Chemical-damage MINE: A database of curated and predicted spontaneous metabolic reactions

Jeffryes, James G.; Lerma-Ortiz, Claudia; Liu, Filipe; Golubev, Alexey G.; Niehaus, Thomas D.; Elbadawi-Sidhu, Mona; Fiehn, Oliver; Hanson, Andrew D.; Tyo, Keith EJ.; Henry, Christopher S.

doi:10.1016/j.ymben.2021.11.009

Title: Chemical-damage MINE: A database of curated and predicted spontaneous metabolic reactions

Journal Article · 24 December 2021 · Metabolic Engineering

DOI: https://doi.org/10.1016/j.ymben.2021.11.009 · OSTI ID:1991350

Jeffryes, James G. ^[1];

^[2];

^[3];

^[4];

^[5]; Elbadawi-Sidhu, Mona ^[6]; Fiehn, Oliver ^[6]; Hanson, Andrew D. ^[7]; Tyo, Keith EJ. ^[8]; Henry, Christopher S. ^[3]

Argonne National Laboratory (ANL), Argonne, IL (United States)
University of Chicago, IL (United States); Argonne National Laboratory (ANL), Argonne, IL (United States)
Argonne National Laboratory (ANL), Argonne, IL (United States); University of Chicago, IL (United States)
N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg (Russia)
University of Florida, Gainesville, FL (United States); University of Minnesota, Saint Paul, MN (United States)
University of California, Davis, CA (United States)
University of Florida, Gainesville, FL (United States)
Northwestern University, Evanston, IL (United States)

Spontaneous reactions between metabolites are often neglected in favor of emphasizing enzyme-catalyzed chemistry because spontaneous reaction rates are assumed to be insignificant under physiological conditions. However, synthetic biology and engineering efforts can raise natural metabolites' levels or introduce unnatural ones, so that previously innocuous or nonexistent spontaneous reactions become an issue. Problems arise when spontaneous reaction rates exceed the capacity of a platform organism to dispose of toxic or chemically active reaction products. While various reliable sources list competing or toxic enzymatic pathways' side-reactions, no corresponding compilation of spontaneous side-reactions exists, nor is it possible to predict their occurrence. We addressed this deficiency by creating the Chemical Damage (CD)-MINE resource. First, we used literature data to construct a comprehensive database of metabolite reactions that occur spontaneously in physiological conditions. We then leveraged this data to construct 148 reaction rules describing the known spontaneous chemistry in a substrate-generic way. We applied these rules to all compounds in the ModelSEED database, predicting 180,891 spontaneous reactions. The resulting (CD)-MINE is available at https://minedatabase.mcs.anl. gov/cdmine/#/home and through developer tools. We also demonstrate how damage-prone intermediates and end products are widely distributed among metabolic pathways, and how predicting spontaneous chemical damage helps rationalize toxicity and carbon loss using examples from published pathways to commercial products. We explain how analyzing damage-prone areas in metabolism helps design effective engineering strategies. Finally, we use the CD-MINE toolset to predict the formation of the novel damage product N-carbamoyl proline, and present mass spectrometric evidence for its presence in Escherichia coli.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1991350

Journal Information:: Metabolic Engineering, Journal Name: Metabolic Engineering Vol. 69; ISSN 1096-7176

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (57)

