Natural Biocombinatorics in the Polyketide Synthase Genes of the Actinobacterium Streptomyces avermitilis

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Abstract
Modular polyketide synthases (PKSs) of bacteria provide an enormous reservoir of natural chemical diversity. Studying natural biocombinatorics may aid in the development of concepts for experimental design of genes for the biosynthesis of new bioactive compounds. Here we address the question of how the modularity of biosynthetic enzymes and the prevalence of multiple gene clusters in Streptomyces drive the evolution of metabolic diversity. The phylogeny of ketosynthase (KS) domains of Streptomyces PKSs revealed that the majority of modules involved in the biosynthesis of a single compound evolved by duplication of a single ancestor module. Using Streptomyces avermitilis as a model organism, we have reconstructed the evolutionary relationships of different domain types. This analysis suggests that 65% of the modules were altered by recombinational replacements that occurred within and between biosynthetic gene clusters. The natural reprogramming of the biosynthetic pathways was unambiguously confined to domains that account for the structural diversity of the polyketide products and never observed for the KS domains. We provide examples for natural acyltransferase (AT), ketoreductase (KR), and dehydratase (DH)–KR domain replacements. Potential sites of homologous recombination could be identified in interdomain regions and within domains. Our results indicate that homologous recombination facilitated by the modularity of PKS architecture is the most important mechanism underlying polyketide diversity in bacteria. Modular polyketide synthases (PKSs) of bacteria are multifunctional enzymes providing a molecular construction plan for the stepwise generation of polyketides of high structural complexity. Natural products of the polyketide class belong to the most important medicines used for the treatment of infectious diseases and cancer. The genetic “programming” of the enzymes determines the choice of different carbon units, the reduction state, and the stereochemistry of the polyketide chain. The modular architecture of PKS enzyme systems lends itself to rational engineering in the laboratory using so-called biocombinatorics approaches. Streptomycetes are soil bacteria typically comprising multiple PKS gene clusters. Jenke-Kodama, Börner, and Dittmann have addressed the question whether this prevalence of repetitive PKS modules within a single genome has an impact on the diversification of the polyketide products. Using phylogenetic approaches, the authors provide evidence that homologous recombination has led to exchange, loss, and gain of domains and domain fragments and hence to a natural “reprogramming” of the PKS assembly lines. These data are not only interesting from the evolutionary point of view but might also help to improve protocols for PKS engineering that are being developed for the synthesis of new bioactive compounds and libraries.