skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms

Abstract

The efficient biological production of industrially and economically important compounds is a challenging problem. Brute-force determination of the optimal pathways to efficient production of a target chemical in a chassis organism is computationally intractable. Many current methods provide a single solution to this problem, but fail to provide all optimal pathways, optional sub-optimal solutions or hybrid biological/non-biological solutions. Here we present RetSynth, software with a novel algorithm for determining all optimal biological pathways given a starting biological chassis and target chemical. By dynamically selecting constraints, the number of potential pathways scales by the number of fully independent pathways and not by the number of overall reactions or size of the metabolic network. This feature allows all optimal pathways to be determined for a large number of chemicals and for a large corpus of potential chassis organisms. Additionally, this software contains other features including the ability to collect data from metabolic repositories, perform flux balance analysis, and to view optimal pathways identified by our algorithm using a built-in visualization module. This software also identifies sub-optimal pathways and allows incorporation of non-biological chemical reactions, which may be performed after metabolic production of precursor molecules. The novel algorithm designed for RetSynth streamlines anmore » arduous and complex process in metabolic engineering. Our stand-alone software allows the identification of candidate optimal and additional sub-optimal pathways, and provides the user with necessary ranking criteria such as target yield to decide which route to select for target production. Furthermore, the ability to incorporate non-biological reactions into the final steps allows determination of pathways to production for targets that cannot be solely produced biologically. With this comprehensive suite of features RetSynth exceeds any open-source software or webservice currently available for identifying optimal pathways for target production.« less

Authors:
 [1];  [1];  [1];  [1]; ORCiD logo [1]
  1. Sandia National Lab. (SNL-CA), Livermore, CA (United States)
Publication Date:
Research Org.:
Sandia National Lab. (SNL-CA), Livermore, CA (United States)
Sponsoring Org.:
USDOE Office of Energy Efficiency and Renewable Energy (EERE)
OSTI Identifier:
1570223
Report Number(s):
SAND2019-9488J
Journal ID: ISSN 1471-2105; 678452
Grant/Contract Number:  
AC04-94AL85000
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
BMC Bioinformatics
Additional Journal Information:
Journal Volume: 20; Journal Issue: 1; Journal ID: ISSN 1471-2105
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; mixed integer linear programming; metabolic engineering; flyx balance analysis

Citation Formats

Whitmore, Leanne S., Nguyen, Bernard, Pinar, Ali, George, Anthe, and Hudson, Corey M. RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms. United States: N. p., 2019. Web. doi:10.1186/s12859-019-3025-9.
Whitmore, Leanne S., Nguyen, Bernard, Pinar, Ali, George, Anthe, & Hudson, Corey M. RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms. United States. doi:10.1186/s12859-019-3025-9.
Whitmore, Leanne S., Nguyen, Bernard, Pinar, Ali, George, Anthe, and Hudson, Corey M. Mon . "RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms". United States. doi:10.1186/s12859-019-3025-9. https://www.osti.gov/servlets/purl/1570223.
@article{osti_1570223,
title = {RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms},
author = {Whitmore, Leanne S. and Nguyen, Bernard and Pinar, Ali and George, Anthe and Hudson, Corey M.},
abstractNote = {The efficient biological production of industrially and economically important compounds is a challenging problem. Brute-force determination of the optimal pathways to efficient production of a target chemical in a chassis organism is computationally intractable. Many current methods provide a single solution to this problem, but fail to provide all optimal pathways, optional sub-optimal solutions or hybrid biological/non-biological solutions. Here we present RetSynth, software with a novel algorithm for determining all optimal biological pathways given a starting biological chassis and target chemical. By dynamically selecting constraints, the number of potential pathways scales by the number of fully independent pathways and not by the number of overall reactions or size of the metabolic network. This feature allows all optimal pathways to be determined for a large number of chemicals and for a large corpus of potential chassis organisms. Additionally, this software contains other features including the ability to collect data from metabolic repositories, perform flux balance analysis, and to view optimal pathways identified by our algorithm using a built-in visualization module. This software also identifies sub-optimal pathways and allows incorporation of non-biological chemical reactions, which may be performed after metabolic production of precursor molecules. The novel algorithm designed for RetSynth streamlines an arduous and complex process in metabolic engineering. Our stand-alone software allows the identification of candidate optimal and additional sub-optimal pathways, and provides the user with necessary ranking criteria such as target yield to decide which route to select for target production. Furthermore, the ability to incorporate non-biological reactions into the final steps allows determination of pathways to production for targets that cannot be solely produced biologically. With this comprehensive suite of features RetSynth exceeds any open-source software or webservice currently available for identifying optimal pathways for target production.},
doi = {10.1186/s12859-019-3025-9},
journal = {BMC Bioinformatics},
issn = {1471-2105},
number = 1,
volume = 20,
place = {United States},
year = {2019},
month = {9}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Figures / Tables:

