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; George, Anthe; Hudson, Corey M.

doi:10.1186/s12859-019-3025-9

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

Journal Article · Mon Sep 09 00:00:00 EDT 2019 · BMC Bioinformatics

DOI:https://doi.org/10.1186/s12859-019-3025-9· OSTI ID:1570223

Whitmore, Leanne S. ^[1]; Nguyen, Bernard ^[1]; Pinar, Ali ^[1]; George, Anthe ^[1];

^[1]

Sandia National Lab. (SNL-CA), Livermore, CA (United States)

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.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Sandia National Lab. (SNL-CA), Livermore, CA (United States)

Sponsoring Organization:: USDOE Office of Energy Efficiency and Renewable Energy (EERE)

Grant/Contract Number:: AC04-94AL85000

OSTI ID:: 1570223

Report Number(s):: SAND2019-9488J; 678452

Journal Information:: BMC Bioinformatics, Vol. 20, Issue 1; ISSN 1471-2105

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 4 works

Citation information provided by
Web of Science

References (28)

A protocol for generating a high-quality genome-scale metabolic reconstruction Thiele, Ines; Palsson, Bernhard Ø Nature Protocols, Vol. 5, Issue 1 https://doi.org/10.1038/nprot.2009.203	journal	January 2010
MINEs: open access databases of computationally predicted enzyme promiscuity products for untargeted metabolomics Jeffryes, James G.; Colastani, Ricardo L.; Elbadawi-Sidhu, Mona Journal of Cheminformatics, Vol. 7, Issue 1 https://doi.org/10.1186/s13321-015-0087-1	journal	August 2015
Reaction of Nitric Oxide with Amines Itoh, Takashi; Nagata, Kazuhiro; Matsuya, Yûji The Journal of Organic Chemistry, Vol. 62, Issue 11 https://doi.org/10.1021/jo962101e	journal	May 1997
Design of computational retrobiosynthesis tools for the design of de novo synthetic pathways Hadadi, Noushin; Hatzimanikatis, Vassily Current Opinion in Chemical Biology, Vol. 28 https://doi.org/10.1016/j.cbpa.2015.06.025	journal	October 2015
De novo biosynthetic pathways: rational design of microbial chemical factories Prather, Kristala L. Jones; Martin, Collin H. Current Opinion in Biotechnology, Vol. 19, Issue 5, p. 468-474 https://doi.org/10.1016/j.copbio.2008.07.009	journal	October 2008
KEGG: Kyoto Encyclopedia of Genes and Genomes Kanehisa, Minoru; Goto, Susumu Nucleic Acids Research, Vol. 28, Issue 1, p. 27-30 https://doi.org/10.1093/nar/28.1.27	journal	January 2000
A Review of Pterostilbene Antioxidant Activity and Disease Modification McCormack, Denise; McFadden, David Oxidative Medicine and Cellular Longevity, Vol. 2013 https://doi.org/10.1155/2013/575482	journal	January 2013
MetaRoute: fast search for relevant metabolic routes for interactive network navigation and visualization Blum, Torsten; Kohlbacher, Oliver Bioinformatics, Vol. 24, Issue 18 https://doi.org/10.1093/bioinformatics/btn360	journal	July 2008
A retrosynthetic biology approach to metabolic pathway design for therapeutic production Carbonell, Pablo; Planson, Anne-Gaëlle; Fichera, Davide BMC Systems Biology, Vol. 5, Issue 1 https://doi.org/10.1186/1752-0509-5-122	journal	January 2011
Improvements to PATRIC, the all-bacterial Bioinformatics Database and Analysis Resource Center Wattam, Alice R.; Davis, James J.; Assaf, Rida Nucleic Acids Research, Vol. 45, Issue D1 https://doi.org/10.1093/nar/gkw1017	journal	November 2016
Mackinac: a bridge between ModelSEED and COBRApy to generate and analyze genome-scale metabolic models Mundy, Michael; Mendes-Soares, Helena; Chia, Nicholas Bioinformatics, Vol. 33, Issue 15 https://doi.org/10.1093/bioinformatics/btx185	journal	March 2017
OptStrain: A computational framework for redesign of microbial production systems Pharkya, P. Genome Research, Vol. 14, Issue 11 https://doi.org/10.1101/gr.2872004	journal	November 2004
Optimal metabolic route search based on atom mappings Latendresse, Mario; Krummenacker, Markus; Karp, Peter D. Bioinformatics, Vol. 30, Issue 14 https://doi.org/10.1093/bioinformatics/btu150	journal	March 2014
Production of isopropanol by metabolically engineered Escherichia coli Jojima, Toru; Inui, Masayuki; Yukawa, Hideaki Applied Microbiology and Biotechnology, Vol. 77, Issue 6, p. 1219-1224 https://doi.org/10.1007/s00253-007-1246-8	journal	November 2007
SPRESIweb 2.1, a Selective Chemical Synthesis and Reaction Database Roth, Dana L. Journal of Chemical Information and Modeling, Vol. 45, Issue 5 https://doi.org/10.1021/ci050274b	journal	August 2005
Enumerating metabolic pathways for the production of heterologous target chemicals in chassis organisms Carbonell, Pablo; Fichera, Davide; Pandit, Shashi B. BMC Systems Biology, Vol. 6, Issue 1 https://doi.org/10.1186/1752-0509-6-10	journal	January 2012
ClusterCAD: a computational platform for type I modular polyketide synthase design Eng, Clara H.; Backman, Tyler W. H.; Bailey, Constance B. Nucleic Acids Research, Vol. 46, Issue D1 https://doi.org/10.1093/nar/gkx893	journal	October 2017
Using KBase to Assemble and Annotate Prokaryotic Genomes Allen, Benjamin; Drake, Meghan; Harris, Nomi Current Protocols in Microbiology, Vol. 46, Issue 1 https://doi.org/10.1002/cpmc.37	journal	August 2017
The MetaCyc database of metabolic pathways and enzymes Caspi, Ron; Billington, Richard; Fulcher, Carol A. Nucleic Acids Research, Vol. 46, Issue D1 https://doi.org/10.1093/nar/gkx935	journal	October 2017
What is flux balance analysis? Orth, Jeffrey D.; Thiele, Ines; Palsson, Bernhard Ø Nature Biotechnology, Vol. 28, Issue 3 https://doi.org/10.1038/nbt.1614	journal	March 2010
LibSBML: an API Library for SBML Bornstein, B. J.; Keating, S. M.; Jouraku, A. Bioinformatics, Vol. 24, Issue 6 https://doi.org/10.1093/bioinformatics/btn051	journal	February 2008
Non-fermentative pathways for synthesis of branched-chain higher alcohols as biofuels Atsumi, Shota; Hanai, Taizo; Liao, James C. Nature, Vol. 451, Issue 7174, p. 86-89 https://doi.org/10.1038/nature06450	journal	January 2008
RetroPath2.0: A retrosynthesis workflow for metabolic engineers Delépine, Baudoin; Duigou, Thomas; Carbonell, Pablo Metabolic Engineering, Vol. 45 https://doi.org/10.1016/j.ymben.2017.12.002	journal	January 2018
Generation of an atlas for commodity chemical production in Escherichia coli and a novel pathway prediction algorithm, GEM-Path Campodonico, Miguel A.; Andrews, Barbara A.; Asenjo, Juan A. Metabolic Engineering, Vol. 25 https://doi.org/10.1016/j.ymben.2014.07.009	journal	September 2014
COBRApy: COnstraints-Based Reconstruction and Analysis for Python Ebrahim, Ali; Lerman, Joshua A.; Palsson, Bernhard O. BMC Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1186/1752-0509-7-74	journal	January 2013
ATLAS of Biochemistry: A Repository of All Possible Biochemical Reactions for Synthetic Biology and Metabolic Engineering Studies Hadadi, Noushin; Hafner, Jasmin; Shajkofci, Adrian ACS Synthetic Biology, Vol. 5, Issue 10 https://doi.org/10.1021/acssynbio.6b00054	journal	June 2016
SPRESIweb 2.1, a Selective Chemical Synthesis and Reaction Database. Roth, Dana L. ChemInform, Vol. 36, Issue 49 https://doi.org/10.1002/chin.200549211	journal	December 2005
Red versus green leaves: transcriptomic comparison of foliar senescence between two Prunus cerasifera genotypes Vangelisti, Alberto; Guidi, Lucia; Cavallini, Andrea Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-58878-8	journal	February 2020

