Oxytetracycline biosynthesis

Rhodes, P.M., Winskill, N., Friend, E.J. Warren, M. Biochemical and genetic characterization of Streptomyces rimosus mutants impaired in oxytetracycline biosynthesis. J. Gen. Microbiol. 124, 329-338 (1981). 

Binnie, G., Warren, M. Butler, M.J. Cloning and heterologous expression in Streptomyces lividans of Streptomyces rimosus genes involved in oxytetracycline biosynthesis. J. Bacterid. 

The tetracyclines were discovered towards the end of the 1940 s (structure of oxytetracycline shown in Figure 5), They have a broader spectrum of activity than the early penicillins. In addition effects on bacteria are different. The penicillins are bactericidal whereas the tetracyclines are bacteriostatic, reflecting differing modes of action. Tetracyclines disrupt protein synthesis by binding to the bacterial ribosome whilst the P-lactams inhibit bacterial cell wall biosynthesis. During the 60 s, 70 s and early 80 s, tetracycline-based products made the biggest commercial impact in the animal health industry. 

Type II polyketide synthases, also referred to as bacterial aromatic polyketide synthases (25) are involved in the biosynthesis of a number of clinically important bacterial aromatic polyketides products exhibiting antitumor or antibiotic activity, such as doxorubicin and oxytetracycline. As mentioned, type II synthases are evolutionarily and structurally related to type II FASs, which occurr as heteromultimeric complexes. In contrast to type I synthases however, where multiple catalytic sites occur within a given subunit, the polypeptides associated with type II synthase complexes are typically monofimctional and dissociable 20,30). 

Polyketides constitute a class of antibiotics which are made in pathways like fatty acid biosynthesis, but in which one or more of the activities are missing (Figure 18.35). Example polyketides include erythromycin and oxytetracycline. 

Polyketides are a class of antibiotics found in bacteria and fungi. Erythromycin and oxytetracycline are examples. The pathway for polyketide synthesis contains part of the fatty acid biosynthesis pathway, except that one or more of the enzymes are missing at various points in the pathway (Figure 18.35). This leads to a diverse set of products containing internal hydroxyls and ketone groups. 

See also Polyketides, Erythromycin, Oxytetracycline, Fatty Acid Biosynthesis Strategy... 

Most of the type II PKSs studied so far used acetate as a starter unit. The minimal PKS appears to have intrinsic starter unit specificity for acetyl CoA, which could also be derived by decarboxylation from malonyl CoA, at least in vitro [173,183, 184]. Little is known about how a type II PKS chooses a starter imit other than acetate. The biosynthesis of 13 and 14 in S. peucetius and Streptomyces sp. C5, and oxytetracycline in Streptomyces rimosus are known examples in which a type II PKS used propionyl CoA [84,153,163] and malonamyl CoA [152] as a starter unit, respectively. However, engineered PKSs consisting of the KSa/KSp pair from either the dps [163] or otc [152] cluster produced poiyketides exclusively with an acetate starter, reinforcing the notion that the minimal PKS has an intrinsic specificity for an acetate starter. At least for the biosynthesis of 13 and 14 the choice of the propionate starter unit has been shown to depend on dedicated subunits, in addition to the minimal dps PKS, and on the protein/protein interactions among all the subunits of the resulting PKS complex [84,153,163]. 

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