Other Regulatory Phenomena

The H -ion concentration has myriad functions within the cell. It acts, for example, as a substrate or product of dehydrogenases and as a factor affecting the ionization of groups which comprise the active site or stabilize its conformation. Substrate ionization may also be responsive to changes in A discussion of the manner in which one may analyze the effect of pH on both the apparent Km and the apparent I max is available in Dixon and Webb (1964). Recently, Knowles (1976) has evaluated the nature of the experiments that have hitherto been used to assess the relationship of pH optima to putative sites involved in the catalytic activity of a particular enzyme. His review defines limits to overambitious interpretations and extrapolations regarding participation of particular groups in the reaction mechanism. 

Intracellular pH has been measured by several methods. Data obtained for mammalian liver indicate that intracellular pH approxi- 

It is unlikely that under normal conditions, temperature will exercise any role in modulating enzymic activity. However, temperature effects on enzymes may achieve some importance in poikilothermic species and possibly also during the decrease in body temperature that occurs during hibernation. More importantly temperature may have been an important factor in determining the nature of binding interactions for specific enzymes which have evolved under different thermal environments, a fascinating possibility which has been elaborated by Somero and Low (1976). 

Divalent cations, univalent cations, or both are essential cofactors for a large number of enzymes. Kinases as a class, for example, share the requirement for such cations, while in other instances, other metal ions are inhibitors of metal-activated enzymes, e.g., activation by Mg and inhibition by Ca for many kinases and synthetases. Mildvan (1970) has reviewed the models that have been proposed to account for activation (or inhibition) of enzymes by metal ions. The substrate bridge and metal bridge models conceive of the metal ions either combining with the substrate to form a chelate or interacting with the enzyme to complete the required binding site. These complexes usually involve the active site, but Schramm (1974) has demonstrated activation of AMP nucleosidase by MgATP at a modifier site instead. 

Of course, as with other ligands, metal ions may interact at sites distinct from those occupied by substrates or modifiers and may influence catalytic activity in a less direct manner. It is interesting in this regard that metal-ion activation does not usually display the kinetically higher-order initial rate profile considered characteristic of most allosteric modifiers (Barden and Scrutton, 1974). 

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Review of the roles of GSK3 in carbohydrate metabolism and in other regulatory phenomena. 

While reproducible for many receptors, this phenomenon is not universal for GPCRs. For example, in the case of the M2 muscarinic receptor, while two-thirds of intracellular loop clusters of Ser/Thr residues ( Ser- "Ser and " Thr- "Ser) mediate internalization, only the carboxyl terminal ( Thr- "Ser) cluster mediates desensitization (136). In conclusion, internalization may follow desensitization, or it may occur independently (160) with or without the influence of other regulatory processes (161). 

Several lines of evidence indicate that macromolecules of as yet unidentified chemical nature, produced by cancers and released into the systemic circulation, are responsible for the biochemical alterations in the liver and other host organs. In view of the diverse regulatory properties of the many different enzymes that increase or decrease towards their immature level (see Table III), a deficiency or excess in any given endocrine or dietary factor can clearly not explain the phenomenon. Nor has it been possible to implicate reductions in the efficacy of these factors. Subnormal concentration of the nuclear thyroid hormone receptor has been noted in the liver of tumor-bearing animals(24) however, since losses in the T3-inducible catalysts of the same liver occurred at much earlier stages of tumor-bearing,(24) the subnormal receptor concentration could clearly not be the cause of these losses but was probably another, and rather late, reflection of the process of biochemical undifferentiation. 

For linear systems, the principle of superposition applies, and different oscillatory modes can evolve independently of one another. However, biological systems in general are not linear, and separation of different regulatory mechanisms may not be justified, even when they involve different time scales. One type of phenomenon that can arise from the interaction between two oscillatory modes is modulation of the amplitude and frequency of the faster mode in dependence of the phase of the slower mode. This type of phenomenon was demonstrated in Fig. 12.2c where the frequency of the myogenic mode fjast changes in step with the amplitude of the TGF-mediated mode. Similar modulation phenomena can be expected to occur in many other biological systems such as, for instance, the interaction between the circadian and the ultradian rhythms of hormone secretion [25]. 

A major advantage of this mode of regulation is that a given regulatory protein can have different effects, depending on what other proteins are present in the same cell. This phenomenon, called combinatorial control, is crucial to... 

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