Secondary metabolites metabolic reactions

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. 

A comparable reaction was seen decades ago in the metabolism of methadone [173 - 175]. This well-known synthetic opiate undergoes A-demeth-ylation as a major metabolic reaction in humans and laboratory animals. The resulting secondary amine (11.168, Fig. 11.21) has never been isolated, as it undergoes practically instantaneous cyclization. The reaction is believed to proceed via the carbinolamine with formation of metabolite 11.169 as the major urinary metabolite in humans. This structurally intriguing basic compound is, in its neutral form, a pyrrolidine with an exocyclic C=C bond,... 

The synthesis of secondary metabolites requires materials in the form of atoms that compose the secondary metabolites, energy to form covalent bonds between the atoms, the enzymes that carry out the formation reactions, the genetic material that codes and synthesizes the enzymes, and the cellular machinery that maintains pH, ionic strength, and redox potentials within a range that allow enzymes to function properly.85 Some materials such as hydrogen and oxygen are readily available and cheap, and contribute little to the material cost of synthesis. Other materials such as phosphorus and nitrogen are of limited supply in many marine habitats.86 The use of these rare materials in secondary metabolites is probably costly as they limit many primary metabolic pathways, which helps explain the rarity of secondary metabolites that contain N or P.2 Fixed carbon... 

In addition to the primary metabolic reactions, which are similar in all living organisms, a vast number of metabolic pathways lead to the formation of compounds peculiar to a few species or even to a single chemical race only. These reactions are summed up under the term secondary metabolism, and their products are called secondary metabolites (Grierson, 1993 Herbert, 1989 Porter and Spurgeon, 1981, 1983 Stafford, 1990). 

Precursors. Precursors for this reaction are compounds exhibiting keto-enol tau-tomerism. These compounds are usually secondary metabolites derived from the glycolysis cycle of yeast metabolism during fermentation. Pyruvic acid is one of the main precursor compounds involved in this type of reaction. During yeast fermentation it is decarboxylated to acetaldehyde and then reduced to ethanol. Acetone, ace-toin (3-hydroxybutan-2-one), oxalacetic acid, acetoacetic acid and diacetyl, among others, are also secondary metabolites likely to participate in this kind of condensation reaction with anthocyanins. 

Many times, bisdcalkylation of a tertiary amine leads to the coiTe.sponding primary aliphatic amine metabolite, which is susceptible to further oxidation. For example, the bisdes-methyl metabolite of the H -histamine antagonist brompheniramine (Dimetane) undergoes oxidative deamination and further oxidation to the corresponding propionic acid metabolite."" Oxidative deamination is discussed in greater detail when we examine the metabolic reactions of secondary and primary amines. 

Haloperidol undergoes extensive metabolism to form a myriad of primary and secondary metabolites (479-486). The principal phase I reactions involve the following oxidative N-dealkylation to initially form 4-fluoro-phenylbenzoylpropionaldehyde (which is rapidly oxidized to the acid) and 4-(4-chlorophenyl)-4-hydroxypiperidine (479,480, 483-485) N-oxidation to form haloperidol-iV-oxide (485) and reversible reduction of the carbonyl group to the alcohol, or reduced haloperidol (481,487). A phase II metabolite, hal-operidol-O-glucuronide, accounts for as much... 

The condensation of acetyl co-enzyme A with oxaloacetic acid and the decarboxylation steps illustrate two of the general metabolic reactions of citric acid intermediates that play an important role in their utilization to form secondary metabolites. 

Despite the thousands of secondary metabolites made by microorganisms, they are synthesized from only a few key precursors in pathways that comprise a relatively small number of reactions and which branch off from primary metabolism at a limited number of points. Acetyl-CoA and propionyl-CoA are the most important precursors in secondary metabolism, leading to polyketides, terpenes, steroids, and metabolites derived from fatty acids. Other secondary metabolites are derived from intermediates of the shikimic acid pathway, the tricarboxylic acid cycle, and from amino acids. The regulation of the biosynthesis of secondary metabolites is similar to that of the primary processes, involving induction, feedback regulation, and catabolite repression [6]. 

Many FAD-dependent enzymes catalyzing these reactions are found in bacteria and fungi, either in pathways allowing them to metabolize hydrocarbons or in pathways that synthesize secondary metabolites such as antibiotics." " " There has been long-standing interest in using these enzymes for enantioselective chemical syntheses, either as purified enzymes or expressed in engineered microbes for bioreactors. 

One of the advantages of studying secondary metabolites is that they are not normally indispensable for the maintenance and propagation of the cell. As a consequence they can be totally absent in the cell prior to stimulation greatly facilitating the analytical procedures required. In other words the response must often be an on/off reaction in contrast to that to primary metabolites. Here the response is detected as a fluctuation of small concentrations which furthermore is intricately connected to the biochemical regulation of intermediary metabolism. 

Many drugs, such as buspirone, undergo multiple oxidative biotransformation reactions. In cases such as buspirone the secondary metabolites, which are minor metabolites in vitro, are major metabolites in the circulation or excreta in humans and animals because primary metabolites are rapidly converted to secondary metabolites. To determine the formation pathways and structures of secondary or sequential metabolites, a method using metabolite incubation and HPLC MSC MS analysis was developed and demonstrated using buspirone as an example (Zhu, 2002). [ Cjbuspirone was incubated with HLM, and metabolic profiling was carried out using HPLC-MSC. The... 

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