Objective
Complex polyketides are microbial natural products (including clinically-useful medicines) whose chemical structures correlate with the sequence of the modular enzymes responsible for their biosynthesis. This unique paradigm means that the structure of the gene can be inferred from the chemical structure of the molecule, and (with less certainty) the reverse is true. Now, genome-scale sequencing of actinomycetes has revealed untapped chemical diversity in culturable streptomycetes: there are many biosynthetic clusters present but most are cryptic (silent). Expression of biosynthetic genes is now a severe bottleneck in trying to develop a genuine “synthetic biology” of natural products, in which PKSs are designed and fabricated to order to produce a specificed target molecule. We have sequenced and will study an extreme example of “one strain-many clusters”: a strain of Streptomyces violaceusniger which houses 11 clusters (of which seven silent and some are novel). We will: (1) use in-frame PKS gene deletion followed by chemical analysis of the resulting mutants, to test whether and how inactivation of one pathway affects the simultaneous production of others; (2) attempt to activate cryptic pathway genes by alterations in regulatory genes and by ribosome engineering, and isolate any new products; (3) clone whole PKS clusters in high-yielding (and sequenced) strains of, respectively, the monensin-producing Streptomyces cinnamonensis and the erythromycin-producing Saccharopolyspora erythraea for heterologous expression of polyketides in “pre-optimised” backgrounds; and (4) use genome reduction triggered by cre-loxP recombination, to radically simplify the secondary metabolite profile of all three strains and test the mutants for improved expression of cloned PKS genes.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences synthetic biology
- natural sciences biological sciences genetics genomes
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2010-IIF
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
CB2 1TN CAMBRIDGE
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.