Metabolic regulation allosteric enzymes

Metabolic regulation is achieved via regulating enzyme activity in three prominent ways allosteric regulation, covalent modi-... 

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. 

Most enzyme inhibitors act reversibly—i. e., they do not cause any permanent changes in the enzyme. However, there are also irreversible inhibitors that permanently modify the target enzyme. The mechanism of action of an inhibitor—its inhibition type—can be determined by comparing the kinetics (see p.92) of the inhibited and uninhibited reactions (B). This makes it possible to distinguish competitive inhibitors (left) from noncompetitive inhibitors (right), for example. Allosteric inhibition is particularly important for metabolic regulation (see below). 

Inhibition of the initial step of a biosynthetic pathway by an end product of the pathway is a recurrent theme in metabolic regulation. In addition, many key enzymes are regulated by ATP, adenosine diphosphate (ADP), AMP, or inorganic phosphate ion (Pi). The concentrations of these materials provide a cell with an index of whether energy is abundant or in short supply. Because ATP, ADP, AMP, or P often are chemically unrelated to the substrate of the enzyme that must be regulated, they usually bind to an allosteric site rather than to the active site. 

The theoretical analysis of the metabolic fate of PAC or xenobiotics in general demands a systems approach since individual components of the metabolic networks are closely linked via common substrates or cofactors as well as allosteric enzyme regulation [40, 41]. As shown in a later section, drug catabolites especially affect cell physiology and thereby greatly impinge on cellular drug action. 

Allosteric Effectors. Many enzymes are subject to metabolic regulation through interaction with metabolites that often act at allosteric sites, which are distinct from the active site. The kinetic behavior of such enzymes is often more complex than the behavior we have discussed above, and such complex kinetics may serve as an indication that you are dealing with an allosteric enzyme. Further discussion of this subject is found in Experiments 9 and 15. 

Study of the Phosphoryl Group Transfer Cascade Governing Glucose Metabolism Allosteric and Covalent Regulation of Enzyme Activity... 

In addition to regulating the direction of metabolic pathways, cells, especially those in multicellular organisms, also exert control at three different levels allosteric enzymes, hormones, and enzyme concentration. 

Competitive product inhibition and allosteric regulation (fastest). Many enzymes are inhibited by either their products, or by other chemicals, often those from further down a metabolic pathway. Such enzymes may be gatekeepers to a specific branch of metabolism, and they usually catalyse a true equilibrium reaction, j.e., one that doesn t go to completion (note this is not exactly the same reaction in the forward and backwards directions, so we are not defying the law that states enzymes do not alter the equilibrium point). 

Aside from the inordinately dominant light of molecular genetics, the new wave in biochemistry today is, what has come to be called, metabolic control analysis (MCA) (Comish-Bowden and Cardenas, 1990). The impetus behind this wave is the desire to achieve a holistic view of the control of metabolic systems, with emphasis on the notion of system. The classical, singular focus on individual, feedback-modulated (e.g., allosteric), rate-limiting enzymes entails a naive and myopic view of metabolic regulation. It has become increasingly evident that control of metabolic pathways is distributive, rather than localized to one reaction. MCA places a given enzyme reaction into the kinetic context of the network of substrate-product connections, effector relationships, etc., as supposedly exist in situ, it shows that control of fluxes, metabolite concentrations, inter alia, is a systemic function and not an inherent property of individual enzymes. Such... 

The inhibition of certain enzymes by specific metabolites is an important element in the regulation of intermediary metabolism and most often occurs with cooperative enzymes that are regulated allosterically. Inhibition of enzymes that obey the Michaelis-Menten equation, noncooperative enzymes, is more commonly used by pharmacists to alter a patient s metabolism. Reversible inhibition of noncooperative enzymes is classified into three groups which can be distinguished kinetically and which have different mechanisms and effects when administered. The classes are called competitive, uncompetitive, and noncompetitive inhibition. Mixed inhibition also occurs. In all these types of inhibition, the inhibitor (usually a small molecule) binds reversibly and rapidly with the enzyme. 

There is some confusion in the literature about the use of the term "allosteric" for an enzyme. Many authors restrict this term to multi-subunit enzymes that show substrate cooperativity and sigmoidal kinetics. Other authors, however, are less specific and their definitions include enzymes that follow Michaelis- Menten kinetics and have non- or uncompetitive inhibitors. Fortunately, in metabolism, regulated enzymes are generally multi-subunit, cooperative, enzymes and fall into the more specific use of the term. 

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