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

Abstract

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.

Authors:
 [1];  [2];  [3];  [4];  [2];  [5];  [4];  [6]
+ Show Author Affiliations
  1. Univ. of California, Berkeley, CA (United States). Dept. of Chemical and Biomolecular Engineering
  2. 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
  3. Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
  4. Univ. of California, Irvine, CA (United States). Dept. of Computer Science and Inst. for Genomics and Bioinformatics
  5. Univ. of California, Berkeley, CA (United States). QB3 Inst.
  6. 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
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Energy Efficiency and Renewable Energy (EERE), Sustainable Transportation Office. Bioenergy Technologies Office; OpenEye Scientific Software, Santa Fe, NM (United States); ChemAxon, Budapest (Hungary); Defense Advanced Research Projects Agency (DARPA); National Science Foundation (NSF)
OSTI Identifier:
1433111
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
Resource Type:
Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 46; Journal Issue: D1; Related Information: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.; Journal ID: ISSN 0305-1048
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English
Subject:
97 MATHEMATICS AND COMPUTING; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Eng, Clara H., Backman, Tyler W H, Bailey, Constance B., Magnan, Christophe, Garcia Martin, Hector, Katz, Leonard, Baldi, Pierre, and Keasling, Jay D. ClusterCAD: a computational platform for type I modular polyketide synthase design. United States: N. p., 2017. Web. doi:10.1093/nar/gkx893.
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Eng, Clara H., Backman, Tyler W H, Bailey, Constance B., Magnan, Christophe, Garcia Martin, Hector, Katz, Leonard, Baldi, Pierre, & Keasling, Jay D. ClusterCAD: a computational platform for type I modular polyketide synthase design. United States. https://doi.org/10.1093/nar/gkx893
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Eng, Clara H., Backman, Tyler W H, Bailey, Constance B., Magnan, Christophe, Garcia Martin, Hector, Katz, Leonard, Baldi, Pierre, and Keasling, Jay D. Wed . "ClusterCAD: a computational platform for type I modular polyketide synthase design". United States. https://doi.org/10.1093/nar/gkx893. https://www.osti.gov/servlets/purl/1433111.
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@article{osti_1433111,
title = {ClusterCAD: a computational platform for type I modular polyketide synthase design},
author = {Eng, Clara H. and Backman, Tyler W H and Bailey, Constance B. and Magnan, Christophe and Garcia Martin, Hector and Katz, Leonard and Baldi, Pierre and Keasling, Jay D.},
abstractNote = {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.},
doi = {10.1093/nar/gkx893},
journal = {Nucleic Acids Research},
number = D1,
volume = 46,
place = {United States},
year = {2017},
month = {10}
}
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https://doi.org/10.1093/nar/gkx893
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