Generation of multiple bioactive macrolides by hybrid modular polyketide synthases in Streptomyces venezuelae.
The plasmid-based replacement of the multifunctional protein subunits of the pikromycin PKS in S. venezuelae by the corresponding subunits from heterologous modular PKSs resulted in recombinant strains that produce both 12- and 14-membered ring macrolactones with predicted structural alterations. In all cases, novel macrolactones were produced and further modified by the DesVII glycosyltransferase and PikC hydroxylase, leading to biologically active macrolide structures. These results demonstrate that hybrid PKSs in S. venezuelae can produce a multiplicity of new macrolactones that are modified further by the highly flexible DesVII glycosyltransferase and PikC hydroxylase tailoring enzymes. This work demonstrates the unique capacity of the S. venezuelae pikromycin pathway to expand the toolbox of combinatorial biosynthesis and to accelerate the creation of novel biologically active natural products.
Yoon
Yeo Joon
YJ
Department of Microbiology and Biotechnology Institute, University of Minnesota, Mayo Mail Code 196, 1460 Mayo Memorial Building, Minneapolis, MN 55455, USA.
Beck
Brian J
BJ
Kim
Beom Seok
BS
Kang
Han Young
HY
Reynolds
Kevin A
KA
Sherman
David H
DH
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D017353:Gene Deletion; D005816:Genetic Complementation Test; D005818:Genetic Engineering; D018942:Macrolides; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D018942:Macrolides; D009097:Multienzyme Complexes