Aspects of Metabolism

The metabolism of tryptophan has been of interest to investigators in many different fields of biochemistry and medicine. The biological transformations of this indole derivative are very complex and involve a series of enzymes, which cause i) changes of the side chain (transaminases, decarboxylases, etc.) ii) splitting of the indole nucleus from the side chain (tryptophanase) iii) changes in the pyrrole nucleus (tryptophan pyrrolase, kynureninase, etc.) iiii) changes in the benzene ring (hydroxylases, etc.). 

It is beyond the scope of this review article to discuss details of tryptophan metabolism, since detailed reviews are available 8, 36, 59, 445), while summaries dealing with biochemical transformations of the indole nucleus of tryptophan can be found also in books of general biochemistry.  

Tryptophan is metabolized by several different pathways (Fig. 1) each yielding biologically important substances such as tryptamine and in particular serotonin (5-hydroxytryptamine), which seems to be involved in certain mental disorders. Indole-3-acetic acid is a plant growth hormone its precursor is tryptamine or indole-3-pyruvic acid. In humans, the microorganisms of the large intestine can further degrade indole-3-acetic acid to yield indole, skatole (3-methyl-indole) and other substances. 

The major and most important metabolic pathway of tryptophan is, however, the kynurenine pathway (Fig. 2). Tryptophan undergoes oxidative cleavage between C-2 and C-3, giving formylkynurenine (32) by the action of tryptophan pyrrolase 164). 3H-Indolylhydroperoxides (31) have been proposed 109, 442) as intermediates in the formation of formylkynurenine and reviews discussing this oxidative cleavage are available 8, 165, 402). 

Kynurenine, which is formed from the formyl derivative by the action of formamidase, may be metabolized to a quinoline derivative, kynurenic acid. Alanine may be removed from kynurenine by kynureninase to form anthranilic acid. 

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Turkall, R.M. (1979) Gold sodium thiomalate selected aspects of metabolism and distribution. Ph. D. Thesis, University of Ohio. 

Dynamic and quantitative aspects of metabolism bioenergetics and enzyme kinetics... 

The calcium ion is a key factor in human nutrition. It has an important structural role in bone and teeth and is a regulatory factor in many aspects of metabolism. 

It has been decided as a general scheme that the volumes first issued shall deal with the pure chemistry of physiological products and with certain general aspects of the subject. Subsequent monographs will be devoted to such questions as the chemistry of special tissues and particular aspects of metabolism. So the series, if continued, will proceed from physiological chemistry to what may be now more properly termed chemical physiology. This will depend upon the success which the first series achieves, and upon the divisions of the subject which may be of interest at the time. 

Dmg metabolism is the main cause for the absence of correlation between permeability and bioavailability in low dose PK experiments, as illustrated in Figure 3.1. Refined aspects of metabolism are presented in Chapter 7. As a first approach one can use the following relation to connect the fraction bioavaUable with its basic components ... 

In addition to this known aspect of metabolism, there is another one, albeit less frequent, that refers to the interaction of novel compounds. This is important, as it gives die possibility of permanent changes, and is associated with adaptation and evolution. In odier words, one should consider two aspects of metabolism/cognition the normal homeostatic metabolism, which corresponds to die normal life and self-maintenance of the cell from within and a metabolism of novel elements diat may operate changes in die structure. 

The use of tissue slices is a standard technique in all aspects of metabolic biochemistry. The tissue is cut into slices, sufficiently thin to allow adequate rates of diffusion in and out of the tissue. The slices are submerged in physiological saline to which substrates or other compounds may be added. 

In vitro systems containing human xenobiotic-metabolizing enzymes can provide qualitative data, such as the human metabolites which may be produced in vivo and which enzymes are capable of producing these metabolites. When comparing quantitative aspects of metabolism among different cytochrome P450 forms in a cDNA expression system, the data can be interpreted in two contexts ... 

Although many aspects of cell structure and function are influenced by pH, it is the catalytic activity of enzymes that is especially sensitive. Enzymes typically show maximal catalytic activity at a characteristic pH, called the pH optimum (Fig. 2-21). On either side of the optimum pH their catalytic activity often declines sharply. Thus, a small change in pH can make a large difference in the rate of some crucial enzyme-catalyzed reactions. Biological control of the pH of cells and body fluids is therefore of central importance in all aspects of metabolism and cellular activities. 

