Tetracyclines pathway

The substrate for the enzyme (anhydrotetracycline, ATC) is one of the few intermediates in the tetracycline pathway chat is stable in aqueous solution. 

The tetracycline molecule (1) presents a special challenge with regard to the study of stmcture—activity relationships. The difficulty has been to devise chemical pathways that preserve the BCD ring chromophore and its antibacterial properties. The labiUty of the 6-hydroxy group to acid and base degradation (12,13), plus the ease of epimerization (23) at position 4, contribute to chemical instabiUty under many reaction conditions. 

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 three tetracyclines most recently marketed were made by a semisynthetic pathway. The first of these were methacycline (6-methylene oxytetracycline) (5), C22H22N2OS. and its reduction product doxycycline (6). C22H24CIN2O2- The latter compound is a potent antibiotic which is well-absorbed and slowly excreted, thus allowing small and infrequent (once or twice a day) dosage schedules. Finally, the most recent addition to the commercial tetracyclines is minocycline (7). C21H27N3O7. which is also well-absorbed and slowly excreted. 

Inhibitors are substances that tend to decrease the rate of an enzyme-catalysed reaction. Although some act on the substrate, the discussion here will be restricted to those inhibitors which combine directly with the enzyme. Inhibitors have many uses, not only in the determination of the characteristics of enzymes, but also in aiding research into metabolic pathways where an inhibited enzyme will allow metabolites to build up so that they are present in detectable levels. Another important use is in the control of infection where drugs such as sulphanilamides competitively inhibit the synthesis of tetrahydrofolates which are vitamins essential to the growth of some bacteria. Many antibiotics are inhibitors of bacterial protein synthesis (e.g. tetracyclin) and cell-wall synthesis (e.g. penicillin). 

Secondary metabolism is commonly achieved by uncoupling the anabolic from the growth pathways. The subsequent overflow metabolites are then channelled towards secondary products which may include such antibiotics as penicillin, tetracyclin and streptomycin. Figure 5.16 shows the relationship between secondary products and central anabolic pathways. 

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... 

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

Others Sequestration Immunity Proteins Target Modification Altered Metabohc Pathway Target Overexpression P-Lactams, Enediynes Bleomycin, Tetracycline Fluoroquinolones, Macrolides Vancomycin Trimethoprim... 

Over the years, various tetracyclines have been used in the treatment of acne. Their mechanism of action is not clear, but appears to be not purely antimicrobial, since they reduce chemotaxis of polymorphonuclear leukocytes, modify complement pathways, and inhibit the polymorphonuclear leukocyte chemotactic factor and lipase production in Propionibacterium acnes (33). They may also have a direct effect on sebum secretion (34), for example by modification of free fatty acids (35). 

Furthermore, the ability of the neonate to eliminate drugs via the kidney, the major excretion pathway, is significantly limited by the state of development of these organs. Penicillin and tetracycline (two antibiotics) are excreted more slowly and hence are more toxic in the young. Consideration of these factors indicates that the susceptibility and responsiveness of newborns to drug therapy are different from those of adults. 

The tetracyclines are effective in reducing P. acnes7 In addition to their antibacterial effects, they reduce the amount of keratin in sebaceous follicles and inhibit chemotaxis, phagocytosis, complement activation (by the alternate pathway), and cell-mediated immunity. Tetracyclines also appear to have an affinity for inflammatory cells and... 

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... 

---