Metabolites from polyketide pathway

The Polyketide Pathway One metabolic process that has received much attention from natural product chemists is the production of secondary metabolites via polyketide synthase (PKS) enzymes. Polyketide synthases condense small starting... 

Metabolites of the phylum Porifera account for almost 50% of the natural products reported from marine invertebrates. Of the 2609 poriferan metabolites, 98% are derived from amino acid, acetogenin, or isoprenoid pathways. Isoprenoids account for 50% of all sponge metabolites, while amino acid and polyketide pathways account for 26% and 22%, respectively. A significant number of sponge metabolites appear to be derived from mixed biosynthetic pathways. Most structures reported containing carbohydrate moieties were glycosides. 

Of the more than 20,000 known species of lichens, only a few have been analyzed and identified as containing biologically active secondary compounds. Most of the unique secondary metabolites that are present in lichens are derived from the polyketide pathway, with a few originating from the shikimic acid and mevalonic acid pathways (Table 1.1). Previous studies have suggested that the para-depsides are precursors to mefa-depsides, depsones, diphenyl ethers, depsidones and dibenzofurans.9,12... 

Many secondary metabolites with complex chemical structures, including pigments (Figure 2) and monacolins (Figure 2), are synthesized from the polyketide pathway in Monascus spp. (Simpson, 1986). Several effectors controlling the polyketide synthesis of Monascus have been reported by using submerged culture systems (Lin, 1991). Considerable research has been conducted on the industrial production of Monascus in complex liquid media (Shepherd and Carels, 1983). 

Polyketide biosynthesis has been well smdied and there are several reviews regarding the general construction of these metabolites. " " Generally, polyketides are initiated with acetate (or propionate) derived from either acetyl-CoA (or propionyl-CoA) or malonyl-CoA (or methyknalonyl-CoA). The chain is extended by further addition of acetate units by a ketosynthase and acyltransferase domain. The acetate units can then be altered by the inclusion of a variety of domains within the PKS pathway. Common examples of alterations are ketoreductase,... 

Metabolites Derived from the Fatty Acid or Polyketide Pathways... 

Antifungal metabolites which are derived from either the fatty acid or polyketide pathway or a combination of the two are included in this section. 

Metabolites From the Polyketide Pathway Simple Aromatic Metabolites... 

Lovastatin is an inhibitor of the enzyme (35)-hydrooxymethylglutaryl-CoA (HMG-CoA) reductase tliat catalyzes the reduction of HMG-CoA to mevalonate, a key step in cholesterol biosynthesis. Tliis activity confers on lovastatin its medically important anti-hyperchoilesterolemic activity and other potentially important uses. It is a secondary metabolite from the filamentous fungus Aspergillus terreus and has been shown to be derived from acetate via a polyketide pathway. 

Many metabolites of the actinomycetes are biosynthesized through the polyketide biosynthetic pathway. For example, it was clarified that the pieri-cidins, isolated from the fermentation broth of Streptomyces pactum and possessing a pyridine nucleus, are produced through the polyketide pathway, as is nigrifactin. The biosynthetic pathway was clarified by stable isotope feeding experiments [5]. Piericidin Aj, the first piericidin derivative, was obtained as an insecticide [6] and the chemical structure, including the absolute configuration, was reported [7]. Other piericidin derivatives, pieri-cidins A2-A4, B1-B4, C1-C4, and D1-D4, were also isolated [8]. 

Lichens had to evolve diverse biosynthetic pathways to produce such complex arrays of secondary metabolites polyketide, shikimic acid, and mevalonic acid pathways. Most of the lichen substances are phenolic compounds. Polyketide-derived aromatic compounds, depsides, depsidones, dibenzofurans, xanthones, and naphthoquinones, are of great interest. Compounds from other pathways are esters, terpenes, steroids, terphenylquinones, and pulvinic acid (Fahselt 1994 Cohen and Towers 1995 Muller 2001 Brunauer et al. 2006, 2007 Stocker-Worgotter and Elix 2002 Johnson et al. 2011 Manojlovic et al. 2012). So, many lichens and lichen products have proved to be a source of important secondary metabolites for food and pharmaceutical industries (Huneck 1999 Oksanen 2006)... 

Precursor selection An important step in designing a microbial labeling process is the identification of one or more suitable labeled precursors. Generally, secondary metabolites are biosynthesized via primary metabolites from five metabolic sources. These are amino acids, shikimic acid (shikimic acid pathway), acetate and its homologues (polyketide pathway), mevalonic acid (isoprene pathway) and carbohydrates. Selection of a suitable precursor is primarily influenced by the biosynthetic pathway(s) involved, but also depends on the desired position of label in the product and the availability of labeled precursors. 

The biosynthetic studies undertaken to date on microbial marine natural products well illustrate the diversity of metabolic pathways encountered in cultured marine bacteria. Examples include brominated alkaloids such as pentabromopseudiline (Structure 2.1),19 polyketide or mixed polyketide metabolites such as oncorhyncholide (Structure 2.2),20 aplasmomycin (Structure 2.3),21 and andrimid (Structure 2.4),22 or the cyclic depsipeptide salinamide A (Structure 2.5).23 As researchers continue to define more specific culture media and a wider range of marine bacteria from diverse habitats are successfully placed into culture, the true biosynthetic potential of these prolific and adaptable microorganisms can be explored. 

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