Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functio...Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functionalities.Polyketides encompass one of the largest classes of chemically diverse natural products.With thousands of known polyketides,modular polyketide synthases(PKSs)share a particularly attractive biosynthetic logic for generating chemical diversity.The engineering of modular PKSs could open access to the deliberate production of both existing and novel compounds.In this review,we discuss PKS engineering efforts applied at both the protein and cellular level for the generation of a diverse range of chemical structures,and we examine future applications of PKSs in the production of medicines,fuels and other industrially relevant chemicals.展开更多
The authors regret that following the publication of the original article,the authors noticed that some of the structures in Fig.10 were incorrect.Below is the corrected figure.
Modular polyketide synthases(PKSs)are a multidomain megasynthase class of biosynthetic enzymes that have great promise for the development of new compounds,from new pharmaceuticals to high value commodity and specialt...Modular polyketide synthases(PKSs)are a multidomain megasynthase class of biosynthetic enzymes that have great promise for the development of new compounds,from new pharmaceuticals to high value commodity and specialty chemicals.Their colinear biosynthetic logic has been viewed as a promising platform for synthetic biology for decades.Due to this colinearity,domain swapping has long been used as a strategy to introduce molecular diversity.However,domain swapping often fails because it perturbs critical protein-protein interactions within the PKS.With our increased level of structural elucidation of PKSs,using judicious targeted mutations of individual residues is a more precise way to introduce molecular diversity with less potential for global disruption of the protein architecture.Here we review examples of targeted point mutagenesis to one or a few residues harbored within the PKS that alter domain specificity or selectivity,affect protein stability and interdomain communication,and promote more complex catalytic reactivity.展开更多
基金This work was funded by the Joint BioEnergy Institute(JBEI),which is funded by the U.S.Department of Energy,Office of Science,Office of Biological and Environmental Research,under Contract DE-AC02-05CH11231by the National Science Foundation under awards MCB-1442724,NSF-GRFP DGE-1106400 and CBET-1437775+1 种基金as part of the Co-Optimization of Fuels&Engines(Co-Optima)project sponsored by the U.S.Department of Energy(DOE)Office of Energy Efficiency and Renewable Energy(EERE)Bioenergy Technologies and Vehicle Technologies Offices,and by the DOE Agile-Biofoundry(https://agilebiofoundry.org)supported by the U.S.Department of Energy,Energy Efficiency and Renewable Energy,Bioenergy Technologies Office,through contract DE-AC02-05CH11231 between Lawrence Berkeley National Laboratory and the U.S.Department of Energy.The United States Government retains and the publisher,by accepting the article for publication,acknowledges that the United States Government retains a nonexclusive,paid-up,irrevocable,world-wide license to publish or reproduce the published form of this manuscript,or allowothers to do so,for United States Government purposes.Additional funding was provided by the National Science Foundation Graduate Research Fellowship under Grant No.(DGE 1106400).
文摘Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functionalities.Polyketides encompass one of the largest classes of chemically diverse natural products.With thousands of known polyketides,modular polyketide synthases(PKSs)share a particularly attractive biosynthetic logic for generating chemical diversity.The engineering of modular PKSs could open access to the deliberate production of both existing and novel compounds.In this review,we discuss PKS engineering efforts applied at both the protein and cellular level for the generation of a diverse range of chemical structures,and we examine future applications of PKSs in the production of medicines,fuels and other industrially relevant chemicals.
文摘The authors regret that following the publication of the original article,the authors noticed that some of the structures in Fig.10 were incorrect.Below is the corrected figure.
基金This work was supported by funding provided by the University of Tennessee,Knoxville.
文摘Modular polyketide synthases(PKSs)are a multidomain megasynthase class of biosynthetic enzymes that have great promise for the development of new compounds,from new pharmaceuticals to high value commodity and specialty chemicals.Their colinear biosynthetic logic has been viewed as a promising platform for synthetic biology for decades.Due to this colinearity,domain swapping has long been used as a strategy to introduce molecular diversity.However,domain swapping often fails because it perturbs critical protein-protein interactions within the PKS.With our increased level of structural elucidation of PKSs,using judicious targeted mutations of individual residues is a more precise way to introduce molecular diversity with less potential for global disruption of the protein architecture.Here we review examples of targeted point mutagenesis to one or a few residues harbored within the PKS that alter domain specificity or selectivity,affect protein stability and interdomain communication,and promote more complex catalytic reactivity.
