Primary metabolic steps

Q5.1 The primary metabolic step involves a different mechanism for each of the drugs listed in Figure 5.11. Select the appropriate transformation for each drug from the following list aliphatic hydroxylation, oxidative N-dealkylation, hydrolysis, aromatic hydroxylation, oxidative O-dealkylation. Draw the structure of the primary metabolite in each case. 

Nature provides striking examples of each of the types of PCET discussed in this chapter. Enzymes often rely on PCET to affect primary metabolic steps involving charge transport and catalysis. Amino acid radical generation and transport is synonymous with PCET [187], as is the activation of substrate bonds at enzyme active sites [29]. PCET is especially prevalent for metallo-cofactors that activate... 

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

Arterial blood gases are measured to determine oxygenation and acid-base status (Fig. 74-1). Low pH values (less than 7.35) indicate acidemia, whereas high values (greater than 7.45) indicate alkalemia. The PaC02 value helps to determine if there is a primary respiratory abnormality, whereas the I IC( )3 concentration helps to determine if there is a primary metabolic abnormality. Steps in acid-base interpretation are described in Table 74-2. 

The primary metabolic information can also be obtained from PathDB of National Center for Genome Resources (NCGR) at http //www.ncgr.org/software/ pathdb/. Click Simple Web Query to open the query page. Choose Pathway/Step/ Catalyst or Compound from the Retrieve pop-up list (search by compound is the... 

By metabolism or primary metabolism is meant the biochanical processes, sequences, or pathways by which cells grow and proliferate, and are sustained. The various steps involved are each selectively catalyzed by a particular enzyme, which may in turn be inhibited, blocked, controlled, or modulated by other substances called enzyme inhibitors. As had been noted the latter may be internally generated or may be administered from external sources. The action can therefore be described as biochemical, both of the enzymes and of the inhibitors. 

In the present review we divide the pathway leading to the Catharanthus alkaloids into five parts (Fig. 2). The first two concern the biosynthesis of tryptophan and geraniol diphosphate they are similar to (or even part of) primary metabolism and occur in all plant species. Whether these pathways in C. roseus are differently regulated, or whether even an additional pathway exists parallel to the normal primary metabolism, is a question not yet answered. The third and the fourth part coneern the steps from tryptophan to tryptamine and from geraniol to secologanin, respectively. Both pathways occur also in other plants, including plants that do not produce terpenoid indole alkaloids. The fifth part is the condensation of secologanin and tryptamine to strictosidine and the subsequent conversion into a plethora... 

Considering the activities of the enzymes TDC, SSS, and SG in cultured C. roseus cells, it is clear that the actual production of alkaloids is considerably lower than that which could have been produced by these enzymes. In other words, there seems to be an overcapacity in the activity of these enzymes. Thus, there is a limiting step in the pathway before these enzymes, or the carbon flux from primary metabolism into the pathway is limited, for example, by competition with other pathways or by transport and com-partmentation. A clear limiting factor is the iridoid pathway, in which geraniol-lO-hydroxylase is an obvious point of regulation. Catabolism is a further factor which in cell cultures does limit the alkaloid accumulation. 

The precursor substrates and enzymes necessary for the first committed steps often appear to have been recruited from primary metabolic pathways, such as glycolysis, the Krebs cycle, the pentose phosphate pathway and the shikimate pathway [32], For example, the aromatic amino acid s L-phenylalanine and L-tyrosine, produced by the shikimate pathway, are precursors for a wide spectrum of natural products including phenylpropanoids, flavonoids, lignins, coumarins, cyanogenic glycosides, glucosinolates, and alkaloids [33],... 

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