Plants must be especially versatile in their handling of carbohydrates, for several reasons. First, plants are autotrophs, able to convert inorganic carbon (as C02) into organic compounds. Second, biosynthesis occurs primarily in plastids, membrane-bounded organelles unique to plants, and the movement of intermediates between cellular compartments is an important aspect of metabolism. Third, plants are not motile they cannot move to find better supplies of water, sunlight, or nutrients. They must have sufficient metabolic flexibility to allow them to adapt to changing conditions in the place where they are rooted. Finally, plants have thick cell walls made of carbohydrate polymers, which must be assembled outside the plasma membrane and which constitute a significant proportion of the cell s carbohydrate. 

This approach can be applied to many aspects of metabolic control including cell growth.20... 

The control of glycogen phosphorylase by the phosphorylation-dephosphorylation cycle was discovered in 1955 by Edmond Fischer and Edwin Krebs50 and was at first regarded as peculiar to glycogen breakdown. However, it is now abundantly clear that similar reactions control most aspects of metabolism.51 Phosphorylation of proteins is involved in control of carbohydrate, lipid, and amino acid metabolism in control of muscular contraction, regulation of photosynthesis in plants,52 transcription of genes,51 protein syntheses,53 and cell division and in mediating most effects of hormones. 

The geometry of cell construction provides another important aspect of metabolic control. In a bacterium, the periplasmic space (Fig. 8-28) provides a compartment that is separate from the cytosol. Some enzymes are localized in this space and do not mix with those within the cell. Other enzymes are fixed within or attached to the membrane. Eukaryotic cells have more compartments nuclei, mitochondria (containing both matrix and intermembrane spaces), lysosomes, microbodies, plastids, and vacuoles. Within the cytosol the tubules and vesicles of the endoplasmic reticulum (ER) separate off other membrane-bounded compartments. The rate of transport of metabolites through the membranes between compartments is limited and often is controlled tightly. 

Why do we need vitamins Early clues came in 1935 when nicotinamide was found in NAD+ by H. von Euler and associates and in NADP+ by Warburg and Christian. Two years later, K. Lohman and P. Schuster isolated pure cocarboxylase, a dialyz-able material required for decarboxylation of pyruvate by an enzyme from yeast. It was shown to be thiamin diphosphate (Fig. 15-3). Most of the water-soluble vitamins are converted into coenzymes or are covalently bound into active sites of enzymes. Some lipid-soluble vitamins have similar functions but others, such as vitamin D and some metabolites of vitamin A, act more like hormones, binding to receptors that control gene expression or other aspects of metabolism. 

An initially surprising conclusion drawn from the studies of Schoenheimer and Rittenberg was that proteins within cells are in a continuous steady state of synthesis and degradation. The initial biosynthesis, the processing, oxidative and hydrolytic degradative reactions of peptides, and further catabolism of amino acids all combine to form a series of metabolic loops as discussed in Chapter 17 and dealt with further in Chapters 12 and 29. Within cells some proteins are degraded much more rapidly than others, an important aspect of metabolic control. This is accomplished with the aid of the ubiquitin system (Box 10-C) and proteasomes (Box 7-A).107 Proteins secreted into extracellular fluids often undergo more rapid turnover than do those that remain within cells. 

Adipokinetic hormones control metabolism of insects during long-distance flight.359 363 In the migratory locust these hormones consist of a pair of related octapeptides and a decapeptide (Table 30-5). The hormones stimulate triacylglycerol lipase in the insects fat bodies, induce release of carbohydrates from body stores, and affect many other aspects of metabolism.363 Insects also have hormones of the insulin family, proteins consisting of disulfide-linked A and B chains as in insulin. The silkworm Bombyx mori has 38 genes for the insulinlike bombyxins, which are synthesized in the brain.364... 

As with every aspect of metabolism, homeostasis is essential to the immune system, which must be able to both grow and shrink rapidly.3733 Antigens, cytokines, apoptosis-inducing signals, immune inhibitor receptors,22913 and receptor tyrosine kinases373d all participate in preserving the delicate balance that is required. 

Large metabolic charts have been designed to display all the major biochemical pathways. Such charts present a bewildering array of interconnected pathways, making it difficult to appreciate relationships between different pathways. The overall operational aspects of metabolism may be clarified by simpler block diagrams that omit details and focus on functional relationships. Such a functional block diagram for a typical heterotrophic aerobic cell is shown in figure 11.4. The metabolism of such a system is symbolized by two functional blocks ... 

Nucleotides play important roles in all major aspects of metabolism. ATP, an adenine nucleotide, is the major substance used by all organisms for the transfer of chemical energy from energy-yielding reactions to energy-requiring reactions such as biosynthesis. Other nucleotides are activated intermediates in the synthesis of carbohydrates, lipids, proteins, and nucleic acids. Adenine nucleotides are components of many major coenzymes, such as NAD+, NADP+, FAD, and CoA. (See chapter 10 for structures of these coenzymes.)... 

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