Secondary metabolic pathways products

The activity of PK and NRPSs is often precluded and/or followed by actions upon the natural products by modifying enzymes. There exists a first level of diversity in which the monomers for respective synthases must be created. For instance, in the case of many NRPs, noncanonical amino acids must be biosynthesized by a series of enzymes found within the biosynthetic gene cluster in order for the peptides to be available for elongation by the NRPS. A second level of molecular diversity comes into play via post-synthase modification. Examples of these activities include macrocyclization, heterocyclization, aromatization, methylation, oxidation, reduction, halogenation, and glycosylation. Finally, a third level of diversity can occur in which molecules from disparate secondary metabolic pathways may interact, such as the modification of a natural product by an isoprenoid oligomer. Here, we will cover only a small subsection of... 

Tenser T, Gee DR. [2005). Modelling the evolution of secondary metabolic pathways. University of York, MPhil Project Report Abstract). Plants and microbes invest heavily in producing chemicals termed Natural Products. These chemicals are produced in secondary metabolic pathways. In this report, we develop a model for the evolution of secondary pathways, and investigate what factors are important in aUowing these pathways to arise and persist. The results imply that certain mutation rates are important in generating chemical diversity, and we give conditions on these for optimal fitness in a population. We also find that the rate of competitive evolution and the chances that new compounds have to be beneficial or harmful are important factors. 

Viral particle production from cell cultures has several differences from other bioprocesses. The production of molecules like enzymes, toxins, or other proteins synthesized by bacteria, fungi or animals, depend upon culture parameters, such as pH, temperature, dissolved oxygen, or nutrients. Product formation may occur through secondary metabolic pathways, which are not related to the development or growth of the cell. In these situations, research and technological development must be directed to the specific cell and this involves the improvement of the cell as a better molecular production unit. So, there is a direct relation between nutrient conversion, cell growth, and the expected improvement of the final productivity. 

Viral particle production processes by cell culture infection, cannot be characterized in such a simple way, since the final product - virus -does not result from a secondary metabolic pathway. However, it can be better described as a process redirecting the cell machinery towards viral particle production, which only happens after viral infection. The virus production process can be divided into two different steps. The first involves cell multiplication, which results from the conversion of culture medium substrates into cell mass. At the instant of viral infection, the cellular production unit no longer exists, since the viral genetic material forms a new production unit, initiating the second step of the virus production process. This production unit is the infected cell and is the producer of new viral particles. This production phase requires nutritional and metabolic conditions that are not observed during cell growth. These conditions are normally studied separately. Nevertheless, virus production... 

Besides the engineering of S. cerevisiae for organic acid production, through metabolic engineering it is possible to reconstruct entire pathways. In 1994, Yamano et al. [163] reported the reconstruction of a complete secondary metabolic pathway in S. cerevisiae, resulting in the ability of the yeast to produce p-carotene and lycopene. Carotenoids are a class of pigments used in the food industry and, due to their antioxidant properties, they have wide commercial interest. The biosynthesis of these compounds does naturally not occur in S. cerevisiae and to allow... 

This latter more focussed approach involves the identification of genes encoding metabolic enzymes which will allow full control of a given pathway. Indeed, the engineering of medicinal plants for the production of valuable natural products has been attained [48,61,170]. However, the major barrier for the successful metabolic engineering of pathways is still the limited knowledge of secondary metabolism pathways. 

The understanding of the degradation of natural products such as camphor has been greatly enhanced by understanding the catalytic cycle of the cytochrome P-450 enzyme P-450cam in structural detail.3,4 These enzymes catalyze the addition of 02 to nonactivated hydrocarbons at room temperatures and pressures - a reaction that requires high temperature to proceed in the absence of a catalyst. O-Methyltransferases are central to the secondary metabolic pathway of phenylpropanoid biosynthesis. The structural basis of the diverse substrate specificities of such enzymes has been studied by solving the crystal structures of chalcone O-methyltransferase and isoflavone O-methyltransferase complexed with the reaction products.5 Structures of these and other enzymes are obviously important for the development of biomimetic and thus environmentally more friendly approaches to natural product synthesis. 

The organism eliminates toxic substances or their metabolites through the kidneys, bile, lungs, saliva, stools and skin. The excretion by the kidneys is of the main importance. This mechanism is the same as that during the excretion of final products of primary and secondary metabolic pathways. Substances absorbed in the gastrointestinal tract are eliminated from the blood by the liver. These substances can be removed by the liver prior to reaching the circulation system. Substances which enter the body by inhalation are also eliminated from the lung (carbon monoxide, alcohol, volatile substances). The excretion system is not specialized and it operates on the basis of a simple diffusion [7-9]. 

Higher plants have evolved an extraordinary variety of secondary metabolic pathways, the resulting products of which have been put to use by man providing pharmaceuticals for drug use, insecticides and various allelochemicals for pest control, and extracts for the flavor and fragrances industries. In spite of advances in synthetic organic chemistry, plants remain a major source of natural products, particularly in the specialty chemicals industry. Compounds, such as the insecticide derived from Azadiraohta indioa or the antitumor alkaloids vinblastine and vincristine found in periwinkle (Catharanthus roseus) (1 ), have complicated structures which preclude at the present time the development of an economical chemical synthesis (Figure 1). In the case of... 

The production of shikonins is an example of both the promise and limitations of current plant cell culture procedures in the area of natureJ products. While productivity at least 10-fold higher than in plants was obtained, this was the result of a systematic but empirical search for the optimal conditions for shikonin accumulation. In many cases it has not been possible to find the culture conditions appropriate for the expression of a secondary metabolic pathway (H, 15). About a dozen examples are known of cell cultures producing a secondary metabolite at levels equal to or higher than in the whole plant (Table I), but with the exception of shikonin none of these systems has commercial use, or is competitive with existing extraction technology. 

These same features appear to be responsible for creating diversity in other secondary metabolic pathways. For example, in both polyketide and teipene formation, repetitive addition of either C2 or C5 carbon subunits leads to the formation of a variety of carbon skeletons. In addition, in nearly all groups of secondary metabolites, including alkaloids, phenylpropanoids, and terpenes, the initially-formed products are subjected to a wide variety of oxidative modifications. Thus, despite the seemingly large and chaotic assemblage of secondary metabolites found in plants, their formation may he governed by a few common principles. 

A secondary metabolic pathway can be defined by the branch point fi-om primary metabolism and the consecutive downstream reactions that lead to specific end products. Obviously, catalysis of the branch reaction is crucial for the establishment of a secondary metabolic pathway. This reaction produces the first intermediate, which can be processed further into "useful" products that may be fixed by natural selection. In this review, indole production and fonnation of the benzoxazinoid 2,4-dihydroxy-7-methoxy-2//-l,4-benzoxazin-3(4//)-one (DIMBOA) are used as examples to discuss the evolution of secondary metabolic pathways. 

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