Polyketides chemical structures

Chemical structure can often be used by itself to recognize a secondary metabolite because of their common biosynthetic origin Terpenes and polyketides, for... 

Kosan Biosciences was formed almost 6 years ago, founded on an interest in polyketides, microbial metabolite-based drugs. Polyketides have many diverse chemical structures including erythromycin, which will be mentioned again later. These chemicals include fused-ring aromatic compounds, compounds decorated with sugars, and compounds with large stretches of double bonds. Each of these compounds has different biological activities and utilities, but they are all made in nature by very similar biochemistry. 

Aromatic polyketides are structurally diverse, often polycyclic molecules that are derived from unreduced polyketone chains. This group of compounds is produced with the help of type II polyketide synthase (PKS), a complex of enzymes that catalyzes the iterative decarboxylative condensation of malonyl-CoA extender units with an acyl starter unit [70], The carbon framework of aromatic polyketides is further decorated with different functionalities, and carbohydrates are often one of them. Their presence has profound effects on physico-chemical and biological properties of aromatic polyketides. For example, anthracycline aglycones are stable and unpolar, while polyglycosylated anthracyclines are quite polar and often... 

Dissection of the chemical structure of jamaicamides A-C led to the speculation that these metabolites derive from a mixture of polyketides (nine acetate units), amino acids (t-Ala and p-Ala), and the S-methyl group of methionine. To map out the biosynthetic subunits of these molecules, isotopically labeled precursors were supplied to I. majuscula JHB, and the labeling patterns discerned by NMR spectroscopy (Figure 6.12). From these experiments, insights were gained into the biochemical transformations that produce the jamaicamides, especially the mechanism of formation of the vinyl chloride group [157]. 

Polyketides (PKs) are a typical example of a large and diverse class of NPs that derive from several related biosynthetic pathways. Their stmctures contain repeating units iteratively assembled into a range of diverse chemical structures (Fig. 10.43). PKs can be taken as an example of the application of combinatorial biosynthesis as both the... 

Over the past quarter-century more than 10,000 compounds have been reported from marine-derived organisms. These compounds encompass a wide variety of chemical structures including acetogenins, polyketides, terpenes, alkaloids, peptides and many compounds of mixed biosynthesis. A number of excellent books and reviews document the diversity of both structures and bioactivities which have been observed for marine-derived compounds. ... 

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). 

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]. 

The basic skeleton of isoprenoids may be modified by the introduction of a wide variety of chemical groups, by isomerization, shift of double bonds, methyl groups, etc. Hence a bewildering number of chemical structures arises. In addition compounds derived from other biogenic pathways may contain isoprene residues. For instance the K vitamins (D 8.1), ubiquinones (D 8.3), chlorophylls (D 10.1), plastoquinones, and tocopherylquinones (D 22.4) have isoprenoid side chains with up to ten isoprene units. Polyketides (D 3.3), alkaloids (D 8.4.2), and coumarins (D 22.2.2) may be substituted by dimethylallyl groups. The terpene residues are attached to nucleophilic sites, such as active methylene groups and phenolic oxygen atoms. 

Bhan, N, Cress, B.F., Linhardt, R.J., and Koffas, M, (2015) Expanding the chemical space of polyketides through structure-guided mutagenesis of Vitis vinifera stilbene synthase. Biochimie, 115, 136-143. 

The discovery of these early statins paved the way for the worldwide development of other drugs based on the statin chemical structure (Figure 8.2). Sankyo and Merck directed their later efforts at manufacturing synthetic analogs. Many different statins are currently available for therapeutic use, but lovastatin and mevastatin remain the only fermentation-derived statins. The lovastatin biosynthetic pathway in A. terreus is well understood. This pathway was the first example of a polyketide synthetic pathway in which two fungal type I polyketide synthases work in combination to produce a product (Hendrickson et al., 1999 Kennedy et al., 1999). Since then several statins, including simvastatin, pravastatin, fluvastatin and atorvastatin, have been approved in many countries and are currently used by millions. 

The resorcinylic macrolides (also known as resordnylic add lactones or RALs) are a family of naturally occurring homologous macrolides. They are derived from polyketide biogenesis in different fungi and have been isolated from different fungal strains [12]. They have unique chemical structures and potent biological activities (antitumoral, antibiotic, and antimalarial activities) [13]. 

Owing to the extreme complexity of their structures, polyketides for clinical use are produced mainly by fermentation rather than chemical synthesis. However, the levels of polyketides produced by microbes from nature are not high enough for commercial purposes thus, strain... 

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