Biosynthesis of pentangular polyphenols: deductions from the benastatin and griseorhodin pathways.
The benastatins, pradimicins, fredericamycins, and members of the griseorhodin/rubromycin family represent a structurally and functionally diverse group of long-chain polyphenols from actinomycetes. Comparison of their biosynthetic gene clusters (ben, prm, fdm, grh, rub) revealed that all loci harbor genes coding for a similar, yet uncharacterized, type of ketoreductases. In a phylogenetic survey of representative KRs involved in type II PKS systems, we found that it is generally possible to deduce the KR regiospecificity (C-9, C-15, C17) from the amino acid sequence and thus to predict the nature of the aromatic polyketide (e.g., angucycline, anthracycline, benzoisochromanequinones). We hypothezised that the new clade of KRs is characteristic for biosynthesis of polyphenols with an extended angular architecture we termed "pentangular". To test this hypothesis, we demonstrated the biogenetic relationship between benastatin and the structurally unrelated spiro ketal griseorhodin by generating a mutant producing collinone, a pentangular pathway intermediate. The benastatin pathway served as a model to characterize the KR. Gene inactivation of benL resulted in the formation of a series of 19-hydroxy benastatin and bequinostatin derivatives (e.g., benastatin K and benastatin L). These results clearly showed that BenL functions as a C-19 KR in pentangular pathways.
Lackner
Gerald
G
Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Beutenbergstrasse 11a, Jena, Germany.
Schenk
Angéla
A
Xu
Zhongli
Z
Reinhardt
Kathrin
K
Yunt
Zeynep S
ZS
Piel
Jörn
J
Hertweck
Christian
C
D039903:Actinobacteria / Q000737:chemistry* / Q000235:genetics; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D009279:Naphthacenes / Q000737:chemistry / Q000378:metabolism*; D009285:Naphthoquinones / Q000737:chemistry / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D048630:Polyketide Synthases / Q000737:chemistry / Q000378:metabolism; D059808:Polyphenols; D013997:Time Factors
D000900:Anti-Bacterial Agents; D005419:Flavonoids; D009279:Naphthacenes; D009285:Naphthoquinones; D010636:Phenols; D059808:Polyphenols; C018070:griseorhodins; C077629:benastatin A; C077630:benastatin B; D048630:Polyketide Synthases; D010088:Oxidoreductases