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Ziemert, N, Jensen PR.  2012.  Phylogenetic approaches to natural product structure prediction. Natural Product Biosynthesis by Microorganisms and Plants, Pt C. 517( Hopwood DA, Ed.).:161-182., San Diego: Elsevier Academic Press Inc   10.1016/8978-0-12-404634-4.00008-5   Abstract

Phylogenetics is the study of the evolutionary relatedness among groups of organisms. Molecular phylogenetics uses sequence data to infer these relationships for both organisms and the genes they maintain. With the large amount of publicly available sequence data, phylogenetic inference has become increasingly important in all fields of biology. In the case of natural product research, phylogenetic relationships are proving to be highly informative in terms of delineating the architecture and function of the genes involved in secondary metabolite biosynthesis. Polyketide synthases and nonribosomal peptide synthetases provide model examples in which individual domain phylogenies display different predictive capacities, resolving features ranging from substrate specificity to structural motifs associated with the final metabolic product. This chapter provides examples in which phylogeny has proven effective in terms of predicting functional or structural aspects of secondary metabolism. The basics of how to build a reliable phylogenetic tree are explained along with information about programs and tools that can be used for this purpose. Furthermore, it introduces the Natural Product Domain Seeker, a recently developed Web tool that employs phylogenetic logic to classify ketosynthase and condensation domains based on established enzyme architecture and biochemical function.

Ziemert, N, Lechner A, Wietz M, Millan-Aguinaga N, Chavarria KL, Jensen PR.  2014.  Diversity and evolution of secondary metabolism in the marine actinomycete genus Salinispora. Proceedings of the National Academy of Sciences of the United States of America. 111:E1130-E1139.   10.1073/pnas.1324161111   AbstractWebsite

Access to genome sequence data has challenged traditional natural product discovery paradigms by revealing that the products of most bacterial biosynthetic pathways have yet to be discovered. Despite the insight afforded by this technology, little is known about the diversity and distributions of natural product biosynthetic pathways among bacteria and how they evolve to generate structural diversity. Here we analyze genome sequence data derived from 75 strains of the marine actinomycete genus Salinispora for pathways associated with polyketide and nonribosomal peptide biosynthesis, the products of which account for some of today's most important medicines. The results reveal high levels of diversity, with a total of 124 pathways identified and 229 predicted with continued sequencing. Recent horizontal gene transfer accounts for the majority of pathways, which occur in only one or two strains. Acquired pathways are incorporated into genomic islands and are commonly exchanged within and between species. Acquisition and transfer events largely involve complete pathways, which subsequently evolve by gene gain, loss, and duplication followed by divergence. The exchange of similar pathway types at the precise chromosomal locations in different strains suggests that the mechanisms of integration include pathway-level homologous recombination. Despite extensive horizontal gene transfer there is clear evidence of species-level vertical inheritance, supporting the concept that secondary metabolites represent functional traits that help define Salinispora species. The plasticity of the Salinispora secondary metabolome provides an effective mechanism to maximize population-level secondary metabolite diversity while limiting the number of pathways maintained within any individual genome.

Ziemert, N, Podell S, Penn K, Badger JH, Allen E, Jensen PR.  2012.  The Natural Product Domain Seeker NaPDoS: A Phylogeny Based Bioinformatic Tool to Classify Secondary Metabolite Gene Diversity. Plos One. 7   10.1371/journal.pone.0034064   AbstractWebsite

New bioinformatic tools are needed to analyze the growing volume of DNA sequence data. This is especially true in the case of secondary metabolite biosynthesis, where the highly repetitive nature of the associated genes creates major challenges for accurate sequence assembly and analysis. Here we introduce the web tool Natural Product Domain Seeker (NaPDoS), which provides an automated method to assess the secondary metabolite biosynthetic gene diversity and novelty of strains or environments. NaPDoS analyses are based on the phylogenetic relationships of sequence tags derived from polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) genes, respectively. The sequence tags correspond to PKS-derived ketosynthase domains and NRPS-derived condensation domains and are compared to an internal database of experimentally characterized biosynthetic genes. NaPDoS provides a rapid mechanism to extract and classify ketosynthase and condensation domains from PCR products, genomes, and metagenomic datasets. Close database matches provide a mechanism to infer the generalized structures of secondary metabolites while new phylogenetic lineages provide targets for the discovery of new enzyme architectures or mechanisms of secondary metabolite assembly. Here we outline the main features of NaPDoS and test it on four draft genome sequences and two metagenomic datasets. The results provide a rapid method to assess secondary metabolite biosynthetic gene diversity and richness in organisms or environments and a mechanism to identify genes that may be associated with uncharacterized biochemistry.