Biosynthesis of tetracyclines. XI. Methylanthrone analog of protetrone

McCormick, J. R. D.; Jensen, Elmer R.; Arnold, Nancy H.; Corey, Howard S.; Joachim, Ursula H.; Johnson, Susan M.; Miller, P.; Sjolander, Newell O.

doi:10.1021/ja01027a046

Cited by 19 publications

(12 citation statements)

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“…As described earlier, very productive studies on the biosynthesis of CTC, produced by S. aureofaciens, were carried out during the 1960s by McCormick et al (27)(28)(29)(30)(31)(32)(33)(34)(35) at Lederle. They applied feeding experiments of the blocked mutants generated through random mutagenesis, which resulted in the production of diff erent TC intermediates or shunt products (27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Section: Biosynthetic Pathway Of Tetracycline Antibioticsmentioning

confidence: 99%

“…They applied feeding experiments of the blocked mutants generated through random mutagenesis, which resulted in the production of diff erent TC intermediates or shunt products (27)(28)(29)(30)(31)(32)(33)(34)(35). The entire biosynthe tic gene clusters encoding CTC and OTC (Fig.…”

Section: Biosynthetic Pathway Of Tetracycline Antibioticsmentioning

confidence: 99%

“…Based on the studies carried out using blocked mutants (27)(28)(29)(30)(31)(32)(33)(34)(35), the fi rst stable OTC intermediate is likely the fully aromatised tetracyclic compound called pretetramide (5 in Fig. 4b), which then undergoes further processing, tailoring reactions of the fully formed TC backbone; this is also called post-PKS tailoring.…”

Section: Formation Of the Tetracycline Backbone In Otc Biosynthesismentioning

confidence: 99%

“…Thus, when considering the biosynthetic pathway involved in the formation of TCs, it is probably not appropriate to defi ne the biosynthetic steps as a number of ordered reactions. However, based on numerous OTC and CTC intermediates or shunt products isolated from blocked mutants of S. rimosus and S. aureofaciens, respectively (27)(28)(29)(30)(31)(32)(33)(34)(35), it is possible to speculate on the preferred order of enzymatic reactions involved in the modifi cation of the early TC intermediate pretetramide (5 in Fig. 4b).…”

Section: Tailoring Reactions Of the Basic Tetracycline Backbonementioning

confidence: 99%

“…4b). Considering that the methyl group at carbon C6 is found in almost all early intermediates in the biosynthesis of OTC and CTC, when blocked mutants were analysed at Lederle (27)(28)(29)(30)(31)(32)(33)(34)(35), it was believed that methylation by methyl-transferase OxyF at the C6 position is one of the earliest steps in the tailoring reactions of the TC backbone (6 in Fig. 4b) (58).…”

Section: Tailoring Reactions Of the Basic Tetracycline Backbonementioning

confidence: 99%

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Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics

Petković

Lukežič²,

Šušković

2017

Food Technol. Biotechnol.

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SummaryNatural tetracycline (TC) antibiotics were the fi rst major class of therapeutics to earn the distinction of 'broad-spectrum antibiotics' and they have been used since the 1940s against a wide range of both Gram-positive and Gram-negative pathogens, mycoplasmas, intracellular chlamydiae, rickett siae and protozoan parasites. The second generation of semisynthetic tetracyclines, such as minocycline and doxycycline, with improved antimicrobial potency, were introduced during the 1960s. Despite emerging resistance to TCs erupting during the 1980s, it was not until 2006, more than four decades later, that a third--generation TC, named tigecycline, was launched. In addition, two TC analogues, omadacycline and eravacycline, developed via (semi)synthetic and fully synthetic routes, respectively, are at present under clinical evaluation. Interestingly, despite very productive early work on the isolation of a Streptomyces aureofaciens mutant strain that produced 6-demethyl-7-chlortetracycline, the key intermediate in the production of second-and third-generation TCs, biosynthetic approaches in TC development have not been productive for more than 50 years. Relatively slow and tedious molecular biology approaches for the genetic manipulation of TC-producing actinobacteria, as well as an insuffi cient understanding of the enzymatic mechanisms involved in TC biosynthesis have signifi cantly contributed to the low success of such biosynthetic engineering eff orts. However, new opportunities in TC drug development have arisen thanks to a signifi cant progress in the development of aff ordable and versatile biosynthetic engineering and synthetic biology approaches, and, importantly, to a much deeper understanding of TC biosynthesis, mostly gained over the last two decades.

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