Phosphoprotein phosphatases activation

Phosphonoacetic acid antiviral activity, 6, 771 Phosphoprotein phosphatases activation... 

In contrast to the situation in the adipocyte, hypothyroidism potentiates /3-ad-renergic receptor-mediated cAMP and glycogen phosphorylase response in rat he-patocytes [88]. Thyroid hormones suppress /3-adrenergic-stimulated phosphorylase b kinase and phosphorylase a activities, while enhancing phosphoprotein phosphatase activity in the same cells [89,90]. In other words, thyroid hormones seem to... 

Figure 18.14 Glycogen biosynthesis and degradation regulation. cAMP activates cAMP-dependent protein kinases. They cause the phosphorylation of glycogen synthase (inactivation), phosphorylase kinase (activation), and the inhibitory protein. The last inhibits phosphoprotein phosphatase. Activated phosphorylase kinase causes the phosphorylation of phosphorylase b, thus activating it to phosphorylase a. Phosphoprotein phosphatase is inhibited by the phosphorylated inhibitor protein. Such inhibition is released when the inhibitor protein is dephosphorylated. The phosphatase then reactivates glycogen synthase and inactivates phosphorylase kinase and phosphorylase a.

Gong, C.X., Singh, T.J., Grundke-Iqbal, I. and Iqbal, K. 1993. Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem. 61 921-927 Gong, C.X., Grundke-Iqbal, I. and Iqbal, K. 1994a. Dephosphorylation of Alzheimer s disease abnormally phosphorylated tau by protein phosphatase-2A. Neuroscience 61 765-772... 

P.B., and Chau, V. (1981) Fluoromet-ric assay for adenosine 3, 5 -cyclic monophosphate-dependent protein kinase and phosphoprotein phosphatase activities. Proc. Nad. Acad. Sci. U.S.A., 78, 6048-6050. 

Dephosphorylation of both glycogen phosphorylase and glycogen synthase is carried out by phosphoprotein phosphatase 1. The action of phosphopro-tein phosphatase 1 inactivates glycogen phosphorylase and activates glycogen synthase. 

Figure 2. Mechanism of PDH. The three different subunits of the PDH complex in the mitochondrial matrix (E, pyruvate decarboxylase E2, dihydrolipoamide acyltrans-ferase Ej, dihydrolipoamide dehydrogenase) catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA and CO2. E, decarboxylates pyruvate and transfers the acetyl-group to lipoamide. Lipoamide is linked to the group of a lysine residue to E2 to form a flexible chain which rotates between the active sites of E, E2, and E3. E2 then transfers the acetyl-group from lipoamide to CoASH leaving the lipoamide in the reduced form. This in turn is oxidized by E3, which is an NAD-dependent (low potential) flavoprotein, completing the catalytic cycle. PDH activity is controlled in two ways by product inhibition by NADH and acetyl-CoA formed from pyruvate (or by P-oxidation), and by inactivation by phosphorylation of Ej by a specific ATP-de-pendent protein kinase associated with the complex, or activation by dephosphorylation by a specific phosphoprotein phosphatase. The phosphatase is activated by increases in the concentration of Ca in the matrix. The combination of insulin with its cell surface receptor activates PDH by activating the phosphatase by an unknown mechanism.

A few enzymes, such as the previously mentioned CNP, are believed to be fairly specific for myelin/oligodendro-cytes. There is much more in the CNS than in peripheral nerve, suggesting some function more specialized to the CNS. In addition, a unique pH 7.2 cholesterol ester hydrolase is also enriched in myelin. On the other hand, there are many enzymes that are not myelin-specific but appear to be intrinsic to myelin and not contaminants. These include cAMP-stimulated kinase, calcium/calmodulin-dependent kinase, protein kinase C, a neutral protease activity and phosphoprotein phosphatases. The protein kinase C and phosphatase activities are presumed to be responsible for the rapid turnover of MBP phosphate groups, and the PLP acylation enzyme activity is also intrinsic to myelin. 

Shiao, M.-S. Drong, R.F. Porter, J.W. The purification and properties of a protein kinase and the partial purification of a phosphoprotein phosphatase that inactivate and activate acetyl-CoA carboxylase. Biochem. Biophys. Res. Commun., 98, 80-87 (1981)... 

