Abstract
The rimJ gene, which codes for a crotonyl-CoA carboxylase/reductase, lies within the biosynthetic gene cluster for two polyketides belonging to the polyene macrolide group (CE-108 and rimocidin) produced by Streptomyces diastaticus var. 108. Disruption of rimJ by insertional inactivation gave rise to a recombinant strain overproducing new polyene derivatives besides the parental CE-108 (2a) and rimocidin (4a). The structure elucidation of one of them, CE-108D (3a), confirmed the incorporation of an alternative extender unit for elongation step 13. Other compounds were also overproduced in the fermentation broth of rimJ disruptant. The new compounds are in vivo substrates for the previously described polyene carboxamide synthase PcsA. The rimJ disruptant strain, constitutively expressing the pcsA gene, allowed the overproduction of CE-108E (3b), the corresponding carboxamide derivative of CE-108D (3a), with improved pharmacological properties.
Highlights
The polyene-macrolides are a group of polyketides that are commercially important because of their antifungal properties
According to our previous findings [20], disruption of the rimJ gene, encoding a crotonyl-CoA carboxylase/reductase belonging to the rimocidin/CE-108 gene cluster, caused some interesting differences in the chromatographic profile of the produced polyenes compared to the wild type strain
During 3a formation, the elongation module 13 incorporates acetate rather than the naturally observed butyrate in the biosynthesis of 2a and 4a [20], indicating a reduced selectivity for the polyketide synthases (PKSs) involved in elongation module 13, which can incorporate methylmalonyl-CoA units when the availability of ethylmalonyl-CoA units is reduced as a consequence of rimJ disruption
Summary
The polyene-macrolides are a group of polyketides that are commercially important because of their antifungal properties. This group includes well-known drugs such as amphotericin B (1), pimaricin, nystatin, 4a, and candicidin. They consist of a macrolactone ring containing several conjugated double bonds, which are in part responsible for the physical and chemical properties of these compounds (strong light sensitivity and low solubility in water). A sugar moiety (typically mycosamine) and a free carboxyl group are usually found on the macrocycle. The biological activity of these polyenes is rather specific for fungi, due to their preferred affinity.
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