Biosynthesis of tetracyclines

Biosynthesis of tetracycline was studied extensively and a number of various intermediates were isolated from the cultivation broth (6-37) [13-16], e.g. isochlortetracycline (6). High amounts of chlortetracycline are used in agriculture, e.g. in food additives on fish farms or also in pig, calf, sheep and poultry breeding. 

Glycosylation seems to occur during the biosynthesis of TETRACYCLINES and related antibiotics 44. Two enzymes, an N-methyl transferase 45 and a tetracycline 5a(lla) dehydrogenase 46 have been described. 

Similarly to the biosynthesis of tetracyclines, even here the bromo analog was produced by simply substituting KBr for KCl in the medium [25], Deuterated griseofulvin has been obtained by cultivation of P. janczewskii in culture medium with D2O. 

Some of the bound keto groups may be reduced by pyridine nucleotide-dependent dehydrogenases (C 2.1, see the formation of 6-methylsalicylic acid, D 3.3.1), and some of the activated CHg-groups may be alkylated by S-adenosyl-L-meth-ionine (C 3.3, see the biosynthesis of tetracyclines, D 3.3.7), or may be substituted by dimethylaUyl pyrophosphate (D 6), see the formulas of lupulone and humulone, the bitter principles of hop cones used in brewing beer (F 1). 

Miller, P. A., and A. Saturnelli Terminal reactions in the biosynthesis of tetracyclines. Paper presented at the Second Internat. Fermentation Symposium, London 1964b. 

Scott, A. I., and C. T. Bedford Simulation of biosynthesis of tetracyclines. A partial synthesis of tetracycline from anhydroaureomycin. J. Am. Chem. Soc. 82, 2271—... 

Two enzymes catalyze the last two steps of tetracycline biosynthesis Anhy-drotetracycline oxygenase produces dehydrotetracycline, and tetracycline dehydrogenase converts dehydrotetracycline to tetracycline. Usage of a diode-... 

Although tetracycline was not the first agent of its class discovered, it nonetheless provides the basis for tetracycline nomenclature (Fig. 6.6). Numerous reviews exist that report on the biosynthesis and use of tetracyclines (82,84-86). 

The enzymes of tetracycline biosynthesis have, with few exceptions, proved particularly difficult to study. The substrates for many of the steps are often insoluble or unstable in aqueous solution—Whence, there has been a paucity of information on them. The enzymes themselves may also be unstable. However, our knowledge of anhydrotetracyclinc oxygenase has advanced in recent years. There are several reasons ... 

Microbiological hydroxylation of i2 -deoxytetracycline to tetracycline has been shown to occur 8 and also the reduction of 5a(ii )-dehydrotetracy-cline . It may be that these processes occur at late stages in the biosynthesis of the tetracycline molecule. 

Other reviews deal with recent advances in the chemistry and biochemistry of tetracyclines, the chemical modification of antibiotics, a survey of antibiotics in chemotherapy, and the cell-free biosynthesis of actinomycins,tetracyclines, and streptomycin further reports call attention to the role of variant bacterial forms and mycoplasmas in disease, to the chemotherapy of enterobacterial infec-tionsi and to the ecology of transferable drug resistance in the enterobacteria. The judicious use of antibiotic combinations has been reviewed from the standpoint of a clinician. ... 

A complete review of tetracycline biosynthesis includes mention of the intriguing non-occurrence of 5-oxychlortetracycline which is, nevertheless, readily formed from its presumed precursor, 5a (11a)-dehydrochlortetracycline, by cell free or whole cell S rimosus preparations. 

A number of features distinguish the biosynthesis of outer membrane and periplasmic proteins from the cytoplasmic proteins. Examination of the sensitivity of cytoplasmic and outer membrane polypeptide synthesis to inhibitors of ribosome function suggests that the outer membrane proteins utilise different biosynthetic machinery. The biosynthesis of envelope proteins is strikingly more resistant to puromycin and kasugomycin than the transcription of cytoplasmic protein. In contrast, the synthesis of cytoplasmic proteins continues at levels of tetracycline and sparsomycin that... 

---