Metabolites, shunt

Specific Control of Phytoalexin Accumulation by "Metabolite Shunting" of Biosynthetic Pathways. Graham and coworkers (personal communication), at the Monsanto Laboratories, St. Louis, have developed techniques to selectively shunt defensive metabolites, particularly of the shikimic acid cycle. Through various techniques, certain compounds are applied to plant aerial or root parts, and these compounds have the property of inducing specific accumulations of secondary metabolites. The directions of these accumulations are under known enzymic control (48), and the regulation of these enzymes is achieved by selecting appropriate inducers. Such inducers seem to provide a novel approach to the control of insects by magnifying the ability of plants to produce and concentrate antiherbivory compounds. 

Cells require a constant supply of N/ X)PH for reductive reactions vital to biosynthetic purposes. Much of this requirement is met by a glucose-based metabolic sequence variously called the pentose phosphate pathway, the hexose monophosphate shunt, or the phosphogluconate pathway. In addition to providing N/VDPH for biosynthetic processes, this pathway produces ribos 5-phosphate, which is essential for nucleic acid synthesis. Several metabolites of the pentose phosphate pathway can also be shuttled into glycolysis. 

Plant metabolism can be separated into primary pathways that are found in all cells and deal with manipulating a uniform group of basic compounds, and secondary pathways that occur in specialized cells and produce a wide variety of unique compounds. The primary pathways deal with the metabolism of carbohydrates, lipids, proteins, and nucleic acids and act through the many-step reactions of glycolysis, the tricarboxylic acid cycle, the pentose phosphate shunt, and lipid, protein, and nucleic acid biosynthesis. In contrast, the secondary metabolites (e.g., terpenes, alkaloids, phenylpropanoids, lignin, flavonoids, coumarins, and related compounds) are produced by the shikimic, malonic, and mevalonic acid pathways, and the methylerythritol phosphate pathway (Fig. 3.1). This chapter concentrates on the synthesis and metabolism of phenolic compounds and on how the activities of these pathways and the compounds produced affect product quality. 

The major toxic effect of exposure to 2-hexanone is neuropathy. Neuropathy can be caused by both 2-hexanone and its metabolite 2,5-hexanedione. A reduction of the neuropathy caused by exposure to 2-hexanone could theoretically be achieved through shunting of metabolism to less toxic metabolites. However, as discussed above, the toxicity of those other metabolites, and the effect of the treatment on metabolism of other potential toxicants, would have to be clearly assessed. 

When drugs are administered orally, they typically are absorbed in the small bowel, enter the portal circulation, and pass through the liver. Both CYP enzymes in the bowel wall and in the hepatocytes can metabolize a fraction of the drug before it reaches the systematic circulation (i.e., first-pass metabolism or first-pass effect). The extent of this effect can be broadly altered by diseases (e.g., cirrhosis, portacaval shunting, persistent hepatitis, congestive heart failure), and by some drugs (e.g., alcohol, ketaconazole, fluoxetine) influencing the peak concentrations achieved and the ratio of the parent compound to metabolites ( 11, 19, 20). 

Mancini I, Guella G, Amade P, Roussakis C, Pietra F (1997) Hanishin, a Semiracemic, Bioactive C9 Alkaloid of the Axinellid Sponge Acanthella carteri from the Hanish Islands. A Shunt Metabolite Tetrahedron Lett 38 6271... 

Clavicipitic acid (129) (naturally occurring as a mixture of C-10 epimers) has been identified as a metabolite which is at a shunt from the main line of... 

Dry reagent chemistries have been described for the analysis of a variety of blood constituents. These include metabolites, enzymes, electrolytes, hormones, and therapeutic drugs. A partial list is presented in Table 3. With the exception of electrolytes, nearly all analyses depend on enzyme-mediated chemistries and that includes immunochemical assays. A brief survey of element structures will illustrate how physical functions and chemical reactions used in conventional multistep procedures are integrated in the construction of dry reagent test devices. These examples will illustrate how reactions in dry reagent elements can be compartmentalized and how end produas are shunted to other compartments for further reaction. In its final form, each element provides a complete analytical procedure. 

Conclusively establishing the role of potential intermediates in a biosynthetic pathway is a difficult aspect of biosynthesis. Typically, intermediates accumulate because subsequent enzymatic reactions are slow. Organisms also produce shunt metabolites that are off the main pathway and may not be further metabolized these will also accumulate. Isolation of an intermediate does not, therefore, establish intermediacy. Trapping experiments are sometimes used to overcome these problems. In the pathway A B C, where A is a known precursor of C, labeled A and non-labeled B are fed at the same time. The latter is metabolized to C and labeled B is produced from A Bis then temporarily available for isolation. An alternative approach for microbial metabolites is to mutate the organism or add specific enzyme inhibitors. This may allow intermediates to accumulate. Incorporation of a labeled, potential intermediate into a product does not prove that the intermediate lies on the main biosynthetic pathway. It may simply serve as a substrate for the enzymes involved. Only when each of the enzymes in a pathway has been isolated and characterized, and the substrate specificity determined, can the intermediates in a biosynthetic route be characterized. 

Arachidonic acid can also be metabolized to a variety of mediators, depending on the cell type. For example, lipoxygenase catalyzes the production of leu-kotrienes, and mixed-function oxygenases catalyze the production of epoxyeicosatrienoic acids. Collectively, these oxygenated metabolites may play a critical role in NSAIEt-induced nephrotic syndrome by shunting arachidonic acid metabolism from prostaglandins to... 

Fig. 2 The red blood cell has played a special role in the development of mathematical models of metabolism given its relative simplicity and the detailed knowledge about its molecular components. The model comprises 44 enzymatic reactions and membrane transport systems and 34 metabolites and ions. The model includes glycolysis, the Rapaport-Leubering shunt, the pentose phosphate pathway, nucleotide metabolism reactions, the sodium/potassium pump, and other membrane transport processes. Analysis of the dynamic model using phase planes, temporal decomposition, and statistical analysis shows that hRBC metabolism is characterized by the formation of pseudoequilibrium concentration states pools or aggregates of concentration variables. (From Ref...

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