Algorithm 1 Algorithm 1: Identifying all enzymes that can be part of an optimal pathway

Save / Share:

Works referenced in this record:

A protocol for generating a high-quality genome-scale metabolic reconstruction
journal, January 2010


MINEs: open access databases of computationally predicted enzyme promiscuity products for untargeted metabolomics
journal, August 2015

  • Jeffryes, James G.; Colastani, Ricardo L.; Elbadawi-Sidhu, Mona
  • Journal of Cheminformatics, Vol. 7, Issue 1
  • DOI: 10.1186/s13321-015-0087-1

Reaction of Nitric Oxide with Amines
journal, May 1997

  • Itoh, Takashi; Nagata, Kazuhiro; Matsuya, Yûji
  • The Journal of Organic Chemistry, Vol. 62, Issue 11
  • DOI: 10.1021/jo962101e

Design of computational retrobiosynthesis tools for the design of de novo synthetic pathways
journal, October 2015


De novo biosynthetic pathways: rational design of microbial chemical factories
journal, October 2008

  • Prather, Kristala L. Jones; Martin, Collin H.
  • Current Opinion in Biotechnology, Vol. 19, Issue 5, p. 468-474
  • DOI: 10.1016/j.copbio.2008.07.009

KEGG: Kyoto Encyclopedia of Genes and Genomes
journal, January 2000

  • Kanehisa, Minoru; Goto, Susumu
  • Nucleic Acids Research, Vol. 28, Issue 1, p. 27-30
  • DOI: 10.1093/nar/28.1.27

A Review of Pterostilbene Antioxidant Activity and Disease Modification
journal, January 2013

  • McCormack, Denise; McFadden, David
  • Oxidative Medicine and Cellular Longevity, Vol. 2013
  • DOI: 10.1155/2013/575482

MetaRoute: fast search for relevant metabolic routes for interactive network navigation and visualization
journal, July 2008


A retrosynthetic biology approach to metabolic pathway design for therapeutic production
journal, January 2011

  • Carbonell, Pablo; Planson, Anne-Gaëlle; Fichera, Davide
  • BMC Systems Biology, Vol. 5, Issue 1
  • DOI: 10.1186/1752-0509-5-122

Improvements to PATRIC, the all-bacterial Bioinformatics Database and Analysis Resource Center
journal, November 2016

  • Wattam, Alice R.; Davis, James J.; Assaf, Rida
  • Nucleic Acids Research, Vol. 45, Issue D1
  • DOI: 10.1093/nar/gkw1017

Mackinac: a bridge between ModelSEED and COBRApy to generate and analyze genome-scale metabolic models
journal, March 2017


OptStrain: A computational framework for redesign of microbial production systems
journal, November 2004


Optimal metabolic route search based on atom mappings
journal, March 2014


Production of isopropanol by metabolically engineered Escherichia coli
journal, November 2007

  • Jojima, Toru; Inui, Masayuki; Yukawa, Hideaki
  • Applied Microbiology and Biotechnology, Vol. 77, Issue 6, p. 1219-1224
  • DOI: 10.1007/s00253-007-1246-8

SPRESIweb 2.1, a Selective Chemical Synthesis and Reaction Database
journal, August 2005

  • Roth, Dana L.
  • Journal of Chemical Information and Modeling, Vol. 45, Issue 5
  • DOI: 10.1021/ci050274b

