Iterative type II polyketide synthases, cyclases and ketoreductases exhibit context-dependent behavior in the biosynthesis of linear and angular decapolyketides

Guido Meurer, Martin Gerlitz, Evelyn Wendt-Pienkowski, Leo C. Vining, Jürgen Rohr, C. Richard Hutchinson

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52 Scopus citations


Background: Iterative type II polyketide synthases (PKSs) produce polyketide chains of variable but defined length from a specific starter unit and a number of extender units. They also specify the initial regiospecific folding and cyclization pattern of nascent polyketides either through the action of a cyclase (CYC) subunit or through the combined action of site-specific ketoreductase (KR) and CYC subunits. Additional CYCs and other modifications may be necessary to produce linear aromatic polyketides. The principles of the assembly of the linear aromatic polyketides, several of which are medically important, are well understood, but it is not clear whether the assembly of the angular aromatic (angucyclic) polyketides follows the same rules. Results: We performed an in vivo evaluation of the subunits of the PKS responsible for the production of the angucyclic polykefide jadomycin (jad), in comparison with their counterparts from the daunorubicin (dps) and tetracenomycin (tcm) PKSs which produce linear aromatic polyketides. No matter which minimal PKS was used to produce the initial polyketide chain, the jadD and DpsF CYCs produced the same two polyketides, in the same ratio; neither product was angularly fused. The set of jadABCED PKS plus putative jadl CYC genes behaved similarly. Furthermore, no angular polyketides were isolated when the entire set of jad PKS enzymes and Jadl or the jad minimal PKS, Jadl and the TcmN CYC were present. The DpsE KR was able to reduce decaketides but not octaketides; in contrast, the KRs from the jad PKS (JadE) or the actinorhodin PKS (ActIII) could reduce octaketide chains, giving three distinct products. Conclusions: It appears that the biosynthesis of angucyclic polyketides cannot be simply accomplished by expressing the known PKS subunits from artificial gene cassettes under the control of a non-native promoter. The characteristic structure of the angucycline ring system may arise from a kinked precursor during later cyclization reactions involving additional, but so far unknown, components of the extended decaketide PKS. Our results also suggest that some KRs have a minimal chain length requirement and that CYC enzymes may act aberrantly as first-ring aromatases that are unable to perform all of the sequential cyclization steps. Both of these characteristics may limit the widespread application of CYC or KR enzymes in the synthesis of novel polyketides.

Original languageEnglish
Pages (from-to)433-443
Number of pages11
JournalChemistry and Biology
Issue number6
StatePublished - Jun 1997

Bibliographical note

Funding Information:
We thank Chaitan Khosla for reference samples of mutactin, dehydromu-tactin, RMPOb, RM20c, SEK4, SEK4b and SEK34. The research was supported in part by a grant from the National Institutes of Health (CA35381) to C.R.H. and a NATO grant (CRG 950391) to J.R. and C.R.H. This study made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grant RR02301 from the Biomedical Research Technology Program, National Center for Research Resources. Equipment in the facility was purchased with funds from the University of Wisconsin, the NSF Biological Instrumentation Program (DMB-8415048) NSF Academic Research Instrumentation Program (BIR-9214394), NIH Biomedical Research Technology Program (RR02301), NIH Shared Instrumentation Program (RR02781 and RR08438), and the U.S. Department of Agriculture. The X-ray spectrum was obtained using an X-ray instrument and computers supported by NSF (grant CHE-9310428) and the University of Wisconsin.


  • Actinorhodin
  • Angucyclines
  • Daunorubicin
  • Jadomycin B
  • Tetracenomycin C

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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