Inhibition allosteric stimulation

The production of acetyl-CoA for the citric acid cycle by the PDH complex is inhibited allosterically by metabolites that signal a sufficiency of metabolic energy (ATP, acetyl-CoA, NADH, and fatty acids) and stimulated by metabolites that indicate a reduced energy supply (AMP, NAD+, CoA). 

Isocitrate dehydrogenase is allosterically stimulated by ADP, which enhances the enzyme s affinity for substrates. The binding of isocitrate, NAD+, Mg2+, and ADP is mutually cooperative. In contrast, NADH inhibits iso-citrate dehydrogenase by directly displacing NAD+. ATP, too, is inhibitory. It is important to note that several steps in the cycle require NAD+ or FAD, which are abundant only when the energy charge is low. 

Although the pathway is reasonably straightforward, it is subjected to a complex mechanism of inhibiting and stimulating factors. Some of the enzymes involved are allosterically stimulated by products of the pathway (such as pyruvate Idnase [PK] by fructose diphosphate), while others may serve as strong inhibitors (such as glucose 6-phosphate for hexo-kinase [HK]). 

Table 7. Allosteric stimulation (-I-) or inhibition (-) of ribonucleotide reductase from Escherichia...

Many plant proteins are of limited nutritional value because of their low content of methionine, which is one of the first essential amino acids to become inadequate in the human diet (Allaway and Thompson, 1966). In spite of the uncertainties of the regulatory scheme shown in Fig. 6, it should provide a useful working model for a rational approach to increasing the methionine content of plants. For example, if the scheme is correct, an overproduction of methionine should result from inhibition of the conversion of methionine to AdoMet, and/or from reducing the allosteric stimulation of... 

In the case of allosteric substances that inhibit or stimulate activity are not bound to the substrate binding site but at another site— hence the name. If the allosteric binding site is occupied by a stimulating or inhibitory substance, changes in the configuration of the enzyme protein are induced, which, in turn, lead to an increase or an inhibition of enzymatic activity. Allosteric inhibition has been investigated most thoroughly. The inhibitory substances are, in this case, end products of synthetic pathways. For this reason the term end product inhibition is used, which must not be confused with end product repression, which we have already discussed. An end product of this kind often inhibits only the first enzyme of the pathway specific for its synthesis (Fig. 155). 

The hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate (Eigure 23.7), like all phosphate ester hydrolyses, is a thermodynamically favorable (exergonic) reaction under standard-state conditions (AG° = —16.7 kj/mol). Under physiological conditions in the liver, the reaction is also exergonic (AG = —8.6 kJ/mol). Fructose-1,6-bisphosphatase is an allosterically regulated enzyme. Citrate stimulates bisphosphatase activity, hut fructose-2,6-bisphosphate is a potent allosteric inhibitor. / MP also inhibits the bisphosphatase the inhibition by / MP is enhanced by fructose-2,6-bisphosphate. 

A feature of Equation 10.6 is the fact that there are conditions where the binding will not diminish to basal levels in the presence of maximal concentrations of allosteric modulator. This effect is exacerbated by high levels of initial stimulation (as [A]/Ka oo). The maximal inhibition by an allosteric modulator for Equation 10.6 is... 

Within glycolysis, the main allosteric control is exercised by phosphofructokinase, a complicated enzyme unusual in that its activity is stimulated by one of its products (ADP) and inhibited by one of its substrates (ATP). One further point about this enzyme which will be important to us later, in Aspergillus spp., elevated levels of ammonium ions relieve phosphofructokinase of inhibition by titrate. 

Fructose 2,6-bisphosphate is formed by phosphorylation of fructose 6-phosphate by phosphofructoki-nase-2. The same enzyme protein is also responsible for its breakdown, since it has fructose-2,6-hisphos-phatase activity. This hifrmctional enzyme is under the allosteric control of fructose 6-phosphate, which stimulates the kinase and inhibits the phosphatase. Hence, when glucose is abundant, the concentration of fructose 2,6-bisphosphate increases, stimulating glycolysis by activating phosphofructokinase-1 and inhibiting... 

The type of interaction of verapamil (solid bar) in the presence of one of the other compounds is indicated Cooperative stimulation (hatched bars) allosteric noncompetitive inhibition (cross-hatched bars) and competitive inhibition (gray bars). (Adapted from Ref. [57].)... 

Regulation of the balance of the concentrations of the four deoxyribonucleotides depends on the properties of only two enzymes, the ribonucleotide reductase complex and deoxy-CMP deaminase. The balance between pyrimidine deoxynucleotides is brought about by the properties of the deoxy-CMP deaminase, which is inhibited by deoxy-TTP and stimulated by deoxy-CTP. The ribonucleotide reductase also possesses allosteric sites which bind all four deoxynucleotide triphosphates, the effect of which is to maintain approximately similar concentrations of all the triphosphates. 

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. 

Fructose 2,6-bisphosphate (Fru-2,6-bP) plays an important part in carbohydrate metabolism. This metabolite is formed in small quantities from fructose 6-phosphate and has purely regulatory functions. It stimulates glycolysis by allosteric activation of phosphofructokinase and inhibits gluconeogenesis by inhibition of fructose 1,6-bisphosphatase. 

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. 

---