Polyketides tetracyclines

The overall biosynthetic pathway to the tetracychnes has been reviewed (74). Studies (75—78) utilising labeled acetate and malonate and nmr analysis of the isolated oxytetracycline (2), have demonstrated the exclusive malonate origin of the tetracycline carbon skeleton, the carboxamide substituent, and the folding mode of the polyketide chain. Feeding experiments using [1- 02] acetate and analysis of the nmr isotope shift effects, led to the location of... 

The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by species of Streptomyces, and several natural and semi-synthetic members are used clinically. They contain a linear tetracyclic skeleton of polyketide origin in which the starter group is malonamyl-CoA (Figure 3.54), i.e. the coenzyme A ester of malonate semi-amide. Thus, in contrast to most acetate-derived compounds, malonate supplies all carbon atoms of the tetracycline skeleton, the starter group as well as the chain extenders. The main features of the pathway (Figure 3.54) were deduced from extensive studies of mutant strains of Streptomyces aureofaciens with genetic blocks... 

The tetracyclines bind ribosomal proteins and inhibit bacterial protein synthesis. The first tetracycline was discovered in 1948. Tetracyclines are classified as polyketides, and all are either isolated from bacteria or derived from other tetracyclines. Common examples include tetracycline (A.30) and doxycycline (A.31) (Figure A.8). 

Like tetracyclines, macrolides are also polyketides that are isolated from bacteria and inhibit protein synthesis in certain bacteria. Erythromycin (A.32) is the original macrolide (Figure A.9). Clarithromycin (Biaxin, A.33) and azithromycin (Zithromax, A.34) are semisynthetic derivatives of erythromycin. 

Macrolides and polyethers such as erythromycin A (4), FK 506, rapamycin or avermectin A (5, Scheme 1) are products of modular type I polyketide-synthases. These compounds are distinguished by extraordinary structural diversity and complexity [1,2]. Because of their biological potency, members of this structural class as well as the aromatic polycyclic products of type II polyketide-synthases, tetracyclines and anthara-cyclines, e.g. adriamycin (6), became useful as pharmaceuticals (antibiotics, cytostatics, immunosuppressives) [1,2],... 

The most clinically significant polyketides are the anthracyclinone and tetracyclinone antibiotics produced in Streptomyces cultures. The tetracyclines demonstrate that chain initiation can occur with a malonamide unit and that a wide range of reactions can occur after the... 

An unusiul priming mechanism is observed in the biosynthetic pathway of tetracycline, one of the most important drugs in treating infectious diseases (30). Tetracyclines are aromatic polyketides synthesized by soil-borne actimonyces using type II PKS. Chlorotetracycline and oxytetracycline are biosynthesized... 

Fu,H., S.Ebert-Khosla, D.A.Hopwood and C.Khosla (1994b). Relaxed specificity of the tetracycline polyketide synthase for an acetate primer in the absence of a malonamyl primer J. Am. Chem. Soc. 116 6443-6444. 

Feeding studies using deuterated [1- 13C] acetate and subsequent location of the deuterated sites by the nmr isotope shift effects showed labeling at carbons 7 and 9. The absence of a detectable p-2H isotope shift at carbon 4a indicates that only one of the carbon-5 hydrogens is acetate-derived and that this is stereospecifically eliminated by carbon-5 a hydroxylation. 8-Methoxychlortetracydines, with and without hydroxyl substitution at carbon-4a, have been isolated. These tetracyclines retain the original oxygen at C-8 from the polyketide chain (79—81). 

Acetate/malonate Fatty acid derivatives (n-alkanes, acetylene derivatives). Polyketides (anthracene derivatives, tetracyclines, griseofulvin, phenolcarboxylic acids from fungi and lichens, pyridine derivatives). 

Several gene dusters encoding the enzymes of polyketide synthesis have been cloned (partially or completely). Aromatic polyketides (e.g., tetracyclines, actinorho-dine, and anthracyclines) are synthesized by type II PKSs, which are multienzyme OMn-plexes similar to FAS type II (63). In contrast, the polyketide chain of mactolide antibiotics such as erythromycin and avermectin are synthesized by PKS type I, consisting of large multifunctional polypeptides similar to FAS type I but composed of repeated units or "modules" with each active site carrying out only one reaction in the assembly and modification of each carbon chain (64,65). 

The most important polyketides of this type are the tetracyclines (Table 35) and derivatives of glutarimide, e.g., cycloheximide, which both are formed in Strepto-mycetes. 

Tetracyclines, e.g. 7-chlorotetracycline (3.100) are commercially important broad-spectrum antibiotics. Detailed information is available on the course of their biosynthesis as a result of an extensive study, using mutants in particular. This involved isolation of new products from differently blocked mutants and testing them as precursors in cross-feeding experiments. The structure (3.99) of mutant produced protetrone indicates the manner of folding in the polyketide as (3.97) (protetrone is a diversion from the main path-... 

Polyketides are an extraordinarily valuable class of natural products, numbering over 10,000 compounds. Commercially important polyketides include antibiotics (erythromycin A, tetracycline) and immunosuppressants (rapamycin), as well as anticancer (doxorubicin), antifungal (amphotericin B), and cholesterol-lowering (lovastatin) agents (Figure 25.15). It has been estimated that the sales of these and other polyketide pharmaceuticals total more than 15 billion per year. 

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