Control of Metabolism

The metabolic pathways, which have been discussed in this chapter are influenced by many factors, some of which are discussed in chapter 5. Such factors may have an effect on the toxicity of a compound as indicated below, and these are discussed in more detail in chapter 5. 

But it is important to appreciate that the metabolism of foreign compounds is not completely separate from intermediary metabolism, but linked to it. Consequently, this will exert a controlling influence on the metabolism of foreign compounds. Some of the important factors controlling xenobiotic metabolism are 

The NADPH level is clearly important for phase 1 reactions, yet many biochemical processes, such as fatty acid biosynthesis, use this coenzyme. It is derived from either the pentose phosphate shunt or isocitrate dehydrogenase. Consequently, the overall metabolic 

Oxygen is normally readily available to all reasonably well-perfused tissues, but deep inside organs such as the liver, especially the centrilobular area (see chap. 6), there will be a reduction in the oxygen concentration. This is clearly important when both oxidative and reductive pathways are available for a particular substrate. Therefore, as conditions in a particular tissue become more anaerobic, reductive pathways will become more important. This is well illustrated by the metabolism of halo thane where, in the rat, hypoxia will increase reductive metabolism and hepa to toxicity (see chap. 7). Glutathione is an extremely important cofactor, involved in both protection and conjugation. It may be depleted by both of these processes, or under certain circumstances, such as hereditary glucose-6-phosphate deficiency in man, supply may be reduced (see chap. 5). This will clearly influence toxicity, and there are a number of examples discussed in chapter 7 in which it is important. 

Other co-substrates possibly limited in supply are inorganic sulfate and glycine for conjugation these may be important factors in paracetamol hepa to toxicity and salicylate poisoning, respectively (chap. 7). 

At the cellular level, chemical processes must take place at rates consistent with the needs of the whole organism. This is achieved by control of enzyme activity, which depends upon  

When ATP is being consumed rapidly, its breakdown ensures a plentiful supply of ADP and phosphoric acid the reaction thus proceeds rapidly from left to right. If, on the other hand, ATP is not being used, the supply of ADP and inorganic phosphate is reduced and so is the speed of the reaction. 

Metabolism is the name given to the sequence or succession of chemical reactions that take place in living organisms. It involves both the synthesis (anabolism) and breakdown (catabolism) of complex compounds. 

Exergonic (catabolic) reactions release energy and endergonic (anabolic) reactions require an input of energy. The two are linked by mediating compounds, the most important of which is adenosine triphosphate (ATP). 

ATP is produced from a number of energy substrates by either substrate-level or oxidative phosphorylation. Glucose is oxidised via the glycolytic pathway and the tricarboxylic cycle. 

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If the kinetics of the reaction disobey the Michaelis-Menten equation, the violation is revealed by a departure from linearity in these straight-line graphs. We shall see in the next chapter that such deviations from linearity are characteristic of the kinetics of regulatory enzymes known as allosteric enzymes. Such regulatory enzymes are very important in the overall control of metabolic pathways. 

Thus ATP is the effective controller of metabolism but because AMP + ADP + ATP is constant, it is really the ratio of adenine nucleotides which is important This ratio is termed die adenylate charge or energy charge and is expressed as ... 

Francis GA, Fayard E, Picard F et al (2003) Nuclear receptors and the control of metabolism. Annu Rev Physiol 65 261-311... 

Fell D Understandinz the Control of Metabolism. Portland Press, 1997. 

F17. Frayn, K. N., Hormonal control of metabolism in trauma and sepsis. Clin. Endocrinol. 24, 577-599(1986). 

Fell DA, Thomas S. Physiologic control of metabolic flux the requirement for multisite modulation. Biochem J 1995 311 35-39. 

Perry and Lambert suggest that the natural role of oxylipins in tunicates may be in the control of metabolic processes [207],... 

In this chapter we will consider definitions of metabolism the biochemistry-physiology continuum. The concept of metabolic pathways and their organization and control of metabolism are likened to a road map involving flow of substrates but with mechanisms to accelerate or slow down pathways or to direct substrates through alternative routes. 

Glycolysis and the Krebs TCA cycle as models of control of metabolic pathways... 

Desvergne, B., and Wahli, W. (1999). Peroxisome proliferator-activated receptors Nuclear control of metabolism. Endocrine Rev. 20, 649-688. 

Enzymes occur in every living cell and are the basic elements in the execution and control of metabolic processes. They are very sophisticated catalysts. In addition to bringing about spectacular rate enhancements, enzymes... 

The regulation of the activity of enzymes by the binding of effector molecules is a ubiquitous and general principle for the fine timing and control of metabolic activity. Effector molecules are often low molecular weight organic compounds. Proteins and metal ions can also exercise the function of effectors. The effector molecules bind specifically to the enzymes and the binding results in inhibition or stimulation of enzymatic activity. 

The control of metabolism, growth, and reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland. The pituitary weighs about 0.6 g and rests at the base of the brain in the bony sella turcica near the optic chiasm and the cavernous sinuses. The pituitary consists of an anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis) (Figure 37-1). It is connected to the overlying hypothalamus... 

Control of metabolism depends on various factors including the availability of cofactors (e.g., NADPH), co-substrates (e.g., oxygen), and the level and activity of particular enzymes. 

However, the control of metabolism appears to be more complicated than this as it also involves the hypothalamus and pituitary gland. It seems that the male hypothalamus produces a factor, which inhibits the release of a hormone and which therefore leaves the liver in a particular male state. In the female, the hypothalamus is inactive, and therefore produces no factor, and hence the pituitary releases a feminizing factor (possibly growth hormone), which changes the liver to the female state. 

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