DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Synthetic biology of polyketide synthases

Journal Article · · Journal of Industrial Microbiology and Biotechnology
 [1];  [2];  [3];  [4]
  1. 0000 0001 2231 4551 grid.184769.5 Biological Systems and Engineering Division Lawrence Berkeley National Laboratory 94720 Berkeley CA USA, 0000 0004 0407 8980 grid.451372.6 Joint BioEnergy Institute 94608 Emeryville CA USA
  2. 0000 0001 2231 4551 grid.184769.5 Biological Systems and Engineering Division Lawrence Berkeley National Laboratory 94720 Berkeley CA USA, 0000 0004 0407 8980 grid.451372.6 Joint BioEnergy Institute 94608 Emeryville CA USA, 0000 0001 2181 7878 grid.47840.3f QB3 Institute University of California 94720 Berkeley CA USA
  3. 0000 0001 2231 4551 grid.184769.5 Biological Systems and Engineering Division Lawrence Berkeley National Laboratory 94720 Berkeley CA USA; 0000 0004 0407 8980 grid.451372.6 Joint BioEnergy Institute 94608 Emeryville CA USA; 0000 0001 2181 7878 grid.47840.3f QB3 Institute University of California 94720 Berkeley CA USA; 0000 0001 2181 7878 grid.47840.3f Department of Bioengineering University of California 94720 Berkeley CA USA; 0000 0001 2181 7878 grid.47840.3f Department of Chemical and Biomolecular Engineering University of California 94720 Berkeley CA USA
  4. 0000 0004 0407 8980 grid.451372.6 Joint BioEnergy Institute 94608 Emeryville CA USA, 0000 0001 2181 7878 grid.47840.3f QB3 Institute University of California 94720 Berkeley CA USA

Abstract Complex reduced polyketides represent the largest class of natural products that have applications in medicine, agriculture, and animal health. This structurally diverse class of compounds shares a common methodology of biosynthesis employing modular enzyme systems called polyketide synthases (PKSs). The modules are composed of enzymatic domains that share sequence and functional similarity across all known PKSs. We have used the nomenclature of synthetic biology to classify the enzymatic domains and modules as parts and devices, respectively, and have generated detailed lists of both. In addition, we describe the chassis (hosts) that are used to assemble, express, and engineer the parts and devices to produce polyketides. We describe a recently developed software tool to design PKS system and provide an example of its use. Finally, we provide perspectives of what needs to be accomplished to fully realize the potential that synthetic biology approaches bring to this class of molecules.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE; USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1773512
Journal Information:
Journal of Industrial Microbiology and Biotechnology, Journal Name: Journal of Industrial Microbiology and Biotechnology Journal Issue: 7 Vol. 45; ISSN 1367-5435
Publisher:
Oxford University PressCopyright Statement
Country of Publication:
Germany
Language:
English

References (52)

