An acetyltransferase controls the metabolic flux in rubromycin polyketide biosynthesis by direct modulation of redox tailoring enzymes

• DOI: 10.1039/d2sc01952c
• Publication Date: 2022-05-17T07:02:00Z
• Authors: Marina Toplak; Adelheid Nagel; Britta Frensch; Thorsten Lechtenberg; Robin Teufel
• Keywords: Natural product; Acetyltransferases; Synthetic Biology

The often complex control of bacterial natural product biosynthesis typically involves global and pathway-specific transcriptional regulators gene expression, which limits the yield bioactive compounds under laboratory conditions. However, little is known about regulation mechanisms on enzymatic level. Here, we report a novel regulatory principle for products involving dedicated acetyltransferase, modifies redox-tailoring enzyme thereby enables pathway furcation alternating pharmacophore assembly in rubromycin polyketide biosynthesis. rubromycins such as griseorhodin (grh) A are aromatic polyketides from Actinobacteria with hallmark bisbenzannulated [5,6]-spiroketal that mainly installed by two flavoprotein monooxygenases. First, GrhO5 converts advanced precursor collinone into [6,6]-spiroketal containing dihydrolenticulone, before GrhO6 effectuates ring contraction to afford [5,6]-spiroketal. Our results show addition acetyl-CoA-dependent acetyltransferase GrhJ activates allow rapid generation release its labile product, subsequently sequestered ketoreductase GrhO10 converted stable intermediate. Consequently, directed canonical rubromycins, while alternative spontaneous hydrolysis ring-opened thwarted. Presumably, this allows bacteria rapidly adjust functionally distinct secondary metabolites depending nutrient (i.e. acetyl-CoA) availability. study thus illustrates how can be enzymatically regulated provides new perspectives improvement vitro activities titers via biotechnological approaches.