Pathway of secondary metabolism

Eleven of the CYPs from S. avermitilis were located in known gene clusters involved in secondary metabolism, including that of geosmin, avermectin, filipin, and pentalenolactone biosynthesis, and again, as in S. coelicolor, others appear to be involved in uncharacterized pathways of secondary metabolism. CYP178A1 is in a cluster with a nomibosomal peptide synthase, CYP107Y1 and CYP 181A1 are associated with a T5q>e n... 

The emergence of further streptomycete genomes will add to our understanding of CYP evolution, and the numbers of CYPs in unknown pathways of secondary metabolism will reveal new natural products. Given the estimate that only 1% of microorganisms are culturable, the depth of the biocatalytic reservoir of CYPs becomes evident. The reason why the streptomycetes and mycobacteria have many CYPs is not clear, as other soil bacteria contain either small numbers of CYPs (Table 13.1) or none. 

In addition to the primary metabolites, there are also compounds produced by other metabolic pathways which have no apparent necessity or use in the cell. These are secondary metabolites produced by pathways of secondary metabolism and are frequently only formed when the cell ceases active growth. 

As pointed out by Bu lock the basic pathways of secondary metabolism have been free to radiate to many different end-products and often utilise enzymes of rather broad specificity. We have exploited the lack of enzyme specificity and shown that the mutant Bl-41a will metabolise structural analogues of the natural biosynthetic intermediates into the corresponding analogues of the normal secondary metabolites produced by the wild-type strains. The results are reviewed by Hedden et al. (16). 

Berberine biosynthesis in Coptis cultures involves formation of a mediylenedioxy bridge into tetrahydrocolum-bamine (73) to yield canadine (74) (Fig. 32.23). TTie pathway differs in Berberis cultures. This should be a warning not to generalize pathways of secondary metabolism unless the enzymatic steps have been elucidated for each species (Hartmann, 1991). ( —)-Canadine (50) was efficiently incorporated into berberine in Hydrastis canadensis (Bhakuni and Jain, 1986). 

Mahadevan reviewed research up to 1973, with respect to the pathways of oxime metabolism in plants, and evaluated a series of aliphatic and aromatic oximes that are precursors for the biosynthesis of plant secondary metabolites (as opposed to basic metabolism products that are essential for cell survival), such as cyanogenic glycosides, glucosinolates and certain phytohormones . Some of these oximes are shown below. 

The tightly regulated pathway specifying aromatic amino acid biosynthesis within the plastid compartment implies maintenance of an amino acid pool to mediate regulation. Thus, we have concluded that loss to the cytoplasm of aromatic amino acids synthesized in the chloroplast compartment is unlikely (13). Yet a source of aromatic amino acids is needed in the cytosol to support protein synthesis. Furthermore, since the enzyme systems of the general phenylpropanoid pathway and its specialized branches of secondary metabolism are located in the cytosol (17), aromatic amino acids (especially L-phenylalanine) are also required in the cytosol as initial substrates for secondary metabolism. The simplest possibility would be that a second, complete pathway of aromatic amino acid biosynthesis exists in the cytosol. Ample precedent has been established for duplicate, major biochemical pathways (glycolysis and oxidative pentose phosphate cycle) of higher plants that are separated from one another in the plastid and cytosolic compartments (18). Evidence to support the hypothesis for a cytosolic pathway (1,13) and the various approaches underway to prove or disprove the dual-pathway hypothesis are summarized in this paper. 

Since the presumed cytosolic pathway interfaces directly with the network of secondary metabolism, the observed induction of DS-Co and CM-2 isozymes in response to wounding was expected. However, the even greater response of plastidic isozymes was unexpected. Perhaps the increased pull on carbohydrate metabolism in the cytosol affects the balance of substrates feeding into the aromatic pathway of the plastid. If so, a tendency to starvation for pathway endproducts may trigger derepression of the plastidic-pathway isozymes. 

Inhibition of aflatoxin biosynthesis by neem extracts in fungal cells appear to occur in the very early stages of the biosynthetic pathway (i.e., prior to norsolorinic acid synthesis) because after the initiation of secondary metabolism, the inhibitory effect of the neem leaf constituents was lost (84). 

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. 

In individuals with PKU, a secondary, normally little-used pathway of phenylalanine metabolism comes into play. In this pathway phenylalanine undergoes transamination with pyruvate to yield phenylpyruvate (Fig. 18-25). Phenylalanine and phenylpyruvate accumulate in the blood and tissues and are excreted in the urine—hence the name phenylketonuria. Much of the phenylpyruvate, rather than being excreted as such, is either decarboxylated to phenylacetate or reduced to phenyllactate. Phenylacetate imparts a characteristic odor to the urine, which nurses have traditionally used to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe mental retardation. This may be caused by excess phenylalanine competing with other amino acids for transport across the blood-brain barrier, resulting in a deficit of required metabolites. 

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