This article in the journal Microbiology describes the identification of the biosynthetic gene cluster for chelocardin, a broad-spectrum tetracyclic antibiotic with potent bacteriolytic activity produced in Amycolatopsis sulphurea. Several structural features as well as mode of action of chelocardin differ substantially from other tetracyclines. One of the key differences is the presence of acetate priming, compared to malonamate priming of polyketide chain in most other tetracycline structures. The likely reason for this difference was found to be related to the lack of an acyltransferase homologue in the gene cluster. Considering that most often AT enzyme (or AT domains in the modular PKS of Type II, like FK506 PKS) are playing very important role in the priming reactions of Type II PKS, findings described in this article offer new approaches for generation of novel polyketide compounds using biosynthetic engineering, particularly novel possibilities for using acyltransferase homologues.
COBISS.SI-ID: 27043111
In this article is described construction of strains of Streptomyces rapamycinicus which efficiently produces rapamycin analogs and enable execution of pre-clinical and early stage clinical trials. These strains enabled mutasynthetic approaches to new rapalogs that could not readily be isolated from lower titre strains when fed DHCHC analogs. Mutasynthesis of some rapalogs resulted predominantly in compounds lacking late post polyketide synthase biosynthetic modifications. To enhance the relative production of fully elaborated rapalogs, genes encoding late-acting biosynthetic pathway enzymes, which failed to act efficiently on the novel compounds were over-expressed, what lead efficient production of rapalogs. Obtained observation will improve our understanding of production of novel rapalogs and simplify execution of activities in continuation of project.
COBISS.SI-ID: 4189560