Divergent Mechanistic Routes for the Formation of gem -Dimethyl Groups in the Biosynthesis of Complex Polyketides journal January 2015
Streptomyces and Saccharopolyspora hosts for heterologous expression of secondary metabolite gene clusters journal May 2010
Novel features in a combined polyketide synthase/non-ribosomal peptide synthetase: the myxalamid biosynthetic gene cluster of the myxobacterium Stigmatella aurantiaca Sga1511This article is dedicated to Prof. Dr. E. Leistner on the occasion of his 60th birthday. journal January 2001
Biosynthesis of the polyene antifungal antibiotic nystatin in Streptomyces noursei ATCC 11455: analysis of the gene cluster and deduction of the biosynthetic pathway journal June 2000
A Complete Gene Cluster from Streptomyces nanchangensis NS3226 Encoding Biosynthesis of the Polyether Ionophore Nanchangmycin journal May 2003
Engineered Biosynthesis of Geldanamycin Analogs for Hsp90 Inhibition journal December 2004
Rational Design and Assembly of Synthetic Trimodular Polyketide Synthases journal February 2007
Structure and mechanism of assembly line polyketide synthases journal December 2016
Engineered polyketides: Synergy between protein and host level engineering journal September 2017
Alteration of Polyketide Stereochemistry from anti to syn by a Ketoreductase Domain Exchange in a Type I Modular Polyketide Synthase Subunit journal March 2016
The Uncommon Enzymology of Cis-Acyltransferase Assembly Lines journal April 2017
Engineering a Polyketide Synthase for In Vitro Production of Adipic Acid journal November 2015
Comprehensive in Vitro Analysis of Acyltransferase Domain Exchanges in Modular Polyketide Synthases and Its Application for Short-Chain Ketone Production journal September 2016
Development of Next Generation Synthetic Biology Tools for Use in Streptomyces venezuelae journal September 2016
A New Era of Genome Integration—Simply Cut and Paste! journal January 2017
Broad Substrate Specificity of the Loading Didomain of the Lipomycin Polyketide Synthase journal May 2013
In Vitro Analysis of Carboxyacyl Substrate Tolerance in the Loading and First Extension Modules of Borrelidin Polyketide Synthase journal September 2014
The Molecular Basis of Celmer's Rules:  The Stereochemistry of the Condensation Step in Chain Extension on the Erythromycin Polyketide Synthase journal November 1997
Mutagenesis of a Modular Polyketide Synthase Enoylreductase Domain Reveals Insights into Catalysis and Stereospecificity journal July 2010
The Missing Linker: A Dimerization Motif Located within Polyketide Synthase Modules journal March 2013
Assessing the Balance between Protein−Protein Interactions and Enzyme−Substrate Interactions in the Channeling of Intermediates between Polyketide Synthase Modules journal July 2001
Extender Unit and Acyl Carrier Protein Specificity of Ketosynthase Domains of the 6-Deoxyerythronolide B Synthase journal March 2006
Stereospecificity of the Dehydratase Domain of the Erythromycin Polyketide Synthase journal October 2010
Elucidation of the Stereospecificity of C -Methyltransferases from trans -AT Polyketide Synthases journal April 2017
Elucidation of the Cryptic Methyl Group Epimerase Activity of Dehydratase Domains from Modular Polyketide Synthases Using a Tandem Modules Epimerase Assay journal July 2017
Biosynthetic Pathway and Gene Cluster Analysis of Curacin A, an Antitubulin Natural Product from the Tropical Marine Cyanobacterium Lyngbya majuscula journal August 2004
Enzyme analysis of the polyketide synthase leads to the discovery of a novel analog of the antibiotic α-lipomycin journal October 2013
Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes journal August 2005
Evidence for a double-helical structure for modular polyketide synthases journal February 1996
Diversity oriented biosynthesis via accelerated evolution of modular gene clusters journal October 2017
PKS and NRPS release mechanisms journal January 2010
Beyond ethylmalonyl-CoA: The functional role of crotonyl-CoAcarboxylase/reductase homologs in expanding polyketide diversity journal January 2012
Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering journal January 2015
Stereocontrol within polyketide assembly lines journal January 2016
Genetic engineering of modular PKSs: from combinatorial biosynthesis to synthetic biology journal January 2016
Biosynthesis of polyketides by trans-AT polyketide synthases journal January 2016
Broadening substrate specificity of a chain-extending ketosynthase through a single active-site mutation journal January 2016
Structure and biosynthesis of the unusual polyketide alkaloid coelimycin P1, a metabolic product of the cpk gene cluster of Streptomyces coelicolor M145 journal January 2012
Analysis of the biosynthetic gene cluster for the polyether antibiotic monensin in Streptomyces cinnamonensis and evidence for the role of monB and monC genes in oxidative cyclization: Monensin biosynthesis in S. cinnamonensis journal August 2003
The biosynthetic gene cluster for the macrolactone ring of the immunosuppressant FK506 journal September 1998
Exploiting a precise design of universal synthetic modular regulatory elements to unlock the microbial natural products in Streptomyces journal September 2015
The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. journal August 1995
Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis journal August 1999
Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel "unnatural" natural products journal March 1999
Protein-Protein Interactions, Not Substrate Recognition, Dominate the Turnover of Chimeric Assembly Line Polyketide Synthases journal May 2016
ClusterCAD: a computational platform for type I modular polyketide synthase design journal October 2017
An acyltransferase domain of FK506 polyketide synthase recognizing both an acyl carrier protein and coenzyme A as acyl donors to transfer allylmalonyl and ethylmalonyl units journal April 2015
Dissecting and Exploiting Intermodular Communication in Polyketide Synthases journal April 1999
Stereospecific acyl transfers on the erythromycin-producing polyketide synthase journal January 1994
Structure and Mechanism of the 6-Deoxyerythronolide B Synthase journal June 2007
Towards Precision Engineering of Canonical Polyketide Synthase Domains: Recent Advances and Future Prospects journal February 2017
Novel avermectins produced by mutational biosynthesis. journal January 1991