REVIEW www.rsc.org/npr | Natural Product Reports Polyketide synthases and nonribosomal peptide synthetases: the emerging view from bacterial genomics Stefano Donadio,* Paolo Monciardini and Margherita Sosio Received (in Cambridge, UK) 27th February 2007 First published as an Advance Article on the web 10th May 2007 DOI: 10.1039/b514050c Covering: bacterial genome sequences to 2005 and post-genomic literature to June 2006 A total of 223 complete bacterial genomes are analyzed, with 281 citations, for the presence of genes encoding modular polyketide synthases (PKS) and nonribosomal peptide synthetases (NRPS). We report on the distribution of these systems in different bacterial taxa and, whenever known, the metabolites they synthesize. We also highlight, in the different bacterial lineages, the PKS and NRPS genes and, whenever known, the corresponding products. 1 Introduction 2 Thiotemplate modular systems 3 A global view of bacterial genomes 4 Commonly encountered natural products 4.1 Cathechol-based iron chelating compounds 4.2 Prodiginines 4.3 Polyunsaturated fatty acids 5 Phylum proteobacteria 5.1 Common natural products 5.2 Class a-Proteobacteria 5.3 Class b-Proteobacteria 5.4 Class c -Proteobacteria 5.5 Classes d - and e-Proteobacteria 6 Phylum Firmicutes 6.1 Class Bacilli, order Bacillales 6.2 Class Bacillales, Order Lactobacillales 6.3 Class Clostridia 7 Phylum Actinobacteria 7.1 Common metabolites 7.2 Genus Corynebacterium 7.3 Genus Mycobacterium 7.4 Genus Streptomyces 7.5 Genus Nocardia 7.6 Propionibacterium acnes 8 Phylum Cyanobacteria 8.1 Order Nostocales, Genus Anabaena 8.2 Order Gloeobacterales: Gloeobacter violaceus 9 Other phyla 9.1 Phylum Planctomycetes 9.2 Other phyla 10 Conclusions 11 References 1 Introduction During the last two decades, enormous progress has been made in elucidating the biosynthesis of hundreds of secondary metabolites, KtedoGen, via Fantoli 16/15, 20132 Milan, Italy. E-mail: stefano.donadio@ ktedogen.com mostly from microorganisms. There is little doubt that the major contribution to this wealth of knowledge has resulted from the application of DNA sequencing to secondary metabolism, facilitated by the fact that microorganisms usually carry all the relevant genes in a contiguous DNA segment known as a gene cluster. These studies were therefore chemistry-driven, i.e. genes were characterized because they participated in the synthesis of known natural products. The data obtained have confirmed that the biosynthesis of a large number of natural products requires the participation of sophisticated molecular machines known as polyketide synthases (PKS) and nonribosomal peptide synthetases (NRPS). There is also little doubt that, around the turn of the millennium, we have fully witnessed the impact of the genomic revolution in our understanding of biology. One of the most outstanding advances from the genomic revolution has been in prokaryotic biology, with over 250 complete bacterial genomes publicly available. It should be noted that bacterial genomes were initially sequenced during the ground work necessary for bigger projects (i.e. the human genome). However, in an era when antibiotic resistance has become a serious medical concern, it was soon realized that an inventory of all the genes present in a bacterial species, as provided by bacterial genomics, would provide all possible targets for the search of new antibiotics, 1 all candidate proteins for vaccine development, 2 or a better understanding of pathogens’ biology. For these reasons, the choice of sequenced strains is heavily biased towards those which are pathogenic to humans, plants or animals. This top-down approach of sequencing entire bacterial genomes has also led to the unexpected outcome that many strains harbor genes highly related to those involved in natural product formation. With few exceptions, bacterial genomes were not specifically analyzed for their potential to synthesize natural products. Here, we try to merge the two worlds of natural product biosynthesis and of bacterial genomes, by reporting the occurrence of typical genes for secondary metabolism in bacterial genomes. We chose to limit our analysis to PKSs and NRPSs, since these two classes participate in the synthesis of many diverse secondary metabolites. In addition, they usually encode easily recognizable large multimodular polypeptides that often comprise a large This journal is © The Royal Society of Chemistry 2007 Nat. Prod. Rep., 2007, 24, 1073–1109 | 1073