Phosphorylation cascade reactions

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. 

Fig. 1. AlFx acts as the messenger of a false information. Its message is greatly amplified during the conversion into the functional response of a cell. The second messenger molecule could be cAMP, 1,4,5-IP3, and DAG. Moreover, AlFx can participate as the analogue in the phosphoryl-transfer reactions involved in the signaling cascade...

Part II of this book represents the bulk of the material on the analysis and modeling of biochemical systems. Concepts covered include biochemical reaction kinetics and kinetics of enzyme-mediated reactions simulation and analysis of biochemical systems including non-equilibrium open systems, metabolic networks, and phosphorylation cascades transport processes including membrane transport and electrophysiological systems. Part III covers the specialized topics of spatially distributed transport modeling and blood-tissue solute exchange, constraint-based analysis of large-scale biochemical networks, protein-protein interactions, and stochastic systems. 

A discrete region of 40 residues in the amino-terminal part of p38 MAPK is mainly responsible for screening of extracellular signals, transmitted by the upstream kinases, whereas the carboxy-terminal half of the AlAPK binds to downstream substrates, such as transcription factors. The amino-terminal recognition region of the MAPK contains an exposed a-helix in the proximity of the catalytic cleft, which is the phosphorylation site recognized by an upstream kinase. Phosphorylation opens the catalytic cleft and activates the kinase. This seems to be a common structural feature of kinases participating in sequential reactions in phosphorylation cascades. 

Are the consequences of the activation of a receptor which provides the input signal and starts a phosphorylation cascade different from the consequences of activation of an enzyme, such as glycogen phosphorylase, wiiich is the first enz3mie feeding substrates into a chain of metabolic reactions and supplying gjycolysis with fuel ... 

In addition to PR-mediated transcriptional activities, progesterone also triggers intracellular phosphorylation cascades of the Src/Ras/mitogen-activated protein kinase pathway via PR [10, 11]. Also independent of the transcriptional activities of the receptor are rapid nongenomic effects of progesterone like modulation of sperm acrosome reaction [12], prevention of preterm labor [13] and Xenopus oocyte maturation [14]. 

Phosphorylation cascades are induced by both the activation of ras and increased levels of DAG and IP3 in the cell following EGF binding. One of the key enzymes activated in the phosphorylation cascade is MAPKK (mitogen activated protein kinase kinase). (A mitogen is any molecule that stimulates cell division). Activated MAPKK then phosphorylates both a tyrosine and a tryptophan of MAP kinase. (This unusual reaction appears to ensure that MAP kinase is activated only by MAPKK.) Active MAP kinase then phosphorylates a variety of cellular proteins. Among those are jun, fos, and myc. Phosphorylated jun and fos proteins then combine to form the transcription factor AP-1. AP-1 subsequently promotes the transcription of several delayed response genes. 

Cascade In several situations in the body, a series of similar enzyme reactions occurs in which a signal is passed and often amplified between the beginning and end of the series. Such a series is called a cascade. The most common types are proteolytic and protein phosphorylation cascades. 

Glycogen synthase is inactivated (switched off) when specific serine residues are phosphorylated. This reaction is catalyzed by glycogen synthase kinase that nses ATP as a cosnbstrate. Glycogen synthase is reactivated (switched on) by protein phosphatase 1 which catalyzes the hydrolysis of the phosphate gronps from the enzyme. Protein phosphatase 1 in tnm is stimulated by insulin. The binding of insulin to insnUn receptors in the plasma membrane of the cell triggers a signaling cascade that stimnlates protein phosphatase 1. 

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). 

Fig. 2. An adrenaline molecule (1) binds to its binding site on the extracellular site of an adrenaline receptor (2). Thereby, the exchange of GDP by GTP in the Ga subunit of a hetero-trimeric G protein (3) is induced, followed by the dissociation of the Ga and Gpr subunits. G now binds and stimulates its effector adenylate cyclase (4), which produces cyclic AMP (5) from ATP (6). This second messenger starts a cascade of enzymatic reactions, which alter the behavior of the cell via several phosphorylation steps... 

Phosphoryl group transfer reactions add or remove phosphoryl groups to or from cellular metabolites and macromolecules, and play a major role in biochemistry. Phosphoryl transfer is the most common enzymatic function coded by the yeast genome and, in addition to its importance in intermediary metabolism (see Chapter 5), the reaction is catalysed by a large number of central regulatory enzymes that are often part of signalling cascades, such as protein kinases, protein phosphatases, ATPases and GTPases. 

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],...

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