Cascade system activation

Dumuis, A, Sebben, M, Haynes, L, Pin, JP and Bockaert, J (1988) NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature 336 68-70. 

Fig. 2. The intrinsic and extinsic cascade coagulation systems. activation -I, inhibition HMK, high molecular kininogen Cl-inh., complement-1 esterase inhibitor AT-III, antithrombin HI a 1 -PI, alpha-1 protein inhibitor pf-3, platelet factor 3.

Cl-Inh belongs to a superfamily of serine protease inhibitors (serpins) and is a major inhibitor of F-XIIa and kallikrein. It is also an inhibitor of activated complement factors C1 q, C1 r, and C1 s. C1 -Inh thus regulates the activation of two important plasma cascade systems. Proteases induce a conformational change in the plasma protein a2-M, which results in entrapment of the protease into the a2-M cage (B4). In vivo, a2-M acts as a second inhibitor of kallikrein. 

Fio. 3. The intrinsic and extrinsic cascade fibrinolytic systems. activation H, inhibition t-PA, tissue plasminogen activator PAI, plasminogen activator inhibitor a2-M, a2-macroglobulin a2-AP, a2-antiplasmin. 

Interaction with Other Cascade Systems. Interactions between the complement system, the kinin, and the coagulation and fibrinolytic systems have repeatedly been reported (S37, PI9). Activation of one system induces activation of the other systems. The reciprocal activation of the various cascade systems may have an important role in the pathogenesis of ARDS and MODS as complications of sepsis. Nevertheless, until now no convincing prophylactic or therapeutic effects of intervention in the complement cascade system on the severity of septic complications have been reported. 

A parameter used to assist in the characterization of enzyme cascade systems. Symbolized by S A, it is equal to [eo.5E]/[eo.5i] where [eo.sE] is the concentration of effector required for 0.5 activation of the converter enzyme E and [eo.5i] is the concentration of effector at which 50% of the interconvertible enzyme (1) has been modified See Enzyme Cascade Kinetics P. B. Chock E. R. Stadtman (1980) Meth. Enzymol. 64, 297. 

Cascade systems also provide for response to more than one allosteric stimulus in a single pathway. Thus, as shown in Fig. 11-4, glycogen catabolism can be initiated in more than one way. Two pathways are known for initiation of both blood clotting and activation of the complement system. Many pathways activate the MAP kinase pathway shown in Fig. 11-13. 

Escherichia coli have also developed an elegant method to control enzyme catalysis that occurs by covalent modification of each subunit. In this latter reaction a single tyrosyl residue per subunit is adenylylated to produce a stable 5 -adenylyl-O-tyrosyl derivative. Recent NMR and fluorescence data will be reviewed concerning the nature of this adenylyl site and its spatial relationship to the metal ions at the catalytic site. The enzymes responsible for the covalent adenylylation reaction comprise a cascade system for amplifying the activation or inactivation of glutamine synthetase molecules (81). 

Industrial polymerisation processes with the use of titanium-, cobalt- and nickel-based aluminium alkyl-activated Ziegler-Natta catalysts, which are employed for the manufacture of cis- 1,4-poly butadiene, involve a solution polymerisation in low-boiling aromatic hydrocarbons such as toluene or in a mixture of aromatic and aliphatic hydrocarbons such as n-heptane or cyclohexane. The polymerisation is carried out in an anhydrous hydrocarbon solvent system. The proper ratio of butadiene monomer and solvent is blended and then completely dried in the tower, followed by molecular sieves. The alkyla-luminium activator is added, the mixture is agitated and then the transition metal precatalyst is introduced. This blend then passes through a series of reactors in a cascade system in which highly exothermic polymerisation occurs. Therefore, the reaction vessels are cooled to slightly below room temperature. 

The operational thermal stability of enzymes can be easily evaluated in experiments carried out in a CSMR fed with a saturating substrate concentration, while varying the temperature but maintaining all the other parameters constant. Each enzyme of the cascade system was tested by feeding the CSMR with the appropriate substrate. The kinetic characterization of amidase-catalyzed reactions in runs fed with a nitrile was hampered by the fact that the intracellular enzyme works in cascade with nitrile hydratase. The concentration of amide, produced in situ in the first step, varied with the time and reaction conditions and did not assure the differential conditions needed for an accurate analysis, the amide being completely converted by amidase in some runs. Hence, amidase activity was characterized independently by feeding the reactor with amide as the substrate [35]. 

As demonstrated elsewhere [34], it is possible to utilize such a different thermal dependence of the enzymes involved in the cascade system for process control. The appropriate choice of operational conditions allowed the enzyme activities to be controlled and directed the selectively of the process to the first reaction product, the amide or to the second reaction product, the acid. A higher process temperature and residence time (20 °C and r = lOh) favor production of the acid (amidase activity prevails), while a lower temperature and residence time (5 °C and t = 5 h) allow the production of the intermediate amide (amidase activity negligible) [34]. 

This was performed for each enzyme independently, feeding the reactor with the appropriate substrate (nitrile for the cascade reaction, amide for the sole amidase). The activation energies of both catalysed reactions were evaluated together with those of the inactivation process that inevitably takes place even under the most suitable operational conditions. In the nitrile hydratase/amidase cascade system nitrile hydratase is the more labile enzyme that imposes process temperature choice. These findings make accessible the complete kinetic expression of the dependence from temperature of reaction rate, allowing accurate prediction on reactor performances for process scale-up. 

B. Cascade release/activation mechanisms initiated by an enzymatic triggering step i. Linear releasing system... 

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