ClusterCAD: a computational platform for type I modular polyketide synthase design

Eng, Clara H.; Backman, Tyler W H; Bailey, Constance B.; Magnan, Christophe; Garcia Martin, Hector; Katz, Leonard; Baldi, Pierre; Keasling, Jay D.

doi:10.1093/nar/gkx893

Title: ClusterCAD: a computational platform for type I modular polyketide synthase design

Journal Article · 11 October 2017 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gkx893 · OSTI ID:1433111

Eng, Clara H. ^[1]; Backman, Tyler W H ^[2]; Bailey, Constance B. ^[3]; Magnan, Christophe ^[4]; Garcia Martin, Hector ^[2]; Katz, Leonard ^[5]; Baldi, Pierre ^[4]; Keasling, Jay D. ^[6]

Univ. of California, Berkeley, CA (United States). Dept. of Chemical and Biomolecular Engineering
Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Agile BioFoundry, Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Univ. of California, Irvine, CA (United States). Dept. of Computer Science and Inst. for Genomics and Bioinformatics
Univ. of California, Berkeley, CA (United States). QB3 Inst.
Univ. of California, Berkeley, CA (United States). Dept. of Chemical and Biomolecular Engineering and QB3 Inst. and Dept. of Bioengineering; Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Agile BioFoundry, Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Technical Univ. of Denmark, Horsholm (Denmark). Novo Nordisk Foundation Center for Biosustainability

Here, we present ClusterCAD, a web-based toolkit designed to leverage the collinear structure and deterministic logic of type I modular polyketide synthases (PKSs) for synthetic biology applications. The unique organization of these megasynthases, combined with the diversity of their catalytic domain building blocks, has fueled an interest in harnessing the biosynthetic potential of PKSs for the microbial production of both novel natural product analogs and industrially relevant small molecules. However, a limited theoretical understanding of the determinants of PKS fold and function poses a substantial barrier to the design of active variants, and identifying strategies to reliably construct functional PKS chimeras remains an active area of research. In this work, we formalize a paradigm for the design of PKS chimeras and introduce ClusterCAD as a computational platform to streamline and simplify the process of designing experiments to test strategies for engineering PKS variants. ClusterCAD provides chemical structures with stereochemistry for the intermediates generated by each PKS module, as well as sequence- and structure-based search tools that allow users to identify modules based either on amino acid sequence or on the chemical structure of the cognate polyketide intermediate. ClusterCAD can be accessed at https://clustercad.jbei.org and at http://clustercad.igb.uci.edu.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Energy Efficiency and Renewable Energy (EERE), Sustainable Transportation Office. Bioenergy Technologies Office (BETO); OpenEye Scientific Software, Santa Fe, NM (United States); ChemAxon, Budapest (Hungary); Defense Advanced Research Projects Agency (DARPA); National Science Foundation (NSF)

Grant/Contract Number:: AC02-05CH11231; BM0101020-05450-1004171; 28712; AC02-05C11231; HR0011-15-2-0045; CBET-1437775; EEC-0540879; MCB-1341894; IIS-1321053; DGE 1106400

OSTI ID:: 1433111

Journal Information:: Nucleic Acids Research, Vol. 46, Issue D1; Related Information: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 43 works

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Bio-based production of fuels and industrial chemicals by repurposing antibiotic-producing type I modular polyketide synthases: opportunities and challenges Yuzawa, Satoshi; Keasling, Jay D.; Katz, Leonard The Journal of Antibiotics, Vol. 70, Issue 4 https://doi.org/10.1038/ja.2016.136	journal	November 2016
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Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection Nguyen, TuAnh; Ishida, Keishi; Jenke-Kodama, Holger Nature Biotechnology, Vol. 26, Issue 2 https://doi.org/10.1038/nbt1379	journal	January 2008
Minimum Information about a Biosynthetic Gene cluster Medema, Marnix H.; Kottmann, Renzo; Yilmaz, Pelin Nature Chemical Biology, Vol. 11, Issue 9 https://doi.org/10.1038/nchembio.1890	journal	August 2015
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The structures of type I polyketide synthases Keatinge-Clay, Adrian T. Natural Product Reports, Vol. 29, Issue 10 https://doi.org/10.1039/c2np20019h	journal	January 2012
SSpro/ACCpro 5: almost perfect prediction of protein secondary structure and relative solvent accessibility using profiles, machine learning and structural similarity Magnan, C. N.; Baldi, P. Bioinformatics, Vol. 30, Issue 18 https://doi.org/10.1093/bioinformatics/btu352	journal	May 2014
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SBSPKSv2: structure-based sequence analysis of polyketide synthases and non-ribosomal peptide synthetases Khater, Shradha; Gupta, Money; Agrawal, Priyesh Nucleic Acids Research, Vol. 45, Issue W1 https://doi.org/10.1093/nar/gkx344	journal	April 2017
Engineering the acyltransferase substrate specificity of assembly line polyketide synthases Dunn, Briana J.; Khosla, Chaitan Journal of The Royal Society Interface, Vol. 10, Issue 85 https://doi.org/10.1098/rsif.2013.0297	journal	August 2013
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Structure and Mechanism of the 6-Deoxyerythronolide B Synthase Khosla, Chaitan; Tang, Yinyan; Chen, Alice Y. Annual Review of Biochemistry, Vol. 76, Issue 1 https://doi.org/10.1146/annurev.biochem.76.053105.093515	journal	June 2007
BLAST+: architecture and applications Camacho, Christiam; Coulouris, George; Avagyan, Vahram BMC Bioinformatics, Vol. 10, Issue 1 https://doi.org/10.1186/1471-2105-10-421	journal	January 2009

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Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution Awakawa, Takayoshi; Fujioka, Takuma; Zhang, Lihan Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-05877-z	journal	August 2018
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RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms Whitmore, Leanne S.; Nguyen, Bernard; Pinar, Ali BMC Bioinformatics, Vol. 20, Issue 1 https://doi.org/10.1186/s12859-019-3025-9	journal	September 2019
Structural insights into dehydratase substrate selection for the borrelidin and fluvirucin polyketide synthases Barajas, Jesus F.; McAndrew, Ryan P.; Thompson, Mitchell G. Journal of Industrial Microbiology & Biotechnology, Vol. 46, Issue 8 https://doi.org/10.1007/s10295-019-02189-z	journal	May 2019
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RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms Whitmore, Leanne S.; Nguyen, Bernard; Pinar, Ali BMC Bioinformatics, Vol. 20, Issue 1 https://doi.org/10.1186/s12859-019-3025-9	journal	September 2019

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