated PTPase domains in the cytoplasmic segment. The role of each PTPase domain in mediating PTPase activity remains unclear; however, it has been proposed that PTPase activity is associated with only the first of the two domains, PTPase domain 1, and the membrane-distal PTPase domain 2, which has no catalytic activity, would regulate substrate specificity. In this paper, we examine the function of each PTPase domain of LAR in vivo using a potential physiological substrate, namely insulin receptor, and LAR mutant proteins in which the conserved cysteine residue was changed to a serine residue in the active site of either or both PTPase domains. LAR associated with and preferentially dephosphorylated the insulin receptor that was tyrosine phosphorylated by insulin stimulation. Its association was mediated by PTPase domain 2, because the mutation of Cys-1813 to Ser in domain 2 resulted in weakening of the association. The Cys-1522 to Ser mutant protein, which is defective in the LAR PTPase domain 1 catalytic site, was tightly associated with tyrosine-phosphorylated insulin receptor, but failed to dephosphorylate it, indicating that LAR PTPase domain 1 is critical for dephosphorylation of tyrosine-phosphorylated insulin receptor. This hypothesis was further confirmed by using LAR mutants in which either PTPase domain 1 or domain 2 was deleted. Moreover, the association of the extracellular domains of both LAR and insulin receptor was supported by using the LAR mutant protein without the two PTPase domains. LAR was phosphorylated by insulin receptor tyrosine kinase and autodephosphorylated by the catalytic activity of the PTPase domain 1. These results indicate that each domain of LAR plays distinct functional roles through phosphorylation and dephosphorylation in vivo.

scholarly journals The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Jai Prakash Singh ◽  
Yang Li ◽  
Yi-Yun Chen ◽  
Shang-Te Danny Hsu ◽  
Rebecca Page ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Protein ◽  
Resonance Spectroscopy ◽  
Protein Tyrosine ◽  
Intrinsically Disordered ◽  
X Ray Scattering ◽  
Cancer And Inflammation ◽  
Chemical Cross Linking

AbstractT-Cell Protein Tyrosine Phosphatase (TCPTP, PTPN2) is a non-receptor type protein tyrosine phosphatase that is ubiquitously expressed in human cells. TCPTP is a critical component of a variety of key signaling pathways that are directly associated with the formation of cancer and inflammation. Thus, understanding the molecular mechanism of TCPTP activation and regulation is essential for the development of TCPTP therapeutics. Under basal conditions, TCPTP is largely inactive, although how this is achieved is poorly understood. By combining biomolecular nuclear magnetic resonance spectroscopy, small-angle X-ray scattering, and chemical cross-linking coupled with mass spectrometry, we show that the C-terminal intrinsically disordered tail of TCPTP functions as an intramolecular autoinhibitory element that controls the TCPTP catalytic activity. Activation of TCPTP is achieved by cellular competition, i.e., the intrinsically disordered cytosolic tail of Integrin-α1 displaces the TCPTP autoinhibitory tail, allowing for the full activation of TCPTP. This work not only defines the mechanism by which TCPTP is regulated but also reveals that the intrinsically disordered tails of two of the most closely related PTPs (PTP1B and TCPTP) autoregulate the activity of their cognate PTPs via completely different mechanisms.

scholarly journals Experimental and Computational Study to Reveal the Potential of Non-Polar Constituents from Hizikia fusiformis as Dual Protein Tyrosine Phosphatase 1B and α-Glucosidase Inhibitors

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 302 ◽  
Author(s):  
Su Hui Seong ◽  
Duc Hung Nguyen ◽  
Aditi Wagle ◽  
Mi Hee Woo ◽  
Hyun Ah Jung ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Protein Tyrosine Phosphatase ◽  
Methanol Extract ◽  
Competitive Inhibition ◽  
Computational Study ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B ◽  
Hizikia Fusiformis ◽  
Protein Tyrosine

Hizikia fusiformis (Harvey) Okamura is an edible marine alga that has been widely used in Korea, China, and Japan as a rich source of dietary fiber and essential minerals. In our previous study, we observed that the methanol extract of H. fusiformis and its non-polar fractions showed potent protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibition. Therefore, the aim of the present study was to identify the active ingredient in the methanol extract of H. fusiformis. We isolated a new glycerol fatty acid (13) and 20 known compounds including 9 fatty acids (1–3, 7–12), mixture of 24R and 24S-saringosterol (4), fucosterol (5), mixture of 24R,28R and 24S,28R-epoxy-24-ethylcholesterol (6), cedrusin (14), 1-(4-hydroxy-3-methoxyphenyl)-2-[2-hydroxy -4-(3-hydroxypropyl)phenoxy]-1,3-propanediol (15), benzyl alcohol alloside (16), madhusic acid A (17), glycyrrhizin (18), glycyrrhizin-6’-methyl ester (19), apo-9′-fucoxanthinone (20) and tyramine (21) from the non-polar fraction of H. fusiformis. New glycerol fatty acid 13 was identified as 2-(7′- (2″-hydroxy-3″-((5Z,8Z,11Z)-icosatrienoyloxy)propoxy)-7′-oxoheptanoyl)oxymethylpropenoic acid by spectroscopic analysis using NMR, IR, and HR-ESI-MS. We investigated the effect of the 21 isolated compounds and metabolites (22 and 23) of 18 against the inhibition of PTP1B and α-glucosidase enzymes. All fatty acids showed potent PTP1B inhibition at low concentrations. In particular, new compound 13 and fucosterol epoxide (6) showed noncompetitive inhibitory activity against PTP1B. Metabolites of glycyrrhizin, 22 and 23, exhibited competitive inhibition against PTP1B. These findings suggest that H. fusiformis, a widely consumed seafood, may be effective as a dietary supplement for the management of diabetes through the inhibition of PTP1B.

Sign in / Sign up

Export Citation Format

Share Document