Enumerating metabolic pathways for the production of heterologous target chemicals in chassis organisms
journal, January 2012

  • Carbonell, Pablo; Fichera, Davide; Pandit, Shashi B.
  • BMC Systems Biology, Vol. 6, Issue 1
  • DOI: 10.1186/1752-0509-6-10

ClusterCAD: a computational platform for type I modular polyketide synthase design
journal, October 2017

  • Eng, Clara H.; Backman, Tyler W. H.; Bailey, Constance B.
  • Nucleic Acids Research, Vol. 46, Issue D1
  • DOI: 10.1093/nar/gkx893

Using KBase to Assemble and Annotate Prokaryotic Genomes
journal, August 2017

  • Allen, Benjamin; Drake, Meghan; Harris, Nomi
  • Current Protocols in Microbiology, Vol. 46, Issue 1
  • DOI: 10.1002/cpmc.37

The MetaCyc database of metabolic pathways and enzymes
journal, October 2017

  • Caspi, Ron; Billington, Richard; Fulcher, Carol A.
  • Nucleic Acids Research, Vol. 46, Issue D1
  • DOI: 10.1093/nar/gkx935

What is flux balance analysis?
journal, March 2010

  • Orth, Jeffrey D.; Thiele, Ines; Palsson, Bernhard Ø
  • Nature Biotechnology, Vol. 28, Issue 3
  • DOI: 10.1038/nbt.1614

LibSBML: an API Library for SBML
journal, February 2008


Non-fermentative pathways for synthesis of branched-chain higher alcohols as biofuels
journal, January 2008

  • Atsumi, Shota; Hanai, Taizo; Liao, James C.
  • Nature, Vol. 451, Issue 7174, p. 86-89
  • DOI: 10.1038/nature06450

RetroPath2.0: A retrosynthesis workflow for metabolic engineers
journal, January 2018


Generation of an atlas for commodity chemical production in Escherichia coli and a novel pathway prediction algorithm, GEM-Path
journal, September 2014


COBRApy: COnstraints-Based Reconstruction and Analysis for Python
journal, January 2013

  • Ebrahim, Ali; Lerman, Joshua A.; Palsson, Bernhard O.
  • BMC Systems Biology, Vol. 7, Issue 1
  • DOI: 10.1186/1752-0509-7-74

ATLAS of Biochemistry: A Repository of All Possible Biochemical Reactions for Synthetic Biology and Metabolic Engineering Studies
journal, June 2016


    Works referencing / citing this record:

    Using KBase to Assemble and Annotate Prokaryotic Genomes
    journal, August 2017

    • Allen, Benjamin; Drake, Meghan; Harris, Nomi
    • Current Protocols in Microbiology, Vol. 46, Issue 1
    • DOI: 10.1002/cpmc.37

    Production of isopropanol by metabolically engineered Escherichia coli
    journal, November 2007

    • Jojima, Toru; Inui, Masayuki; Yukawa, Hideaki
    • Applied Microbiology and Biotechnology, Vol. 77, Issue 6, p. 1219-1224
    • DOI: 10.1007/s00253-007-1246-8

    Design of computational retrobiosynthesis tools for the design of de novo synthetic pathways
    journal, October 2015


    De novo biosynthetic pathways: rational design of microbial chemical factories
    journal, October 2008

    • Prather, Kristala L. Jones; Martin, Collin H.
    • Current Opinion in Biotechnology, Vol. 19, Issue 5, p. 468-474
    • DOI: 10.1016/j.copbio.2008.07.009

    Generation of an atlas for commodity chemical production in Escherichia coli and a novel pathway prediction algorithm, GEM-Path
    journal, September 2014


    RetroPath2.0: A retrosynthesis workflow for metabolic engineers
    journal, January 2018


    ATLAS of Biochemistry: A Repository of All Possible Biochemical Reactions for Synthetic Biology and Metabolic Engineering Studies
    journal, June 2016


    SPRESIweb 2.1, a Selective Chemical Synthesis and Reaction Database
    journal, August 2005

    • Roth, Dana L.
    • Journal of Chemical Information and Modeling, Vol. 45, Issue 5
    • DOI: 10.1021/ci050274b

