Metabolic control allosterism

The metabolic control is exercised on certain key regulatory enzymes of a pathway called allosteric enzymes. These are enzymes whose catalytic activity is modulated through non-covalent binding of a specific metabolite at a site on the protein other than the catalytic site. Such enzymes may be allosterically inhibited by ATP or allosterically activated by ATP (some by ADP and/or AMP). 

ALLOSTERIC HORMONAL MECHANISMS ARE IMPORTANT IN THE METABOLIC CONTROL OF ENZYME-CATALYZED REACTIONS... 

The symmetry model is useful even if it does oversimplify the situation, because it provides a conceptual framework for discussing the relationships between conformational transitions and the effects of allosteric activators and inhibitors. In the following sections we consider three oligomeric enzymes that are under metabolic control and see that substrates and allosteric effectors do tend to stabilize each of these enzymes in one or the other of two distinctly different conformations. 

Many aspects of metabolic control are not readily apparent when isolated enzymes are characterized in vitro. The regulatory function of allosteric properties and putative enzyme complexes are best studied in vivo. For this purpose, metabolic engineering can be used as a basic research tool to investigate the effect of specific perturbations on the overall flux through an alkaloid pathway. The first application of metabolic engineering to plant alkaloid biosynthesis involved the transformation... 

Enzyme activity can be regulated by covalent modification or by noncovalent (allosteric) modification. A few enzymes can undergo both forms of modification (e.g., glycogen phosphorylase and glutamine synthetase). Some covalent chemical modifications are phosphorylation and dephosphorylation, acetylation and deacetylation, adeny-lylation and deadenylylation, uridylylation and deuridyly-lation, and methylation and demethylation. In mammalian systems, phosphorylation and dephosphorylation are most commonly used as means of metabolic control. Phosphorylation is catalyzed by protein kinases and occurs at specific seryl (or threonyl) residues and occasionally at tyrosyl residues these amino acid residues are not usually part of the catalytic site of the enzyme. Dephosphorylation is accomplished by phosphoprotein phosphatases ... 

A pair of reactions such as the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate and its hydrolysis back to fructose 6-phosphate is called a substrate cycle. As already mentioned, both reactions are not simultaneously fully active in most cells, because of reciprocal allosteric controls. However, isotope-labeling studies have shown that some fructose 6-phosphate is phosphorylated to fructose 1,6-bisphosphate even during gluconeogenesis. There also is a limited degree of cycling in other pairs of opposed irreversible reactions. This cycling was regarded as an imperfection in metabolic control, and so substrate cycles have sometimes been called... 

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 cell achieves its efficiency, stability, and responsiveness through the use of metabolic pathways. A metabolic pathway is a sequence of enzyme-catalyzed reactions in which the product of one reaction is the substrate for the next. Usually, a pathway ends with the production of a particular product, such as an amino acid needed for protein synthesis. A particular starting material, such as glucose, may be used for a variety of purposes. In this case, the metabolic pathways have an initial section that is common to each purpose eventually, each pathway splits off into its own section. At this point, a key enzyme controls the flow of substrate into the specific section of the pathway. This enzyme is controlled allosterically, typically by a product of the pathway, in a negative feedback loop, as described below. This first step on a unique pathway is called the committed step or committed reaction. 

The NNRTIs all bind to the same hydrophobic pocket on the enzyme and moderate the activity of RT through inhibition of a neighboring (allosteric) site that serves as a metabolic controlling unit to... 

The overall control of lipogenesis has been reviewed by Saggerson (1980). So far as saturated fatty acid synthesis is concerned the activity of both acetyl-CoA carboxylase and fatty acid synthetase can be altered in various ways (Section 11.1.1). Short term or acute control involves metabolic or allosteric regulation and the covalent modification of enzymes. Long-term control involves alterations in the amounts of enzyme protein (Wakil et al, 1983). 

The fundamental communication involved in almost all metabolic control is that between a small molecule and a protein, usually an enzyme. The small molecule may be the substrate, cofactor, product, or an allosteric activator or inhibitor of the enzyme. 

If the kinetics of the reaction disobey the Michaelis-Menten equation, the violation is revealed by a departure from linearity in these straight-line graphs. We shall see in the next chapter that such deviations from linearity are characteristic of the kinetics of regulatory enzymes known as allosteric enzymes. Such regulatory enzymes are very important in the overall control of metabolic pathways. 

Regulatory Control of Fatty Acid Metabolism—An Interplay of Allosteric Modifiers and Phosphorylation-Dephosphorylation Cycles... 

Nitrogen is normally supplied as an ammonium compound in dtric acid fermentations and suffident has to be supplied to enable the effect of manganese deficiency (increased levels of ammonium in the metabolic pool) to occur. Remember that increased metabolic pool ammonium has the effect of releasing the allosteric controls exerted on phosphofructokinase. 

The principal enzymes controlling glycogen metabolism—glycogen phosphorylase and glycogen synthase— are regulated by allosteric mechanisms and covalent modifications due to reversible phosphorylation and... 

Allosteric enzymes show various activation and inhibition effects which are competitive in nature and related to conformational changes in the structure of the enzyme. Such allosteric enzymes are often crucial enzymes in metabolic pathways and exert control over the whole sequence of reactions. The name allostery refers to the fact that inhibition of the enzyme is by substances that are not similar in shape to the substrate. 

There are many examples of phosphorylation/dephosphorylation control of enzymes found in carbohydrate, fat and amino acid metabolism and most are ultimately under the control of a hormone induced second messenger usually, cytosolic cyclic AMP (cAMP). PDH is one of the relatively few mitochondrial enzymes to show covalent modification control, but PDH kinase and PDH phosphatase are controlled primarily by allosteric effects of NADH, acetyl-CoA and calcium ions rather than cAMP (see Table 6.6). 

The third type of inhibition is called allosteric inhibition, and is particularly important in the control of intermediary metabolism This refers to the ability of enzymes to change their shape (tertiary and quaternary structure, see Section 13.3) when exposed to certain molecules. This sometimes leads to inhibition, whereas in other cases it may actually activate the enzyme. The process allows subtle control of enzyme activity according to an organism s demands. Further consideration of this complex phenomenon is outside our immediate needs. 

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