Regulation, feedback mechanisms

For the effects of haem oxygenase deficiency to be so profound we may well wonder whether some degree of oxidative stress is in fact the norm. If so, then haem oxygenase levels presumably change continuously as part of a flexible and self-regulating feedback mechanism. We shall see in Chapter IS that a continuously high haem oxygenase activity probably does have beneficial effects on our health in old age. 

Biochemical pathways consist of networks of individual reactions that have many feedback mechanisms. This makes their study and the elucidation of kinetics of individual reaction steps and their regulation so difficult. Nevertheless, important inroads have already been achieved. Much of this has been done by studying the metabolism of microorganisms in fermentation reactors. 

The metabohtes of vitamin D are usually more toxic than the vitamin because the feedback mechanisms that regulate vitamin D concentrations are circumvented. 25-Hydroxycholecalciferol has a one-hundredfold increase in toxicity over vitamin D when fed to chicks (220) and 1 a,25-dihydroxy vitamin D is several times more toxic than the 25-hydroxy analogue. Vitamin D2 seems to have less toxicity than vitamin D, a circumstance which is beheved to be caused by the more efficient elimination of 25-hydroxy and the 1 a,25-dihydroxy vitamin D2 from the animals. Estimated safe upper dietary levels are given in Table 11. 

The responsiveness of a tissue to a hormone depends on the density of receptors within its component cells. The number of receptors is determined by their rate of synthesis and catabolism, which is itself controlled by complex feedback mechanisms involving hormone action. Some chemicals are known to interfere with this regulation. For example, TCDD can act to increase or decrease the expression of the oestrogen receptor. ... 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Lewcock, ]. W. and Reed, R. R. A feedback mechanism regulates monoallelic odorant receptor expression. Proc. Natl Acad. Sci USA 101 1069-1074, 2004. 

These results indicate it may be possible to improve the efficiency of absorption and assimilation by altering the process of regulation. However the mechanisms governing regulation are poorly understood. It is not known whether the regulation is linked to the concentration of NH4+ or NOs" itself or to the concentrations of products of N assimilation downstream from NH4+ or NOs", such as particular amino acids. Nor is it known what the targets of the resulting feedback mechanisms are. 

Figure 6.19 Regulation of the synthesis of glycogen from glucose in liver and muscle. Insulin is the major factor stimulating glycogen synthesis in muscle it increases glucose transport into the muscle and the activity of glycogen synthase, activity which is also activated by glucose 6-phosphate but inhibited by glycogen. The latter represents a feedback mechanism and the former a feedforward. The mechanism by which glycogen inhibits the activity is not known. The mechanism for the insulin effect is discussed in Chapter 12.

Presynaptic a2-adrenoceptors function like sensors that enable norepinephrine concentration outside the axolemma to be monitored, thus regulating its release via a local feedback mechanism. When presynaptic a2-re-ceptors are stimulated, further release of norepinephrine is inhibited. Conversely, their blockade leads to uncontrolled release of norepinephrine with an overt enhancement of sympathetic effects at Pi-adrenoceptor-mediated myocardial neuroeffector junctions, resulting in tachycardia and tachyarrhythmia. 

Thyroid hormones accelerate metabolism. Their release (A) is regulated by the hypophyseal glycoprotein TSH, whose release, in turn, is controlled by the hypothalamic tripeptide TRH. Secretion of TSH declines as the blood level of thyroid hormones rises by means of this negative feedback mechanism, hormone production is automatically adjusted to demand. 

Once the siderophore-iron complexes are inside the bacteria, the iron is released and utilized for vital cell functions. The iron-free hydroxamate siderophores are commonly re-excreted to bring in an additional iron load (Enterobactin is at least partially degraded by a cytoplasmic esterase This cycle is repeated until specific intracellular ferric uptake regulation proteins (Fur proteins) bind iron, and signal that the intracellular iron level is satisfactory, at -which point ne-w siderophore and siderophore-receptor biosynthesis are halted and the iron-uptake process stops. This intricate feedback mechanism allows a meticulous control over iron(III) uptake and accumulation against an unfavorable concentration gradient so as to maintain the intracellular iron(III) level within the required narrow window. Several excellent reviews concerning siderophore-iron transport mechanisms have been recently published i.3,i6, is,40,45,60-62 ... 

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