Inhibition or Activation of Enzyme

From recent widespread consumption of diets rich in anthocyanin and cate-chin, the evaluation of their in vitro inhibitory effects on two cyclooxygenase 

The activation of caspase-3 assessed by the cleavage of poly ADP-ribose polymerase (PARP), a caspase-3 substrate, was confirmed in flavone-treated cells. Ac-DEVD-FMK (an inhibitory peptide for caspase-3), but not Ac-YVAD- 

COLO205-X with appearance of DNA ladders, caspase-3 activation, and an increase in p21 (not p53) protein. The results indicate that these flavones might effectively induce apoptosis in colorectal carcinoma cells in vitro and in vivo (Fig. 17) [39]. 

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Enzyme inhibitors and activators may be detemoined by employing enzyme reactions. The easiest technique is to measure the decrease or increase in the rate of the enzymatic reaction. Or the enzyme may be titrated with an inhibitor (or vice versa), and the amount of inhibitor required to completely inhibit the reaction measured. Trace elements, for example, have been determined by their inhibition or activation of enzyme reactions. 

Several families of drugs do not act on receptors and their therapeutic properties are attributed to inhibition or activation of enzyme activities. A number of drugs in... 

Covalent modification Inhibition or activation of enzyme depends on formation or breaking of a bond, frequently by phosphorylation or dephosphorylation. (Responds rapidly to external stimuli.) Sodium-potassium pump (Section 8.6) Glycogen phosphorylase, glycogen synthase (Section 18.1)... 

A marked interference with heme synthesis results in a reduction of the hemoglobin concentration in blood. Decreased hemoglobin production, coupled with an increase in erythrocyte destruction, results in a hypochromic, normocytic anemia with associated reticulocytosis. Decreased hemoglobin and anemia have been observed in lead workers and in children with prolonged exposure at higher PbB levels than those noted as threshold levels for inhibition or stimulation of enzyme activities involved in heme synthesis (EPA 1986a). 

The topic of interconversion cycles in providing inhibition or activation of a target enzyme, the activity of which regulates the flux through a pathway, is discussed above. In brief, an enzyme exists in two forms, conventionally designated a and b, one being a covalent modification of the other. This is brought about, for example, by phosphorylation with ATP, so that one form is a phos-... 

G-protein in the cytoplasm to an intracellular binding domain of the receptor molecule. This may either result in the opening or closing of an ion channel or the inhibition or activation of an enzyme. 

Hundreds of metabolic reactions take place simultaneously in cells. There are branched and parallel pathways, and a single biochemical may participate in severm distinct reactions. Through mass action, concentration changes caused by one reaction may effect the kinetics and equilibrium concentrations of another. In order to prevent accumulation of too much of a biochemical, the product or an intermediate in the pathway may slow the production of an enzyme or may inhibit the activation of enzymes regulating the pathway. This is termed feedback control and is shown in Fig. 24-1. More complicated examples are known where two biochemicals act in concert to inhibit an enzyme. As accumulation of excessive amounts of a certain biochemical may be the key to economic success, creating mutant cultures with defective metabolic controls has great value to the production of a given product. 

The impact of plant products on the metabolism of synthetic dmgs results from the inhibition or activation of cytochrome P-450 (CYP) enzymes. Evaluation of the potential activation of CYP by administration of natural plant products or dietary supplements is important for prediction of interactions between their components and dmgs. Therefore, attention is directed to research on the impact of products available on the food market known as natural non-nutritive substances on dmg absorption. Non-nutritive dietary components are mainly secondary plant metabolites, which include, among others, phenolic compounds such as phenolic acids and flavonoids. The health effects of non-nutritive substances are not yet known. So far, there is no answer on the extent to which they are absorbed and metabolized by the body, and there is no information on the permitted daily intake for these compounds. This information is particularly important because certain non-nutritive natural substances are simultaneously considered to be anti-nutritional factors, mainly because they inhibit digestion and reduce the bioavailability of nutrients or dmgs. It is also possible that they form undesirable interactions with dmgs. The positive health effects of non-nutritive natural substances are not only attributed to their antioxidant properties. These substances are involved in various metabolic... 

