Dephosphorylation, cascade

The classical PTPs can be subdivided into receptorlike PTPs and nonreceptor, cytosolic PTPs. The second category of PTPs are broadly defined as dual specificity phosphatases (DSPs), which dephosphorylate pSer/ pThr as well as pTyr. MAP kinase phosphatases (MKPs) ( MAP kinase cascades) and PTEN are examples of DSP family members. Remarkably, PTEN also has lipid phosphatase activity that is specific for phosphatidylinositol-3,4,5-trisphosphate generated in response to the actions of PI3K. Finally, the class of low molecular mass (LM-) PTPs and that of CDC25 PTPs accomplish the cells repertoire of PTPs (Fig. 3). 

For the purpose of discussion, crossbridge regulation can be split into three overlapping sets of reactions (a) the Ca-calmodulin cascade (MLCK activation), (b) the phosphorylation-dephosphorylation cycle (the Four State Model), and (c) actin-myosin cycle (chemomechanical transduction). 

Phosphorylation by protein kinases of specific seryl, threonyl, or tyrosyl residues—and subsequent dephosphorylation by protein phosphatases—regulates the activity of many human enzymes. The protein kinases and phosphatases that participate in regulatory cascades which respond to hormonal or second messenger signals constimte a bio-organic computer that can process and integrate complex environmental information to produce an appropriate and comprehensive cellular response. 

The phosphorylation and dephosphorylation of seryl, threonyl, and tyrosyl residues regulate the activity of certain enzymes of lipid and carbohydrate metabolism and the properties of proteins that participate in signal transduction cascades. 

Tyrosine kinase activation can also initiate a phosphorylation and dephosphorylation cascade that involves the action of several other protein kinases and the counter-... 

Insulin binding to the extracellular side of cell membranes initiates the insulin cascade , a series of phosphorylation/dephosphorylation steps. A postulated mechanism for vanadium is substitution of vanadate for phosphate in the transition state structure of protein tyrosine phosphatases (PTP).267,268 In normal physiological conditions, the attainable oxidation states of vanadium are V111, Viv and Vv. Relevant species in solution are vanadate, (a mixture of HV042-/ H2VOO and vanadyl V02+. Vanadyl is not a strong inhibitor of PTPs, suggesting other potential mechanisms for insulin mimesis for this cation. 

Fig. 13.6 A m ulti-enzyme one-pot example cascade conversion of glycerol into a heptose sugar through consecutive phosphorylation, oxidation, aldol reaction and dephosphorylation [11],...

Covalent interconversion of enzymes is well established as a fundamental theme in metabolic regulation. The prototypic reversible interconverting systems include the sequence of phosphorylation/dephosphorylation steps in the activation of mammalian glycogen phosphorylase and pyruvate dehydrogenase as well as the nucleotidyla-tion/denucleotidylation using UTP and ATP in the bacterial glutamine synthetase cascade (see Fig. 1.). 

Renewed docking of the catalytic subunit requires the removal of the phosphate residue at the G subunit phosphorylated at the P2 site. This takes place via the protein phosphatases 2A and 2B (calcineurin). Thus, a cascade of protein phosphatases is involved in the regulation of dephosphorylation of key enzymes of glycogen degradation, whereby a phosphatase, namely protein phosphatase I, is indirectly activated by other protein phosphatases. With calcineurin, a Ca -dependent protein phosphatase is involved and thus it is possible to influence glycogen metabolism via Ca -mediated signals. 

Protein phosphorylation may be used to switch enzyme activities on and off. The same is true for dephosphorylation of enzymes. In the cell, we often find phosphorylation cascades in which several phosphorylation reactions are connected to one another. Dephosphorylation reactions may also be elements of these cascades. Furthermore, networks of phosphorylation and dephosphorylation of proteins exist which permit the cell to respond to external stimuli in a finely tuned way. 

One circumstance that triggers this control mechanism is the presence of single-strand breaks in DNA, which leads to arrest of the cell cycle in G2. A specific protein ldnase (called Rad3 in yeast), which is activated by single-strand breaks, triggers a cascade leading to the inactivation of the phosphatase that dephosphorylates Tyr15 of CDK. The CDK remains inactive and the cell is arrested in G2. The cell will not divide until the DNA is repaired and the effects of the cascade are reversed. 

Figure 11-4 Cascades of phosphorylation and dephosphorylation reactions involved in the control of the metabolism of glycogen. Heavy arrows show pathways by which glucosyl emits of glycogen are converted into free glucose or enter the glycolytic pathway. Green arrows trace the corresponding biosynthetic pathways. Gray arrows (— ) trace the...

Figure 11-10 A "monocyclic" regulatory cascade involving phosphorylation and dephosphorylation of an enzyme.

Deoxyhemerythrin, oxygenation of 862 Deoxyhemoglobin 850, 851 Deoxy-D-mannooctulosonic acid (KDO) 180s Deoxyribonuclease 652 - 653 Deoxyribonucleic acid. See DNA 2-Deoxyribose 200s 1-Deoxyxylulose 5-phosphate 735, 736 Dephosphorylation, cascade 542 Depsides 23 Depsipeptide 414... 

Figure 5.28 One-pot dual-enzyme cascade, starting from dihydroxyacetone and propionaldehyde (propanal), with in situ phosphorylation and dephosphorylation steps.

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