Allosteric modifiers

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

As discussed in Chapter 7, antagonists may bind to a separate loci on the receptor and thereby allosterically modify the affinity of the receptor for the agonist. The maximal change in the agonist affinity is denoted by a term a. It is useful to distinguish allosteric effects in terms of whether the modulator affects signaling and affinity or just affinity. In the latter situation, the modulator produces parallel shifts to the right of the concentration response curve up to a maximal point. This is discussed in Section 7.4.1 (t, = 1). Under these circumstances, the curve for... 

Muscle phosphorylase is distinct from that of Hver. It is a dimer, each monomer containing 1 mol of pyridoxal phosphate (vitamin Bg). It is present in two forms phos-phoiylase a, which is phosphorylated and active in either the presence or absence of 5 -AMP (its allosteric modifier) and phosphorylase h, which is dephosphorylated and active only in the presence of 5 -AMP. This occurs during exercise when the level of 5 -AMP rises, providing, by this mechanism, fuel for the muscle. Phosphorylase a is the normal physiologically active form of the enzyme. 

Lipogenesis is regulated at the acetyl-CoA carboxylase step by allosteric modifiers, phosphorylation/de-phosphorylation, and induction and repression of enzyme synthesis. Citrate activates the enzyme, and long-chain acyl-CoA inhibits its activity. Insulin activates acetyl-CoA carboxylase whereas glucagon and epinephrine have opposite actions. 

Miyake M, Grinberg OY, Hou H, et al. The effect of RSRl3, a synthetic allosteric modifier of hemoglobin, on brain tissue p02 (measured by EPR oximetry) following severe hemorrhagic shock in rats. Adv Exp Med Biol 2003 530 319. 

Mehanna, A.S. Abraham, D.J. Comparison of crystal and solution hemoglobin binding of selected antigelling agents and allosteric modifiers. Biochemistry 1990, 29, 3944-3952. 

Allosteric modifiers ofhemoglobin 2-[4-[[(3,5-disubstituted anilino)-carbonyl]methyl]phenoxy]-2-methylpropionic acid derivatives that lower the oxygen affinity ofhemoglobin... 

Kilgore, K.S., Shwartz, C.F., Gallagher, M.A., Steffen, R.P., Mosca, R.S., and Bolling, S.F. RSR13, a synthetic allosteric modifier of hemoglobin, improves myocardial recovery following hypothermic cardiopulmonary bypass. Circulation 1999, 100, 11351-11356. 

A. Analeptic stimulants, such as pentylenetetrazol and picrotoxin, act by inhibiting chloride influx at the GABAa receptor-chloride channel complex. This antagonism can occur through interaction with one of several binding sites or allosteric modifiers of receptor-channel function. 

Binding of allosteric modifiers, especially protons (the Bohr effect), organic phosphate (particularly diphosphoglycerate), and carbon dioxide. 

ENZYME INHIBITORS are important in medicinal chemistry, pharmacology and therapeutics for a number of reasons. Mechanistically, they may act in a number of different ways, mainly as competitive antagonists or allosteric modifiers, and sometimes as irreversible antagonists. Many important enzyme inhibitors are within drug classes vital to everyday therapeutics. Most of the important classes are discussed in more detail elsewhere. 

The fact that the allosterically preferred conformation may be relatively rare in the library of conformations available to the receptor may have kinetic implications. Specifically, if the binding site for the modulator appears only when the preferred conformation is formed spontaneously, then complete conversion to allosterically modified receptor may require a relatively long period of equilibration. For example, the allosteric p38 MAP kinase inhibitor BIRB 796 binds to a conformation of MAP kinase requiring movement of a Phe residue by 10 angstroms (so-called out conformation). The association rate for this modulator is 8.5 x 105 M 1 s 50 times slower than that required for other inhibitors (4.3 x 107 M 1 s ). The result is that while other inhibitors reach equilibrium within 30 minutes, BIRB 376 requires 2 full hours of equilibration time [10],... 

Texture in antagonism where allosterically modified receptors may have different conformations from each other may lead to differences in resistance profiles with chronic treatment. 

Cytoplasmic generation of acetyl-CoA via citrate transport and related reactions. PPP = Pentose phosphate pathway FAS = fatty acid synthase. — -> Negative allosteric modifier. — -> Positive allosteric modifier. 

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