Evolutionary dynamics of modular polyketide synthases, with implications for protein design and engineering

Žučko, Jurica; Cullum, John; Hranueli, Daslav; Long, Paul F.

doi:10.1038/ja.2010.141

Cited by 13 publications

(6 citation statements)

References 28 publications

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“…Further, the overall substitution ratios of the Trichoderma PKS ketoacyl synthase module revealed that it is under strong purifying selection. Similar findings have also been reported for PKS from bacteria (Zucko et al, 2011) and lichenized fungi (Muggia et al, 2008).…”

Section: Discussionsupporting

confidence: 77%

Phylogenomic analysis of polyketide synthase-encoding genes in Trichoderma

et al. 2012

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Members of the economically important ascomycete genus Trichoderma are ubiquitously distributed around the world. The mycoparasitic lifestyle and plant defence-inducing interactions of Trichoderma spp. make them ideal biocontrol agents. Of the Trichoderma enzymes that produce secondary metabolites, some of which likely play important roles in biocontrol processes, polyketide synthase (PKSs) have garnered less attention than non-ribosomal peptide synthetases such as those that produce peptaibols. We have taken a phylogenomic approach to study the PKS repertoire encoded in the genomes of Trichoderma reesei, Trichoderma atroviride and Trichoderma virens. Our analysis lays a foundation for future research related to PKSs within the genus Trichoderma and in other filamentous fungi. INTRODUCTIONGiven its important roles in bioenergy-related enzyme production and plant and fungal health, the genus Trichoderma has a significant economic footprint (Schuster & Schmoll, 2010). This genus is well known for its opportunistic lifestyle that includes saprotrophy, mycoparasitism, endophytism, and interactions with plants and animals. Because of their ability to antagonize other fungi and stimulate plant defences against phytopathogens, Trichoderma strains have become prominent biocontrol agents (Schuster & Schmoll, 2010). Further highlighting their mycoparasitic lifestyle, sequencing and analysis of the genomes from two mycoparasitic Trichoderma species (Trichoderma virens, Trichoderma atroviride) have shown that these genomes encode a rich catalogue of fungal cell wall-degrading chitinases and a relative paucity of plant cell wall-degrading enzymes (Kubicek et al., 2011;Martinez et al., 2008).As biocontrol agents and pathogens of fungal food crops, secondary metabolite production in Trichoderma spp. is of particular importance. Trichoderma and other filamentous fungi are well known for the production of a diverse array of secondary metabolites. Non-ribosomal peptides and polyketides comprise a major portion of these products, which are synthesized by large proteins composed of various domains for the individual enzymic steps (Cox, 2007). Both broad and genus-specific phylogenomic and functional analysis of polyketide synthase (PKS)-and non-ribosomal peptide synthetase (NRPS)-encoding genes have been performed, which has accelerated the pace at which genes and pathways are being linked to specific secondary metabolites (Bushley & Turgeon, 2010;Bushley et al., 2008;Chiang et al., 2010;Cramer et al., 2006;Gaffoor et al., 2005;Kroken et al., 2003;Kubicek et al., 2011;Lee et al., 2005).Trichoderma spp. are probably best known for their production of peptaibols, which are non-ribosomal peptides with antimicrobial and plant defence-stimulating activity (Viterbo et al., 2007). Relatively less studied in Trichoderma are PKSs. The recent analysis of the three available Trichoderma genome sequences has indicated that the genomes of these organisms encode only a small catalogue of PKSs: T. atroviride and T. virens each encode 18, and Tric...

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Section: Discussionsupporting

confidence: 77%

Phylogenomic analysis of polyketide synthase-encoding genes in Trichoderma

et al. 2012

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“…Studies on the natural evolution of modular PKSs suggest that recombination plays a major role [10]. In vitro construction of hybrid PKSs creates unnatural junctions, which may account for the low product yield as there is evidence for strong purifying selection in PKS modules [30], i.e. most variation in amino acid sequence is not tolerated.…”

Section: Introductionmentioning

confidence: 99%

Recombinatorial biosynthesis of polyketides

Starčević

Wolf

Diminić

et al. 2012

Journal of Industrial Microbiology and Biotechnology

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Modular polyketide synthases (PKSs) from Streptomyces and related genera of bacteria produce many important pharmaceuticals. A program called CompGen was developed to carry out in silico homologous recombination between gene clusters encoding PKSs and determine whether recombinants have cluster architectures compatible with the production of polyketides. The chemical structure of recombinant polyketides was also predicted. In silico recombination was carried out for 47 well-characterised clusters. The predicted recombinants would produce 11,796 different polyketide structures. The molecular weights and average degree of reduction of the chemical structures are dispersed around the parental structures indicating that they are likely to include pharmaceutically interesting compounds. The details of the recombinants and the chemical structures were entered in a database called r-CSDB. The virtual compound library is a useful resource for computer-aided drug design and chemoinformatics strategies for finding pharmaceutically relevant chemical entities. A strategy to construct recombinant Streptomyces strains to produce these polyketides is described and the critical steps of mobilizing large biosynthetic clusters and producing new linear cloning vectors are illustrated by experimental data.

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“…BGCs also exhibit high rates of insertions, deletions, duplications and rearrangements [19], often exchanging multi-gene blocks with primary metabolism [31] or other BGCs [19]. Shared loci within functional domains, many of which contribute to metabolite chemistry, are under a wide array of selective pressures both across and within clusters [32]. …”

Section: Evolution Of Biosynthetic Pathwaysmentioning

confidence: 99%

Interpreting Microbial Biosynthesis in the Genomic Age: Biological and Practical Considerations

2017

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Genome mining has become an increasingly powerful, scalable, and economically accessible tool for the study of natural product biosynthesis and drug discovery. However, there remain important biological and practical problems that can complicate or obscure biosynthetic analysis in genomic and metagenomic sequencing projects. Here, we focus on limitations of available technology as well as computational and experimental strategies to overcome them. We review the unique challenges and approaches in the study of symbiotic and uncultured systems, as well as those associated with biosynthetic gene cluster (BGC) assembly and product prediction. Finally, to explore sequencing parameters that affect the recovery and contiguity of large and repetitive BGCs assembled de novo, we simulate Illumina and PacBio sequencing of the Salinispora tropica genome focusing on assembly of the salinilactam (slm) BGC.

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Evolutionary dynamics of modular polyketide synthases, with implications for protein design and engineering

Cited by 13 publications

References 28 publications

Phylogenomic analysis of polyketide synthase-encoding genes in Trichoderma

Phylogenomic analysis of polyketide synthase-encoding genes in Trichoderma

Recombinatorial biosynthesis of polyketides

Interpreting Microbial Biosynthesis in the Genomic Age: Biological and Practical Considerations

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