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            <h3>Technical University of Denmark</h3>
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            <h1>The Synthesizer</h1>
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    <p>Nonribosomal peptides, polyketides and hybrids thereof are secondary metabolites that are biosynthesized by condensation of amino and/or carboxylic acids. These metabolites have a wide variety of important biological activities that include antibacterial, anticancer and immunosuppressing activities.</p>
+
      <p>Non-ribosomal peptides have important anti-bacterial, anti-cancer, and immunosuppressive biological activities. They are synthesized by modular, high molecular weight enzymes that assemble more than 500 different amino acid substrates in an assembly line manner. For this reason, synthetic biologists have tried to engineer these proteins and to switch modules to create analogs and novel natural products, but with little success. Despite being modular, the interactions between modules have evolved to be highly specific, making synthetic Non-Ribosomal Peptide Synthases (NRPS) a challenge to engineer. Instead of switching modules we introduced a recombination system targeting oligo integration in Bacillus subtilis. We used the recombineering system to alter the active sites determining substrate specificity, thereby creating variants of antibiotics. Our focus was the tyrocidine antibiotic, which cannot be used intravenously due to its toxicity. Our goal is to create new analogs through multiplex automated genome engineering to reduce toxicity.</p>
  
<p>New ways to rationally design such products and creation of libraries that can be tested for desired activities can lead to new medicinally and industrially important products.</p>
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<p>Nonribosomal peptide synthetases(nrps) and polyketide synthases(pks) consist of many modules that incorporate one amino or carboxylic acid unto a growing chain. These modules can be rearranged and their specificity can be altered in order to make new products. The aim of our project is to design modules that can be combined in order to create nrps/pks hybrids as well as an easy way to create libraries of similar compounds with altered side chains based on an existing scaffold.</p>
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            <strong>Technical University of Denmark</strong><br>
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            Department of Systems Biology <br>
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            Søltofts Plads 221 <br>
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            2800 Kgs. Lyngby<br>
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Revision as of 10:10, 18 August 2015


Technical University of Denmark

The Synthesizer


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Project description

Non-ribosomal peptides have important anti-bacterial, anti-cancer, and immunosuppressive biological activities. They are synthesized by modular, high molecular weight enzymes that assemble more than 500 different amino acid substrates in an assembly line manner. For this reason, synthetic biologists have tried to engineer these proteins and to switch modules to create analogs and novel natural products, but with little success. Despite being modular, the interactions between modules have evolved to be highly specific, making synthetic Non-Ribosomal Peptide Synthases (NRPS) a challenge to engineer. Instead of switching modules we introduced a recombination system targeting oligo integration in Bacillus subtilis. We used the recombineering system to alter the active sites determining substrate specificity, thereby creating variants of antibiotics. Our focus was the tyrocidine antibiotic, which cannot be used intravenously due to its toxicity. Our goal is to create new analogs through multiplex automated genome engineering to reduce toxicity.

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Technical University of Denmark
Department of Systems Biology
Søltofts Plads 221
2800 Kgs. Lyngby
Denmark
P: +45 45 25 25 25
M: dtu-igem-2015@googlegroups.com