Cholinesterases also have a peripheral, allosteric site that can reversibly bind substrates and other ligands. This site has no catalytic activity. However, binding of a ligand to the site can cause either inhibition or activation of the enzyme. 

Allosteric Effectors (substrates, products, or coenzymes) of a pathway inhibit or activate an enzyme. (Responds rapidly to external stimuli.) ATCase (Section 7.2) Phosphofructokinase (Section 17.2)... 

Amphetamine and related substances show symphaticomimetic and CNS stimulant activity. Amphetamines are indirect monoamine agonists and interact with the membrane transporters involved in neurotransmitter reuptake and vesicular storage systems. Therefore, they stimulate the release of norepinephrine, dopamine, and serotonin from presynaptic terminals in the CNS and at the peripheral level (De La Torre et al., 2004). Methamphetamine and the methylenedioxy derivatives (MDA, MDMA, MDEA, MBDB) can inhibit the activity of enzymes of dopamine or serotonin biosynthesis (De La Torre et al., 2004). 

An allosteric inhibitor or activator inhibits or activates an enzyme by binding to a site on the enzyme other than the active site, which affects the function of the active site. 

In general, a compound may affect lysosomes in vitro (1) by changing the permeability of their membranes, or (2) by inhibiting or activating their enzymes. 

Although most anesthetics are achiral or are adininistered as racemic mixture, the anesthetic actions are stereoselective. This property can define a specific, rather than a nonspecific, site of action. Stereoselectivity is observed for such barbiturates as thiopental, pentobarbital, and secobarbital. The (3)-enantiomer is modestly more potent (56,57). Additionally, the volatile anesthetic isoflurane also shows stereoselectivity. The (3)-enantiomer is the more active (58). Further evidence that proteins might serve as appropriate targets for general anesthetics come from observations that anesthetics inhibit the activity of the enzyme luciferase. The potencies parallel the anesthetic activities closely (59,60). 

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

Inhibitors of the catalytic activities of enzymes provide both pharmacologic agents and research tools for study of the mechanism of enzyme action. Inhibitors can be classified based upon their site of action on the enzyme, on whether or not they chemically modify the enzyme, or on the kinetic parameters they influence. KineticaUy, we distinguish two classes of inhibitors based upon whether raising the substrate concentration does or does not overcome the inhibition. 

Polyphenols and flavanoids in rat liver microsomal fractions have been demonstrated to inhibit glucuronidation of estrone and estradiol in vitro (Zhu et al, 1998). In addition, flavonoids have also been found to induce phase I and II enzymes in rats including UDP-glucuronosyl transferase (Seiss et al, 1996). However, the effects of phytoestrogens have not been evaluated for either their inhibition or induction of glucuronosyl transferase activity. 

The mechanism of action proposed is based on a direct binding to the channel and the following partial block of the ATP-binding pocket of CFTR (French et al., 1997), a mechanism similar to that used by genistein to inhibit the activity of other ATP-utilizing enzymes such as protein kinases and topoisomerase II (Polkowski and Mazurek, 2000 and refs therein). The selection of flavonoid compounds or the development of synthetic drugs reasonably selective for CFTR activation might be an area for future clinical trials. 

Addition of rice bran to the mixture of wheat bran and rice husk was the best substrates for the fungal pectinase production. The solid substrates that composed of wheat bran, rice bran and rice husk at the ratio of 6 12 2 was selected to be the best since rice bran are easily found in South-east Asian countries. Addition of either raw cassava starch or pectin as inducer is not needed. On the otherhand, pectin even inhibited the activity of the enzyme as well as that reported by Elegado and Fujio (6). 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

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