Metabolic regulation feedback inhibition

Feedback control. The binding of metaboUtes, i.e. substrates/products or effectors to enzymes is an important mode of regulation. Feedback inhibition (negative feedback control) is an important example, in which the first committed step in a biosynthetic pathway is inhibited by the ultimate end product of the pathway (Stadtman, 1966). Table 11.14 summarizes different modes of negative feedback controls that have been evolved to accommodate the regulation of divergent metabolic pathways. 

Fig. 3-18. Regulation of galactose metabolism, a Feedback inhibited by UDPN acetylglucosamine b Feedback inhibited by UDP-xylose...

In die metabolic pathway to an amino add several steps are involved. Each step is die result of an enzymatic activity. The key enzymatic activity (usually die first enzyme in the synthesis) is regulated by one of its products (usually die end product, eg die amino add). If die concentration of die amino add is too high die enzymatic activity is decreased by interaction of die inhibitor with the regulatory site of die enzyme (allosteric enzyme). This phenomenon is called feedback inhibition. 

Aiming at a computer-based description of cellular metabolism, we briefly summarize some characteristic rate equations associated with competitive and allosteric regulation. Starting with irreversible Michaelis Menten kinetics, the most common types of feedback inhibition are depicted in Fig. 9. Allowing all possible associations between the enzyme and the inhibitor shown in Fig. 9, the total enzyme concentration Er can be expressed as... 

Metabolism is tightly regulated by a number of mechanisms feedback inhibition, compartmentalization, covalent modification of enzymes (e.g., phosphorylation), and hormone action, among others. 

Finally, the activity of key enzymes can be regulated by ligands (substrates, products, coenzymes, or other effectors), which as allosteric effectors do not bind at the active center itself, but at another site in the enzyme, thereby modulating enzyme activity (6 see p. 116). Key enzymes are often inhibited by immediate reaction products, by end products of the reaction chain concerned feedback inhibition), or by metabolites from completely different metabolic pathways. The precursors for a reaction chain can stimulate their own utilization through enzyme activation. 

A form of regulation in a metabolic pathway in which an end product (or even an intermediate in the pathway) binds to and inhibits an enzyme which catalyzes an earlier reaction in that same pathway. For example, consider the metabolic scheme A B C Din which the steps are respectively catalyzed by the enzymes Ei, E2, and E3. Feedback inhibition would be seen when elevated concentrations of D (or C) inhibited Ei. 

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. 

Fig. 2 Metabolic pathways in C. glutamicum for biosynthesis of the aromatic amino acids tryptophan, tyrosine, and phenylalanine (a) and amino acids belonging to the aspartate family including lysine, methionine, threonine, and isoleucine (b). Metabolic regulation by feedback inhibition is indicated by dotted lines...

Alkaloid metabolism in lupine was proved by Wink and Hartmann to be associated with chloroplasts (34). A series of enzymes involved in the biosynthesis of lupine alkaloids were localized in chloroplasts isolated from leaves of Lupinus polyphylls and seedlings of L. albus by differential centrifugation. They proposed a pathway for the biosynthesis of lupanine via conversion of exogenous 17-oxosparteine to lupanine with intact chloroplasts. The biosynthetic pathway of lupinine was also studied by Wink and Hartmann (35). Two enzymes involved in the biosynthesis of alkaloids, namely, lysine decarboxylase and 17-oxosparteine synthetase, were found in the chloroplast stoma. The activities of the two enzymes were as low as one-thousandth that of diaminopimelate decarboxylase, an enzyme involved in the biosynthetic pathway from lysine to diaminopimelate. It was suggested that these differences are not caused by substrate availability (e,g., lysine concentration) as a critical factor in the synthesis of alkaloids. Feedback inhibition would play a major role in the regulation of amino acid biosynthesis but not in the control of alkaloid formation. 

The flux through a metabolic pathway is invariably controlled or regulated, most commonly by Feedback Inhibition, but also through Feed-forward activation. Regulation is one of the things that makes biochemistry "biological" and it will be a focus in our study. 

There are many examples of competitive inhibition by compounds that bear no structural relationship to the substrate. The inhibitor is generally an end product or near end product of a metabolic pathway the enzyme is one that catalyzes an early reaction (or a branch-point reaction) in the pathway. The phenomenon is called feedback inhibition. The inhibitor (effector, modulator, or regulator) combines with the enzyme at a position other than the active (substrate) site. The combination of the inhibitor with the enzyme causes a change in the conformation (tertiary or quaternary structure) of the enzyme that distorts the substrate site and thereby prevents the substrate from binding (Model 5). 

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