Tetracyclines biosynthetic pathway

The product of the reaction of ATC oxygenase is DHTC, the last intermediate in the tetracycline biosynthetic pathway before tetracycline dehydrogenase converts it to tetracycline. A coupled enzyme system has been developed to assay conversion of DHTC (produced continuously using ATC oxygenase in vitro) to tetracycline (79.86). Tlte system has also been used to investigate the role of S -deazaflavin—the unusual co ctor involved in electron transfer for this last step in tetracycline biosynthesis (87). 

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... 

Depict the biosynthetic pathway of tetracycline by showing structural transformation of each metabolic step. 

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... 

Cultivation of RB50 [pRF69] with fractional C-labeled glucose as carbon source and metabolic flux balancing indicated that riboflavin formation in this strain was still limited by the fluxes through the terminal biosynthetic rather than the central carbon metabolic pathways. To debottleneck the riboflavin biosynthetic pathway further, a similar approach as described above was applied to introduce a second P poz-driven and amplifiable rib expression cassette linked to a tetracycline resistance marker at the bpr locus (map position... 

The proliferation in the number of new and diverse fungal metabolites in recent years complicates a comprehensive survey of their biogenetic origin. The biosynthesis of many metabolites appears to be trivial, because a cursory chemical inspection of the structure allows the formulation of a plausible biosynthetic pathway. For many new metabolites, no toxicological data are available and only the structural elucidation together with a biosynthetic postulate is reported. Thus the biosynthetic origin of viridicatumtoxin (1), a toxic metabolite from Penicillium viridicatum (Kabuto et al., 1976), has not been studied, but is most probably closely modeled on that of the tetracyclines (McCormick, 1967). Similarly, verruculotoxin (2), isolated from cultures of Penicillium verruculosum, is most probably derived from two L-amino acids, phenylalanine and pipecolic acid (Macmillan et aL, 1976). 

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