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Literature summary for 2.1.1.335 extracted from

  • Lukezic, T.; Fayad, A.; Bader, C.; Harmrolfs, K.; Bartuli, J.; Groß, S.; Lesnik, U.; Hennessen, F.; Herrmann, J.; Pikl, A.; Petkovic, H.; Müller, R.
    Engineering atypical tetracycline formation in Amycolatopsis sulphurea for the production of modified chelocardin antibiotics (2019), ACS Chem. Biol., 14, 468-477 .
    View publication on PubMed
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Cloned(Commentary)

Cloned (Comment) Organism
expression in Amycolatopsis sulphurea Streptomyces rimosus

Organism

Organism UniProt Comment Textmining
Streptomyces rimosus Q3S8P6
-
-

Synonyms

Synonyms Comment Organism
oxyT
-
 Streptomyces rimosus

General Information

General Information Comment Organism
drug target biosynthetic engineering of Amycolatopsis sulphurea for derivatization of the atypical tetracycline chelocardin and its potent broadspectrum derivative 2-carboxamido-2-deacetyl-chelocardin. Heterologous biosynthetic genes are introduced into this chelocardin producer to modify functional groups and generate new derivatives. Cooperation of chelocardin polyketide synthase with tailoring enzymes involved in biosynthesis of oxytetracycline from Streptomyces rimosus is demonstrated. An interesting feature of chelocardin, compared with oxytetracycline, is the opposite stereochemistry of the C4 amino group. Genes involved in C4 transamination and N,N-dimethylation of oxytetracycline are heterologously expressed in an Amycolatopsis sulphurea mutant lacking C4-aminotransferase. Chelocardin derivatives with opposite stereochemistry of the C4 amino group, as N,N-dimethyl-epi-chelocardin and N,N-dimethyl-2-carboxamido-2-deacetyl-epi-chelocardin, are produced only when the aminotransferase from oxytetracycline is coexpressed with the N-methyltransferase OxyT. OxyT exclusively accepts intermediates carrying an S-configured amino group at C4 in chelocardin. Applying medicinal chemistry approaches, several 2-carboxamido-2-deacetyl-epi-chelocardin derivatives modified at C4 are produced. Analysis of the antimicrobial activities of the modified compounds demonstrates that the primary amine in the R configuration is a crucial structural feature for activity of chelocardin Streptomyces rimosus