Allosteric concept

It was shown, that phosphofructokinase plays an essential role in these oscillations. If PFK s substrate, fructose-6-phosphate (F-6-P), is added to cell-free extracts, the nucleotide concentrations oscillate. On the other hand, after the injection of PFK s product, fructose-1,6-bisphosphate (F-l,6-bP), no oscillations are observed. PFK displays positive co-operativity, being allosterically activated by several metabolites, including one of its products, ADP. Therefore, the allosteric concepts were applied to explain the damped and sustained oscillations observed in experiments with intact cells, by taking into account non-linear feedback in a system held far from equilibrium. 

Rational design, 148-149, 152 Real-time assays, 83, 88 Receptor(s). See also Drug receptors affinity for, 6, 63 allosteric model of, 143 Clark s work, 3 classical model of, 44-45 concept of, 2-4 conformations, 13-14, 13 Of conservation equation for, 76 constitutive activity of, 49-51 coupling of, 27 definition of, 2 desensitization of, 34 efficacy for, 6... 

A basic concept in receptor pharmacology is the idea of orthosteric and allosteric interaction. Orthosteric interaction occurs when two molecules compete for a single binding domain on the receptor. With allosteric interactions two molecules each have their own binding domain on the receptor and the two interact through effects on the protein (conformational change). Tims, with orthosteric interactions only one molecule may occupy the receptor at any one instant whereas with allosteric interactions both molecules can bind to the receptor at the same time. There are implications for... 

Allosteric has come to be used in receptor pharmacology in at least three different senses, making the concept difficult for the beginner at least. The main usages are ... 

Monod, Changeux and Jacob introduced the concept of allosterism. 

Although haemoglobin is not a catalytic protein, it shares important features in common with enzymes, for example ligand binding, allosterism and inhibition . Before continuing, the reader should ensure familiarity with the concepts of allosterism as described in Section 3.2. 

The development of the concept of allosteric inhibition of enzymes began in the early 1950s but, surprisingly, not with studies on enzymes. It was discovered that addition of an amino acid to a culture of bacteria Escherichia colt)... 

Not only does allosteric regnlation have a profound influence on our understanding of biochemical regulation but the concept has considerable biological importance. These two sites within the enzyme, catalytic and allosteric, can evolve independently to provide the most efficient systems for both catalysis and regnlation. 

Non-competitive inhibitors. These inhibitors bind to the enzyme or the enzyme-substrate complex at a site other than the active site. This results in a decrease in the maximum rate of reaction, but the substrate can still bind to the enzyme. An analogous concept is that of allosteric inhibition. The site of binding of an allosteric inhibitor is distinct from the substrate binding site. In this case, the inhibitor is not a steric analog of the substrate and instead binds to the allosteric site (the phenomenon was termed thus by Monod and Jacob). 

A classic paper introducing the concept of allosteric regulation. 

The concept of control of metabolic activity by allosteric enzymes or the control of enzyme activity by ligand-induced conformational changes arose from the study of metabolic pathways and their regulatory enzymes. A good example is the multi-enzymatic sequence catalysing the conversion of L-threonine to L-isoleucine shown in Fig. 5.32. 

Instead of assuming a solid enzyme, in which active center the substrate molecule is bent (the concept of substrate strain), the idea was developed (Koshland 1958,1966) that enzymes can embrace the substrate molecule flexibly in the active center and effect reaction by the formation of specific interactions, the so-called induced jit . This picture is especially appropriate with allosterically activated enzymes or in situations in which part of the enzyme molecule has to turn or move over longer distances to effect catalysis (hinge movement), as for instance with most NAD(P)(H)-dependent enzymes (Stillman, 1999). 

Receptors, like all proteins, are known to spontaneously adopt a variety of conformations, and current concepts of receptor function (e.g., the extended and cubic ternary complex models) are based on the allosteric transitions between multiple conformational states. Some of these conformations are called active because they are able to interact with cellular signal transduction mechanisms (and are the basis of constitutive receptor activity ). If one assumes that different receptor conformations might present different intracellular portions of a... 

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