Negative feedback inhibitor

Currie KP, Fox AP (1996) ATP serves as a negative feedback inhibitor of voltage-gated Ca2+ channel currents in cultured bovine adrenal chromaffin cells. Neuron 16 1027-36 Decking UKM, Schlieper G, Kroll K, Schrader J (1997) Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release. Circ Res 81 154-64 De Lorenzo S, Veggetti M, Muchnik S et al (2006) Presynaptic inhibition of spontaneous acetylcholine release mediated by P2Y receptors at the mouse neuromuscular junction. Neuroscience. 142 71-85... 

Metabolized to 6-mercaptopurine ribose phosphate (6MPRP), a false negative feedback inhibitor. Blocks transformation of inosinate to adenylate or guanylate. 

In the mitochondrial matrix, acety-CoA molecules are condensed to produce 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next step, catalyzed by HMG-CoA reductase, is the major flux-controlling step. HMG-CoA reductase is modulated by both reversible phosphorylation and allosteric factors, and the activity of the enzyme even shows a circadian rhythm. The regulating influences are summarized in Fig. 12-11, but the most germane factor is the level of cholesterol itself, which acts as a negative feedback inhibitor. Therefore, cells respond to a lack of cholesterol both by expressing more LDL receptors and by increasing their own synthesis of cholesterol. 

No direct phosphorylation of the enzyme was demonstrated, but ATP inhibited the purified enzyme. However, the physiological significance of control by ATP is doubtful as the maximal effect in vitro was obtained at 1.5mM and the endogenous level of ATP was found to be 2.15pM. CMP also reduced activity and may act as a negative feedback Inhibitor. 

Acetyl-CoA carboxylase from animal tissues requires a hydroxy tricarboxylic acid, such as citrate or isocitrate, for its catalytic activity. Because citrate is a precursor of acetyl-CoA, it functions as a positive feedforward activator. Fatty acyl-CoAs which can be regarded as end products of fatty acid synthesis, act as negative feedback inhibitors. 

Negative feedback inhibitors Active at very low concentrations... 

Cortisol is an important component of the body s response to physical and psychological stress. Nervous signals regarding stress are transmitted to the hypothalamus and the release of CRH is stimulated. The resulting increase in cortisol increases levels of glucose, free fatty acids, and amino acids in the blood, providing the metabolic fuels that enable the individual to cope with the stress. A potent inhibitor of this system is cortisol itself. This hormone exerts a negative-feedback effect on the hypothalamus and the adenohypophysis and inhibits the secretion of CRH and ACTH, respectively. 

Reversible inhibitors are more subtle and act usefully to control the rate of particular enzymes. Often, reversible inhibitors are substrates found at or near the end of a pathway. These compounds act in a negative feedback manner to slow down the activity of an enzyme at or near the beginning of the same pathway. Occasionally, feedback inhibitors may be substrates found within a pathway which is functionally related to the one in which the target enzyme can be found. Furthermore, the products of an enzyme-catalysed reaction are often inhibitory to the enzyme that generated them (Figure 3.2). This is should not be surprising from a structural point of view because the product must fit into the active site of the enzyme and so block the binding of substrate. 

Recent in vitro hybridization studies in the rat have demonstrated that t)rpical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the s)mthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid s)mthesis inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRT) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. 

The delay in onset of anxiolytic and antipanic effects of serotonin reuptake inhibitors and related compounds is still an issue of much speculation. It appears paradoxical that serotonin reuptake inhibitors block serotonin uptake immediately, whereas it takes weeks before their therapeutic effects become apparent. Recently, the idea was advanced that the tentative enhanced serotonin neurotransmission caused by short-term administration of serotonin reuptake inhibitors is offset by negative feedback in the raphe nuclei (Artigas 1993 Blier and de Montigny 1994). The increased level of serotonin in the somatodendritic area, resulting from serotonin uptake inhibition, reduces serotonin neuronal firing through activation of the 5-HTj, autoreceptors. Alterations in the feedback regulation upon repeated administration may... 

Ang II inhibits renin secretion. The inhibition, which results from a direct action of the peptide on the juxtaglomerular cells, forms the basis of a short-loop negative feedback mechanism controlling renin secretion. Interruption of this feedback with inhibitors of the renin-angiotensin system (see below) results in stimulation of renin secretion. 

Inhibition of the renin-angiotensin system with ACE inhibitors or ARBs may be incomplete because the drugs disrupt the negative feedback action of Ang II on renin secretion and thereby increase plasma renin activity. Other antihypertensive drugs, notably hydrochlorothiazide and other diuretics, also increase plasma renin activity. Aliskiren not only decreases baseline plasma renin activity in hypertensive subjects but also eliminates the rise produced by ACE inhibitors, ARBs, and diuretics and thereby results in a greater antihypertensive effect (Figure... 

Fig. 1. Positive (autocatalytic) and negative feedback loops between the activator (A) and inhibitor (I) variable.

The simplest form of regulation of a metabolic pathway is the inhibition of an enzyme by the product of the pathway. In Fig. 9-5, the E, s denote enzymes, A and B are metabolites, and the circled minus sign indicates inhibition. If there were no inhibitor of the enzyme (E,) acting on A, the concentration of B would depend entirely on its rate of synthesis or utilization. If the rate of utilization of B decreased or B was supplied from an outside source, its concentration would rise, perhaps even to toxic levels. However, if B is an inhibitor of the first enzyme, then as its concentration rises, the extent of inhibition will increase and its rate of synthesis will decrease. This effect is called feedback inhibition or negative feedback control it is a concept also used in describing electronic circuits. 

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