    Reaction of Nitric Oxide with Amines
    journal, May 1997

    • Itoh, Takashi; Nagata, Kazuhiro; Matsuya, Yûji
    • The Journal of Organic Chemistry, Vol. 62, Issue 11
    • DOI: 10.1021/jo962101e

    Non-fermentative pathways for synthesis of branched-chain higher alcohols as biofuels
    journal, January 2008

    • Atsumi, Shota; Hanai, Taizo; Liao, James C.
    • Nature, Vol. 451, Issue 7174, p. 86-89
    • DOI: 10.1038/nature06450

    What is flux balance analysis?
    journal, March 2010

    • Orth, Jeffrey D.; Thiele, Ines; Palsson, Bernhard Ø
    • Nature Biotechnology, Vol. 28, Issue 3
    • DOI: 10.1038/nbt.1614

    A protocol for generating a high-quality genome-scale metabolic reconstruction
    journal, January 2010


    LibSBML: an API Library for SBML
    journal, February 2008


    MetaRoute: fast search for relevant metabolic routes for interactive network navigation and visualization
    journal, July 2008


    Optimal metabolic route search based on atom mappings
    journal, March 2014


    Mackinac: a bridge between ModelSEED and COBRApy to generate and analyze genome-scale metabolic models
    journal, March 2017


    KEGG: Kyoto Encyclopedia of Genes and Genomes
    journal, January 2000

    • Kanehisa, Minoru; Goto, Susumu
    • Nucleic Acids Research, Vol. 28, Issue 1, p. 27-30
    • DOI: 10.1093/nar/28.1.27

    Improvements to PATRIC, the all-bacterial Bioinformatics Database and Analysis Resource Center
    journal, November 2016

    • Wattam, Alice R.; Davis, James J.; Assaf, Rida
    • Nucleic Acids Research, Vol. 45, Issue D1
    • DOI: 10.1093/nar/gkw1017

    ClusterCAD: a computational platform for type I modular polyketide synthase design
    journal, October 2017

    • Eng, Clara H.; Backman, Tyler W. H.; Bailey, Constance B.
    • Nucleic Acids Research, Vol. 46, Issue D1
    • DOI: 10.1093/nar/gkx893

    The MetaCyc database of metabolic pathways and enzymes
    journal, October 2017

    • Caspi, Ron; Billington, Richard; Fulcher, Carol A.
    • Nucleic Acids Research, Vol. 46, Issue D1
    • DOI: 10.1093/nar/gkx935

    OptStrain: A computational framework for redesign of microbial production systems
    journal, November 2004


    A Review of Pterostilbene Antioxidant Activity and Disease Modification
    journal, January 2013

    • McCormack, Denise; McFadden, David
    • Oxidative Medicine and Cellular Longevity, Vol. 2013
    • DOI: 10.1155/2013/575482

    A retrosynthetic biology approach to metabolic pathway design for therapeutic production
    journal, January 2011

    • Carbonell, Pablo; Planson, Anne-Gaëlle; Fichera, Davide
    • BMC Systems Biology, Vol. 5, Issue 1
    • DOI: 10.1186/1752-0509-5-122

    Enumerating metabolic pathways for the production of heterologous target chemicals in chassis organisms
    journal, January 2012

    • Carbonell, Pablo; Fichera, Davide; Pandit, Shashi B.
    • BMC Systems Biology, Vol. 6, Issue 1
    • DOI: 10.1186/1752-0509-6-10

    COBRApy: COnstraints-Based Reconstruction and Analysis for Python
    journal, January 2013

    • Ebrahim, Ali; Lerman, Joshua A.; Palsson, Bernhard O.
    • BMC Systems Biology, Vol. 7, Issue 1
    • DOI: 10.1186/1752-0509-7-74

    MINEs: open access databases of computationally predicted enzyme promiscuity products for untargeted metabolomics
    journal, August 2015

    • Jeffryes, James G.; Colastani, Ricardo L.; Elbadawi-Sidhu, Mona
    • Journal of Cheminformatics, Vol. 7, Issue 1
    • DOI: 10.1186/s13321-015-0087-1

      Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.