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000119632 0247_ $$2doi$$a10.1039/c3mb70594c
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000119632 0247_ $$2ISSN$$a1742-206X
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000119632 037__ $$aDKFZ-2017-00263
000119632 041__ $$aeng
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000119632 1001_ $$aBeer, Ralf$$b0
000119632 245__ $$aCreating functional engineered variants of the single-module non-ribosomal peptide synthetase IndC by T domain exchange.
000119632 260__ $$aCambridge$$bRoyal Society of Chemistry$$c2014
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000119632 520__ $$aNon-ribosomal peptide synthetases (NRPSs) are enzymes that catalyze ribosome-independent production of small peptides, most of which are bioactive. NRPSs act as peptide assembly lines where individual, often interconnected modules each incorporate a specific amino acid into the nascent chain. The modules themselves consist of several domains that function in the activation, modification and condensation of the substrate. NRPSs are evidently modular, yet experimental proof of the ability to engineer desired permutations of domains and modules is still sought. Here, we use a synthetic-biology approach to create a small library of engineered NRPSs, in which the domain responsible for carrying the activated amino acid (T domain) is exchanged with natural or synthetic T domains. As a model system, we employ the single-module NRPS IndC from Photorhabdus luminescens that produces the blue pigment indigoidine. As chassis we use Escherichia coli. We demonstrate that heterologous T domain exchange is possible, even for T domains derived from different organisms. Interestingly, substitution of the native T domain with a synthetic one enhanced indigoidine production. Moreover, we show that selection of appropriate inter-domain linker regions is critical for functionality. Taken together, our results extend the engineering avenues for NRPSs, as they point out the possibility of combining domain sequences coming from different pathways, organisms or from conservation criteria. Moreover, our data suggest that NRPSs can be rationally engineered to control the level of production of the corresponding peptides. This could have important implications for industrial and medical applications.
000119632 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
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000119632 650_7 $$2NLM Chemicals$$aBacterial Proteins
000119632 650_7 $$2NLM Chemicals$$aPeptides
000119632 650_7 $$2NLM Chemicals$$aPiperidones
000119632 650_7 $$02435-59-8$$2NLM Chemicals$$aindigoidine
000119632 650_7 $$0EC 6.3.2.-$$2NLM Chemicals$$aPeptide Synthases
000119632 650_7 $$0EC 6.3.2.-$$2NLM Chemicals$$anon-ribosomal peptide synthase
000119632 7001_ $$aHerbst, Konrad$$b1
000119632 7001_ $$aIgnatiadis, Nikolaos$$b2
000119632 7001_ $$aKats, Ilia$$b3
000119632 7001_ $$0P:(DE-He78)8173b385148df32ff5e8eeedf187a1ba$$aAdlung, Lorenz$$b4$$udkfz
000119632 7001_ $$aMeyer, Hannah$$b5
000119632 7001_ $$0P:(DE-He78)166a5fd484fa815c122e8a747900dc2c$$aNiopek, Dominik$$b6$$udkfz
000119632 7001_ $$0P:(DE-HGF)0$$aChristiansen, Tania$$b7
000119632 7001_ $$aGeorgi, Fanny$$b8
000119632 7001_ $$0P:(DE-HGF)0$$aKurzawa, Nils$$b9
000119632 7001_ $$0P:(DE-HGF)0$$aMeichsner, Johanna$$b10
000119632 7001_ $$0P:(DE-HGF)0$$aRabe, Sophie$$b11
000119632 7001_ $$0P:(DE-HGF)0$$aRiedel, Anja$$b12
000119632 7001_ $$aSachs, Joshua$$b13
000119632 7001_ $$aSchessner, Julia$$b14
000119632 7001_ $$aSchmidt, Florian$$b15
000119632 7001_ $$0P:(DE-HGF)0$$aWalch, Philipp$$b16
000119632 7001_ $$0P:(DE-He78)7632c5d89e51bc987c039a2e145a13bc$$aNiopek, Katharina$$b17$$udkfz
000119632 7001_ $$0P:(DE-HGF)0$$aHeinemann, Tim$$b18
000119632 7001_ $$0P:(DE-He78)78b6aa82148e60b4d91e3a37a6d3d9a0$$aEils, Roland$$b19$$udkfz
000119632 7001_ $$0P:(DE-HGF)0$$aDi Ventura, Barbara$$b20$$eLast author
000119632 773__ $$0PERI:(DE-600)2188635-0$$a10.1039/c3mb70594c$$gVol. 10, no. 7, p. 1709 -$$n7$$p1709 -$$tMolecular BioSystems$$v10$$x1742-2051$$y2014
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000119632 9141_ $$y2014
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