Abstract
Summary Penicillium chrysogenum is a filamentous fungus that is used to produce β‐lactams at an industrial scale. At an early stage of classical strain improvement, the ability to produce the yellow‐coloured sorbicillinoids was lost through mutation. Sorbicillinoids are highly bioactive of great pharmaceutical interest. By repair of a critical mutation in one of the two polyketide synthases in an industrial P. chrysogenum strain, sorbicillinoid production was restored at high levels. Using this strain, the sorbicillin biosynthesis pathway was elucidated through gene deletion, overexpression and metabolite profiling. The polyketide synthase enzymes SorA and SorB are required to generate the key intermediates sorbicillin and dihydrosorbicillin, which are subsequently converted to (dihydro)sorbillinol by the FAD‐dependent monooxygenase SorC and into the final product oxosorbicillinol by the oxidoreductase SorD. Deletion of either of the two pks genes not only impacted the overall production but also strongly reduce the expression of the pathway genes. Expression is regulated through the interplay of two transcriptional regulators: SorR1 and SorR2. SorR1 acts as a transcriptional activator, while SorR2 controls the expression of sorR1. Furthermore, the sorbicillinoid pathway is regulated through a novel autoinduction mechanism where sorbicillinoids activate transcription.
Highlights
Sorbicillinoids are a large family of hexaketide metabolites that include more than 90 highly oxygenated molecules
Sorbicathecols A/B inhibits the cytopathic effect induced by HIV-1 and influenza virus A (H1N1) in MDCK cells (Nicoletti and Trincone, 2016), whereas isobisvertinol inhibits lipid droplet accumulation in macrophages, an event associated with the initiation of atherosclerosis (Koyama et al, 2007; Xu et al, 2016)
The expression of the aforementioned genes was analysed by qPCR to exclude possible polar effects of the gene deletions and to assess the impact of the deletion of the two putative regulators on the expression of the sorbicillinoid gene cluster
Summary
Sorbicillinoids are a large family of hexaketide metabolites that include more than 90 highly oxygenated molecules These compounds can be structurally classified into four groups: monomeric sorbicillinoids, bisorbicillinoids, trisorbicillinoids and hybrid sorbicillinoids (Meng et al, 2016). P. chrysogenum strain NRRL1951 has been reported to be a natural source of more than 10 sorbicillinoids (Meng et al, 2016) This fungus was the progenitor for the high-b-lactam-yielding strains that are currently used in industry. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology
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