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| - | <div class="bgdiv">
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| - | <img class="logo" src="https://static.igem.org/mediawiki/2014/b/bc/Logo%2Bline.png" />
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| - | <div class="bg">
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| - | <p class="bgp">
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| - | Background
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| - | </div>
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| - | <div class="one">
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| - | <p class="title">
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| - | 1.Antibiotics resistance
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| - | <div class="one1">
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| - | Early in 1945, Alexander Fleming, who discovered the penicillin, had warned that bacteria would finally be resistant to the drug. As time went by, resistance of other follow antibiotics discovered after penicillin have been detected on bacteria. The wide spreads of antibiotics resistance lead to fact that without effective action, we have no way to combat bacteria in the future[1].<br/>We still have ways to fight against the resistance in different aspects, in politics, in public healthcare, and in researchers[1]. As the researchers, new methods should be developed to produce new antibiotics. But the new antibiotics developed are virtually empty.
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| - | 2.Our goal: Programmed synthetsis of polyketide synthase(PKS)
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| - | Polyketides are a large family of compounds that represent a wide range of pharmacological effect[2]. And polyketide can be the precursor of antibiotics. It is synthesized by polykeyide synthase(PKS). Polyketide are structurally complicated because of the complication of modular PKS. Our team try to "programme" the PKS to synthesize custom polyketide.
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| - | 3.Introduction of PKS
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| - | PKS is the assemble line of polyketide. PKS are very complicated that contain several kinds of domain in one module. Each module catalyst to extend,modified or terminated the polyketide chain. The PKS we choose is type I PKS,which is highly modular. The modularity of type I PKS are reflected in three aspect. First, the gene cluster of type I PKS are modular that each enzyme corresponds to the unique sequence of gene cluster. Second, each enzyme of PKS has only one function. Third, the process of polyketide synthsis are modular that each module modify one unit of polyketide chain[3].
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| - | 3.1. PKS: The Domain
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| - | PKS are comprised of a series of module that contain several domains. Each domain have only one catalyst center with defined function which works no matter it's as a part of module. The domain that we use are as follows:a ketosynthase (KS), an acyltransferase (AT), a dehydratase (DH), a ketoreductase (KR), an enoylreductase (ER), an acyl-carrier protein (ACP), and a thioesterase (TE). <br/>
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| - | KS catalyzes a decarboxylative condensation to elongate the polyketide; ACP transfers the newly-formed β-ketoacyl intermediate to processing enzymes; KR can stereoselectively reduce the β-keto group and control the orientation of an a-substituent; DH can catalyzes dehydration to yield a trans-α , β-double bond; ER can stereoselectively reduce the double bond and control the orientation of α -substituent. TE can catalyze the intramolecular cyclization of a polyketide to create a macrolactone[4].
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| - | The domain KS, AT, and ACP are resposible for the elongation of the polyketide chain. And the DH, ER and KR are the processing enzymes that modify the newly-form unit of polyketide chain. TE can terminated the elongation of polyketide. The AT can select the substrate and the processing enzymes can modify the unit, All of that finally determined the structure of polyketide chain.
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| - | <br/><br/>
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| - | 3.2. PKS: The Module
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| - | <div class="five1">
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| - | <p class="words">
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| - | Each module condenses and modifies one unit. Basic function of a module is to elongate the polyketide. So a module contains at least the domain KS, AT, ACP. The exist of DH, ER, KR might change the structure of polyketide as some modules may contain unneccessary domain.
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| - | <br/><br/>
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| - | 3.3 PKS: The Subtrates
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| - | <div class="six1">
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| - | <p class="words">
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| - | The formation of PKS require for the reaction group that come from coenzyme A. So the host should afford to synthesis the substrate. Suitable host can be chosen or engineered the metabolic pathway to provide the substrate.<br/><br/><br/>
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| - | [1]WHO Library Cataloguing-in-Publication Data, Antimicrobial resistance: global report on surveillance[R],France:World Health Organization,2014,1.<br/>
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| - | [2]Brett A. Boghigian, Haoran Zhang, Blaine A. Pfeifer, Multi-Factorial Engineering of Heterologous Polyketide Production in Escherichia coli Reveals Complex Pathway Interactions , Biotechnol. Bioeng. 2011;108: 1360–1371.<br/>
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| - | [3]Jordan L. Meier and Michael D. Burkart, The chemical biology of modular biosynthetic enzymes, Chem. Soc. Rev., 2009, 38: 2012–2045<br/>
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| - | [4]Adrian T. Keatinge-Clay, The structures of type I polyketide synthases, Nat. Prod. Rep.,2012, 29:1050-1073.
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