Phosphorylation Kinases

Sugars very often participate in metabolism in a phosphorylated form. We have just become acquainted with an illustration of this in the Calvin 

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Holz, M. K., and Blenis, J. (2005). Identification of S6 kinase 1 as a novel mammalian target ofrapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem. 280, 26089-26093. 

Coupled folding and binding is a frequent theme in the field of intrinsically disordered proteins (see Chap. 6). One of the earliest examples of this phenomenon was the interaction of the phosphorylated kinase-inducible domain (pKID) of the transcription factor CREB with the KIX domain of the transcriptional coactivator CBP. Free pKID is unfolded in solution [21], but folds into an orthogonal pair of helices, aA and aB, upon binding to the folded KIX domain (Fig. 1.5) [23]. We have recently posed the question, what is the... 

Fig. 6.4. Illustration of the unfolded nature of the phosphorylated kinase-inducible domain (pKID) of CREB (left) and its conformation after folding upon binding to the KIX domain of CBP (right). The mechanism of this process has recently been elucidated by NMR [28] and is discussed more fully in Chap. 1 (Wright). Adapted by permission from [5] (Macmillan Publishers Ltd., copyright 2005)...

VI. Cell Prolileration Diseases Phosphorylation Kinase Inhibitors... 

In an earlier investigation by co-author Matsuno (1), other quinazoline derivatives effective as phosphorylation kinase inhibitors were prepared and are provided in Table 3. 

Chemical tools have played a central role in elucidating the function of posttranslational protein phosphorylation. Kinase and phosphatase inhibitors have played a major role in the study of protein phosphorylation because they allow rapid, reversible inactivation of the target in meaningful contexts (cells and organisms) to study its biologic function. Chemical tools have also helped identify the direct substrates of individual kinases and phosphatases, and conversely, they have helped identify which kinase is responsible for phosphorylating a particular phosphoprotein. Here I will focus on chemical tools developed for protein kinases several reviews discuss chemical tools for protein phosphatases (15, 16). 

ATP dihydrostreptomycin-6-P 3 a-phosphotransferase dihydrostreptomycin 6-phosphate kinase (phosphorylating) kinase (phosphorylating), dihydrostreptomycin 6-phosphate... 

Cox, D.E. Meinke, M.H. Edstrom, R.D. Mechanism of calmodulin inhibition of cAMP-dependent protein kinase activation of phosphorylation kinase. Arch. Biochem. Biophys., 259, 350-362 (1987)... 

Effects of insuiin on phosphoryiation and activity of various enzymes and proteins. The effects are indirect, i.e. Insuiin binds to its receptor on the cell membrane, initiating a chain of events, culminating in the phosphorylation (kinase reaction) or dephosphorylation (phosphatase action) of the enzyme. 

The synthetic ATP is an excellent probe for the stereochemistry and hence reaction mechanism of phosphorylating (kinase) enzymes (see page 109). At least two pathways are possible for the enzyme catalyzed donation of the y-phosphate of ATP to a substrate. This may simply proceed via direct displacement on the enzyme surface, with an overall inversion of configuration in the case of a chiral y-phosphate ... 

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