Enzyme inhibitors Cumulative

Cumulative Feedback Inhibition In cumulative feedback inhibition, the end products can inhibit the reaction of the target enzyme separately. Many textbooks erroneously indicate that the cumulative feedback inhibition of E. coli glutamine synthetase involves separate regulatory sites for each feedback inhibitor. See Cumulative Feedback Inhibition... 

Additive Feedback Inhibition This term is restricted to cases in which the end product inhibitors bind to the target enzyme in a mutually exclusive manner and the degrees of inhibition are additive. Extreme care should be exercised when using this term in most cases, the inhibition is really cumulative feedback inhibition. 

Molecules with structures as diverse as carbamoyl-phosphate, tryptophan, and cytidine triphosphate are feedback inhibitors of the E. coli glutamine synthase. The feedback inhibition is cumulative, with each metabolite exerting a partial inhibition on the enzyme. Why would complete inhibition of the glutamine synthase by a single metabolite be metaboli-cally unsound ... 

The substrate concentration required for half-maximal activity (S0 0 of an allosterically regulated enzyme will depend on the cumulative effects of allosteric activators and/or inhibitors also present. Hence S,)5 may be decreased with allosteric activators and may be increased with allosteric inhibitors. 

An example of absolutely cumulative toxicity is afforded by tri-o-cresyl phosphate or TOCP (figure 2,9). This compound is a cholinesterase inhibitor and neurotoxin. In chickens, an acute dose of 30 mg/kg has a severe toxic effect, which is produced to the same extent by a dose of 1 (mg/kg)/day given for 30 days. This effect may of course be produced by accumulation of the compound in vivo to a threshold toxic level, or it may result from the accumulation of the effect, as it probably does in the case of TOCP. Thus, the inhibition of cholinesterase enzymes by organophosphorus compounds may... 

Cumulative feedback Inhibition - Eight specific feedback inhibitors, which are either metabolic end products of glutamine (tryptophan, histidine, glucosamine-6-phosphate, carbamoyl phosphate, CTP, or AMP) or indicators of the general status of amino acid metabolism (alanine or glycine), can bind to any of the subunits of the enzyme and at least partially inhibit it. The more inhibitors that bind, the greater the inhibition. 

The parameter Ka,s is the dissociation constant for the complex of enzyme a and the effector T or F, labeled s, while ra,s is the ratio of the catalytic rate constants for the enzyme with and without effector bound, respectively. This general form models both activators and inhibitors of the enzyme, depending on whether r is greater than or less than 1. The response described is hyperbolic, with the half-maximum effect exerted when e = K, and saturating at the maximum effect r for very high effector concentrations. The cumulative multiplication of modifying factors reflects the assumption that all effectors function at different sites on the enzyme and that the sites do not communicate. 

When the pattern of primary interaction between toxicant molecules and affected receptors is examined, another primary cumulative effect can be distinguished (in addition to the two mentioned). The third is a mixed type of accumulation in which the radicals of the toxicant are fixed at the receptor site (i.e., reactions involving acylation of new molecules). In this mixed type, particles of material attach to the receptor, but the parent substance is destroyed and therefore incapable of accumulation. This type includes the interaction of organ-ophosphates and carbamates with esterases. The phosphorylation and carbamy-lation of the latter yield an acylated enzyme with a split inhibitor. Only a part of the parent molecule of a substance is the phosphoryl and carbamyl groups remains at the enzyme site. 

A variety of patterns of end-product inhibition have been described [5,69] (1) In enzyme multiplicity inhibition balanced control of an early enzyme of the common part of a branched pathway is obtained because the enzyme is present in the form of several isoenzymes, each specifically inhibited by an end product of one of the branches. (2) In cumulative feedback inhibition an enzyme which mediates the formation of a product used in many pathways is partly inhibited by individual end products of the pathways. Each inhibitor adds its effect to the total inhibition, but the combined effect is less than the sum of the single inhibitions. (3) In concerted feedback inhibition two or more end products are required to act together before any significant inhibition is exhibited. (4) In cooperative feedback inhibition several end products can act as partial inhibitors of an enzyme, but a mixture of two different inhibitors results in greater inhibition than the sum of the individual inhibitions. (5) The term sequential feedback inhibition refers to inhibition of an early enzyme by an intermediate whose accumulation is controlled by inhibition of one or more late pathway enzymes by the end product [71 ]. 

In a third example case, p-carbolines are inhibitors of monoamine oxidases (MAO-A and MAO-B) and can be found in foods, hallucinogenic plants or certain plant dmgs. The referred article described a fast analysis method for p-carbolines based on the inhibition of MAO [79]. The MAO-A is inhibited by all three tested P-carbolines (harmane, norharmane and harmaline), while MAO-B is inhibited only by norharmane. The presence of norharmane in mixtures of p-carbolines can be identified based on the difference between the cumulative inhibition of MAO-A by all p-carbolines and MAO-B inhibition. The enzymes were immobilized on screen-printed electrodes modified with a stabilized film of Pmssian blue that contain also copper. Benzylamine was used as substrate for the enzymatic reaction and the hydrogen peroxide formed was measured amperometrically at —50 mV. The developed biosensors were used for food analysis. The detection limits obtained were 5.0 pM for harmane and 2.5 pM for both harmaline and norharmane. 

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