Tetracycline biosynthesis

Tetracycline, ( )-dedimethylamino-12a-deoxyanhydrc-synthesis, 1, 454 Tetracyclines biosynthesis, 1, 87 growth permittants veterinary use, I, 220 synthesis, 1, 454... 

A. L. Belousova and L. A. Popova (1961). The effect of inorganic phosphorus on tetracycline biosynthesis and the composition of phosphorus fractions in Actinoinyces atireofciciens with respect to the conditions of culture and growth of the mycelia (in Russian). Antibiotiki, 4, 302-307. 

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-... 

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 ... 

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). 

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. 

Aminoglycosides Tetracyclines Chloramphenicol Erythromycin Clindamycin Spectinomycin Mupirodn Fusldfc add Inhibition of protein biosynthesis... 

Genes encoding phosphotransferases confer resistance to streptomycin Genes encoding a drug-resistant dihydropteroate synthase enzyme required for folate biosynthesis confer resistance to sulfonamide Tetracycline... 

The medically useful products demethyltetracycline and doxorubicin (adriamycin) were discovered by simple mutation of the cultures producing tetracycline and daunorubicin (daunomycin), respectively. The tectmique of mutational biosynthesis (mutasynthesis) has been used for the discovery of many new aminoglycoside, macrolide, and anthracycline antibiotics. In this tectmique, a non-producing mutant ( idiotroph ) is isolated and then fed various analogs of the missing moiety. When such a procedure leads to a return of antibiotic activity, it usually is due to the... 

As a group, the protein biosynthesis inhibitors comprise the second largest class of antibiotics available for clinical use. Natural product classes of antibiotics that inhibit the protein biosynthesis are aminoglycosides, tetracyclines, chloramphenicol, macrolides, lincosamides, fusidic acid, streptogramins and mupirocin (Fig. 7). 

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. 

Tetracyclines inhibit protein biosynthesis by acting on the 70S and 80S ribosomes. 

Finally, it has to be noted that glycopeptides only represent one option to combat infections by gram-positive bacteria. Current research is focused on other cell wall biosynthesis inhibitors (e.g., (3-lactams, cephalosporins) or even on the development of antibacterial agents (e.g., tetracyclines, ketohdes, and quinolone antibiotics) against other targets.An important drug candidate in this context is hnezolid (Zyvox), which is an entirely synthetic oxazolidinone antibiotic with in vitro and in vivo efficiency against MRS A and VRE. ... 

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. 

The mechanism of toxicity for aminoglycosides has not been fully explained and is therefore unclear. It is known that the drug attaches to a bacterial cell wall and is drawn into the cell via channels made up of a protein, porin. Once inside the cell, the aminoglycoside attaches to the 30S bacterial ribosomes. Ribosomes are the intracellular structures responsible for manufacturing proteins. This attachment either inhibits protein biosynthesis or causes the cell to produce abnormal, ineffective proteins. The bacterial cell cannot survive with this impediment. This explanation, however, does not account for the potent bactericidal properties of these agents, since other antibiotics that inhibit the synthesis of proteins (such as tetracycline) are not bactericidal. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane probably accounts for most of the bactericidal activity. 

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. 

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