Kinases cAMP-dependent protein kinase

PKA (A kinase) cAMP-dependent protein kinase cAMP Energy signaling (low energy signal)... 

Non-receptor serine/threonine kinases and dual specificity kinases cAMP-dependent protein kinase (PKA) Phosphoinositol-3-kinase (PI-3K) Cyclin-dependent kinase (CDK) Mitogen-activated protein kinase (MAPK) MAPKK (ERK)... 

Lorenz, M., Wessler, S., Follmann, E., Michaelis, W., Dusterhoft, T., Baumann, G., Stangl, K, and Stangl, V., A constituent of green tea, epigallocatechin-3-gallate, activates rndothelial nitric oxide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and leads to endothelial-dependent vasorelaxation, J. Biol Chem., 279, 6190, 2004. 

Jinsart, W Ternai, B. Polya, G.M. Inhibition of myosin light chain kinase, cAMP-dependent protein kinase, protein kinase C and of plant Ca -depen-dent protein kinase by anthraquinones. Biol. Chem. Hoppe-Seyler, 373, 903-910 (1992)... 

The integrated cellular response of the adrenal glomerulosa cell is determined by the activities of three different protein kinases cAMP-dependent protein kinase, CaM-dependent protein kinases, and C-kinase. A sustained response can be produced by the combined activation either of the cAMP- and CaM-dependent kinases, or of the CaM-dependent kinases and C-kinase. Activation of each type of... 

Acetyl-CoA carboxylase can be phosphorylated by two kinases, cAMP-dependent protein kinase or AMP-dependent protein kinase. 

Consensus sites for phosphorylation were evident in the neuronal NOS enzyme from the predicted protein sequences derived from cDNA analysis. In vitro biochemical studies indicate that nNOS can be phosphorylated by calcium/calmodulin-dependent protein kinase, cAMP-dependent protein kinase, cGMP-dependent protein kinase, and protein kinase C. Phosphorylation of nNOS by all of these enzymes decreases NOS catalytic activity in vitro (Dawson and Snyder, 1994 Bredt etal., 1992 Dinerman etal., 1994a). Calcineurin, a protein phosphatase, dephosphorylates NOS and subsequently increases its catalytic activity (T. M. Dawson etal., 1993). Multiple levels of constitutive nNOS regulation are thus possible by phosphorylation. 

C-Kinase protein kinase C, A-kinase cAMP-dependent protein kinase, CaM-kinase Ca +/calmodulin-dependent protein kinase. 

We have previously calculated conformational free energy differences for a well-suited model system, the catalytic subunit of cAMP-dependent protein kinase (cAPK), which is the best characterized member of the protein kinase family. It has been crystallized in three different conformations and our main focus was on how ligand binding shifts the equilibrium among these ([Helms and McCammon 1997]). As an example using state-of-the-art computational techniques, we summarize the main conclusions of this study and discuss a variety of methods that may be used to extend this study into the dynamic regime of protein domain motion. 

Fig. 1. Superposition of three crystal structures of cAMP-dependent protein kinase that show the protein in a closed conformation (straight line), in an intermediate conformation (dashed line), and in an open conformation (broken line). The structures were superimposed on the large lobe. In three locations, arrows identify corresponding amino acid positions in the small lobe.

The procedure is computationally efficient. For example, for the catalytic subunit of the mammalian cAMP-dependent protein kinase and its inhibitor, with 370 residues and 131 titratable groups, an entire calculation requires 10 hours on an SGI 02 workstation with a 175 MHz MIPS RIOOOO processor. The bulk of the computer time is spent on the FDPB calculations. The speed of the procedure is important, because it makes it possible to collect results on many systems and with many different sets of parameters in a reasonable amount of time. Thus, improvements to the method can be made based on a broad sampling of systems. 

Left side of Fig. 4 shows a ribbon model of the catalytic (C-) subunit of the mammalian cAMP-dependent protein kinase. This was the first protein kinase whose structure was determined [35]. Figure 4 includes also a ribbon model of the peptide substrate, and ATP (stick representation) with two manganese ions (CPK representation). All kinetic evidence is consistent with a preferred ordered mechanism of catalysis with ATP binding proceeding substrate binding. 

Karlsson, R., Zheng, J., Zheng, N.-H., Taylor, S. S., Sowadski, J. M. Structure of the mamalian catalytic subunit of cAMP-dependent protein kinase and an inhibitor peptide displays an open conformation. Acta Cryst. D 49 (1993) 381-388. 

Myristic acid may be linked via an amide bond to the a-amino group of the N-terminal glycine residue of selected proteins (Figure 9.18). The reaction is referred to as A -myristoylation and is catalyzed by myristoyl—CoAtprolein N-myris-toyltransferase, known simply as NMT. A -Myristoyl-anchored proteins include the catalytic subunit of cAMP-dependent protein kinase, the ppSff tyrosine kinase, the phosphatase known as calcineurin B, the a-subunit of G proteins (involved in GTP-dependent transmembrane signaling events), and the gag proteins of certain retroviruses, including the FHV-l virus that causes AIDS. 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Phosphorylation by cAMP-dependent protein kinases inactivates the reductase. This inactivation can be reversed by two specific phosphatases (Figure 25.33). 

The cAMP responsive element binding factor (CREB) is also activated by phosphorylation. Depending on the stimuli, CREB is the target of a cAMP dependent protein kinase or of kinases called MAPKs, RSK, and CamKIV. As in AP-1, CREB carries a basic leucine zipper motif (bZDP), which mediates homo dimerization of CREB when bound to the CRE. 

Both phosphorylase a and phosphorylase kinase a are dephosphorylated and inactivated by protein phos-phatase-1. Protein phosphatase-1 is inhibited by a protein, inhibitor-1, which is active only after it has been phosphorylated by cAMP-dependent protein kinase. Thus, cAMP controls both the activation and inactivation of phosphorylase (Figure 18-6). Insulin reinforces this effect by inhibiting the activation of phosphorylase b. It does this indirectly by increasing uptake of glucose, leading to increased formation of glucose 6-phosphate, which is an inhibitor of phosphorylase kinase. 

Figure 18-8. Coordinated control of glycogenolysis and glycogenesis by cAMP-dependent protein kinase. The reactions that lead to glycogenolysis as a result of an increase in cAMP concentrations are shown with bold arrows, and those that are inhibited by activation of protein phosphatase-1 are shown as broken arrows. The reverse occurs when cAMP concentrations decrease as a result of phosphodiesterase activity, leading to glycogenesis.

Glycogen storage disease is a generic term to describe a group of inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in the tissues. The principal glycogenoses are summarized in Table 18—2. Deficiencies of adenylyl kinase and cAMP-dependent protein kinase have also been re-... 

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