Linked Research (4)

Figures / Tables (9)

Similar Records

Unlocking the magic in mycelium: Using synthetic biology to optimize filamentous fungi for biomanufacturing and sustainability

Journal Article · Sat Jan 21 00:00:00 EST 2023 · Materials Today Bio · OSTI ID:1570223

Jo, Charles; Zhang, Jing; Tam, Jenny M.; +4 more

Computational design and analysis of modular cells for large libraries of exchangeable product synthesis modules

Journal Article · Fri Jul 30 00:00:00 EDT 2021 · Metabolic Engineering · OSTI ID:1570223

Garcia, Sergio; Trinh, Cong T.

Engineering Novosphingobium aromaticivorans to produce cis,cis -muconic acid from biomass aromatics

Journal Article · Wed Jan 24 00:00:00 EST 2024 · Applied and Environmental Microbiology · OSTI ID:1570223

Vilbert, Avery C.; Kontur, Wayne S.; Gille, Derek; +3 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
mixed integer linear programming
metabolic engineering
flyx balance analysis

Additional file 1 of RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms Whitmore, Leanne; Nguyen, Bernard; Pinar, Ali https://doi.org/10.6084/m9.figshare.9790517 The current record is supplemented by this text	text	January 2019
Additional file 1 of RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms Whitmore, Leanne; Nguyen, Bernard; Pinar, Ali https://doi.org/10.6084/m9.figshare.9790517.v1 The current record is supplemented by this text	text	January 2019
RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms Whitmore, Leanne; Nguyen, Bernard; Pinar, Ali https://doi.org/10.6084/m9.figshare.c.4660010 The current record is supplemented by this collection	collection	January 2019
RetSynth: determining all optimal and sub-optimal synthetic pathways that facilitate synthesis of target compounds in chassis organisms Whitmore, Leanne; Nguyen, Bernard; Pinar, Ali https://doi.org/10.6084/m9.figshare.c.4660010.v1 The current record is supplemented by this collection	collection	January 2019