Glucagon or epinephrine decreases [fructose 2,6-bisphosphate]. The hormones do this by raising [cAMP] and bringing about phosphorylation of the bifunctional enzyme that makes and breaks down fructose 2,6-bisphosphate. Phosphorylation inactivates PFK-2 and activates FBPase-2, leading to breakdown of fructose 2,6-bisphosphate. Insulin increases [fructose 2,6-bisphosphate] by activating a phosphoprotein phosphatase that dephosphorylates (activates) PFK-2. 

Some bacteria, including E. coli, have the full complement of enzymes for the glyoxylate and citric acid cycles in the cytosol and can therefore grow on acetate as their sole source of carbon and energy. The phosphoprotein phosphatase that activates isocitrate dehydrogenase is stimulated by intermediates of the citric acid cycle and glycolysis and by indicators of reduced cellular energy supply (Fig. 16-23). The same metabolites inhibit the protein kinase activity of the bifunctional polypeptide. Thus, the accumulation of intermediates of... 

CoA reductase activity is controlled covalently through the actions of a protein kinase and a phosphoprotein phosphatase (see Figure 18.6). The phosphorylated form of the enzyme is inactive, whereas the dephosphorylated form is active. [Note Protein kinase is activated by AMP, so cholesterol synthesis is decreased when ATP availability is decreased.]... 

As outlined above, protein phosphorylation is a key process involved in many signal transduction pathways and reversal of this process is catalyzed by a multiplicity of phosphoprotein phosphatases (PPs). Major PPs catalyzing dephosphorylation of phosphoserine or phosphothreonine residues on proteins include PP1 (inhibited by phosphorylated inhibitor protein I-1 and by okadaic acid and microsystins), PP2 (also inhibited by okadaic acid and microcystins), PP2B or calcineurin (CaM-activated and having a CaM-like regulatory subunit) and PP2C (Mg2+-dependent) [18]. These PPs have been found in all eukaryotes so far examined [18, 19]. In addition, a variety of protein phosphotyrosine phosphatases can reverse the consequences of RTK or JAK/STAT receptor activation [20]. 

Several phosphoprotein phosphatases have been isolated. They show a range of relative activities towards Mn2+ and Mg2+,294-296 while some are Mn2+-specific.297... 

Dal Canto, M. C., and Gurney, M. E. (1994). Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am.J. Pathol. 145, 1271-1279. Daniels, K. K., and Vickroy, T. W. (1999). Reversible activation of glutamate transport in rat brain glia by protein kinase C and an okadaic acid-sensitive phosphoprotein phosphatase. Neurochem. Res. 24, 1017-1025. 

Although CsA and FK506 are extremely selective inhibitors of calcineurin, some of the studies above indicate that these drugs could possibly have calcineurin-independent elfects. Moreover, calcineurin shows phosphatase activity towards a wide variety of phosphoprotein substrates, and inhibition of calcineurin by immunosuppressant-immunophilin complexes blocks phosphatase activity toward a broad spectrum of phos-phoproteins. Inhibitors that blocked calcineurin mediated dephosphorylation of a specific substrate (such as NF-AT, or specific isoforms of NF-AT) without affecting the dephosphorylation of other substrates would be of great therapeutic as well as academic interest. The search for... 

The purple acid phosphatases (PAPs) are a class of phosphoprotein phosphatases which possess a p-oxo(hydroxo)-bridged dinuclear iron centre. An enzyme has been isolated from beef spleen which is purple in colour, while a violet phosphatase has been characterised from red kidney beans (KBPase). This latter enzyme consists of two subunits with M = 58200 and contains two equivalents of Zn(II) and Fe(III) per dimer which are essential for catalytic activity. KBPase hydrolyses nucleosidetriphos-phates as well as activated phosphomonoesters such as 4-nitrophenylphosphate or a-naphthyl phosphate (Beck et al., 1986). As with the beef spleen enzyme, KBPase is inhibited by tetrahedral oxoanions such PO and AsO . 

Recently Exton and co-workers [93] have proposed that adrenergic responsiveness in skeletal muscle is regulated by thyroid hormones at two levels, i.e., 1) stimulation of /3-adrenergic receptors and adenylate cyclase activity and 2) increased activity of phosphoprotein phosphatases. Such results would explain the effect of thyroid hormones on glycogen metabolism in muscle although the primary mechanism of these actions remains unknown. 

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