Mechanistic Analysis of an Engineered Enzyme that Catalyzes the Formose Reaction Poust, Sean; Piety, James; Bar‐Even, Arren ChemBioChem, Vol. 16, Issue 13 https://doi.org/10.1002/cbic.201500228	journal	July 2015
Synthesis, Crystal Structure and Hydrogen-Bonding Patterns in (RS)-1-Carbamoyl Pyrrolidine-2-Carboxylic Acid Delgado, Gerzon E.; Seijas, Luis E.; Mora, Asiloé J. Journal of Chemical Crystallography, Vol. 42, Issue 4 https://doi.org/10.1007/s10870-011-0259-4	journal	January 2012
Quantitative metabolomics based on gas chromatography mass spectrometry: status and perspectives Koek, Maud M.; Jellema, Renger H.; van der Greef, Jan Metabolomics, Vol. 7, Issue 3 https://doi.org/10.1007/s11306-010-0254-3	journal	November 2010
Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases Phaniendra, Alugoju; Jestadi, Dinesh Babu; Periyasamy, Latha Indian Journal of Clinical Biochemistry, Vol. 30, Issue 1 https://doi.org/10.1007/s12291-014-0446-0	journal	July 2014
Dopamine produced froml-DOPA is degraded by endogenous monoamine oxidase in neurons of the dorsal raphe nucleus of the rat: an immunohistochemical study Arai, Ryohachi; Karasawa, Nobuyuki; Nagatsu, Ikuko Brain Research, Vol. 722, Issue 1-2 https://doi.org/10.1016/0006-8993(96)00252-1	journal	May 1996
Multiple roles of the active site lysine of Dopa decarboxylase Bertoldi, Mariarita; Voltattorni, Carla Borri Archives of Biochemistry and Biophysics, Vol. 488, Issue 2 https://doi.org/10.1016/j.abb.2009.06.019	journal	August 2009
Identification of p-hydroxybenzyl alcohol, tyrosol, phloretin and its derivate phloridzin as tyrosinase substrates Ortiz-Ruiz, Carmen Vanessa; Berna, Jose; Garcia-Molina, Maria del Mar Bioorganic & Medicinal Chemistry, Vol. 23, Issue 13 https://doi.org/10.1016/j.bmc.2015.04.016	journal	July 2015
Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? DeBerardinis, Ralph J.; Thompson, Craig B. Cell, Vol. 148, Issue 6 https://doi.org/10.1016/j.cell.2012.02.032	journal	March 2012
Exploring and Understanding the Biochemical Diversity of the Human Microbiota Koppel, Nitzan; Balskus, Emily P. Cell Chemical Biology, Vol. 23, Issue 1 https://doi.org/10.1016/j.chembiol.2015.12.008	journal	January 2016
Biological insights through nontargeted metabolomics Sévin, Daniel C.; Kuehne, Andreas; Zamboni, Nicola Current Opinion in Biotechnology, Vol. 34 https://doi.org/10.1016/j.copbio.2014.10.001	journal	August 2015
Metabolic pathway balancing and its role in the production of biofuels and chemicals Jones, J. Andrew; Toparlak, Ö Duhan; Koffas, Mattheos AG Current Opinion in Biotechnology, Vol. 33 https://doi.org/10.1016/j.copbio.2014.11.013	journal	June 2015
The widespread role of non-enzymatic reactions in cellular metabolism Keller, Markus A.; Piedrafita, Gabriel; Ralser, Markus Current Opinion in Biotechnology, Vol. 34 https://doi.org/10.1016/j.copbio.2014.12.020	journal	August 2015
5-S-cysteinyl-dopamine, a neurotoxic endogenous metabolite of dopamine: Implications for Parkinson's disease Badillo-Ramírez, Isidro; Saniger, José M.; Rivas-Arancibia, Selva Neurochemistry International, Vol. 129 https://doi.org/10.1016/j.neuint.2019.104514	journal	October 2019
Cell-free synthetic biology for in vitro biosynthesis of pharmaceutical natural products Li, Jian; Zhang, Lingkai; Liu, Wanqiu Synthetic and Systems Biotechnology, Vol. 3, Issue 2 https://doi.org/10.1016/j.synbio.2018.02.002	journal	June 2018
Bacterial microcompartments and the modular construction of microbial metabolism Kerfeld, Cheryl A.; Erbilgin, Onur Trends in Microbiology, Vol. 23, Issue 1 https://doi.org/10.1016/j.tim.2014.10.003	journal	January 2015
Parts plus pipes: Synthetic biology approaches to metabolic engineering Boyle, Patrick M.; Silver, Pamela A. Metabolic Engineering, Vol. 14, Issue 3 https://doi.org/10.1016/j.ymben.2011.10.003	journal	May 2012
Evolution reveals a glutathione-dependent mechanism of 3-hydroxypropionic acid tolerance Kildegaard, Kanchana R.; Hallström, Björn M.; Blicher, Thomas H. Metabolic Engineering, Vol. 26 https://doi.org/10.1016/j.ymben.2014.09.004	journal	November 2014
Metabolic assessment of E. coli as a Biofactory for commercial products Zhang, Xiaolin; Tervo, Christopher J.; Reed, Jennifer L. Metabolic Engineering, Vol. 35 https://doi.org/10.1016/j.ymben.2016.01.007	journal	May 2016
Metabolite damage and repair in metabolic engineering design Sun, Jiayi; Jeffryes, James G.; Henry, Christopher S. Metabolic Engineering, Vol. 44 https://doi.org/10.1016/j.ymben.2017.10.006	journal	November 2017
Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite Anderson, David G.; Florang, Virginia R.; Schamp, Josephine H. Chemical Research in Toxicology, Vol. 29, Issue 7 https://doi.org/10.1021/acs.chemrestox.5b00528	journal	June 2016
The Length of the Bound Fatty Acid Influences the Dynamics of the Acyl Carrier Protein and the Stability of the Thioester Bond Zornetzer, Gregory A.; Tanem, Justinn; Fox, Brian G. Biochemistry, Vol. 49, Issue 3 https://doi.org/10.1021/bi9014659	journal	January 2010
Carbamylation of N-Terminal Proline Olajuyigbe, Folasade M.; Demitri, Nicola; Ajele, Joshua O. ACS Medicinal Chemistry Letters, Vol. 1, Issue 6 https://doi.org/10.1021/ml100046d	journal	June 2010
Synthetic protein scaffolds provide modular control over metabolic flux Dueber, John E.; Wu, Gabriel C.; Malmirchegini, G. Reza Nature Biotechnology, Vol. 27, Issue 8, p. 753-759 https://doi.org/10.1038/nbt.1557	journal	August 2009
Metabolite damage and its repair or pre-emption Linster, Carole L.; Van Schaftingen, Emile; Hanson, Andrew D. Nature Chemical Biology, Vol. 9, Issue 2 https://doi.org/10.1038/nchembio.1141	journal	January 2013
Metabolite concentrations, fluxes and free energies imply efficient enzyme usage Park, Junyoung O.; Rubin, Sara A.; Xu, Yi-Fan Nature Chemical Biology, Vol. 12, Issue 7 https://doi.org/10.1038/nchembio.2077	journal	May 2016
A bacterial platform for fermentative production of plant alkaloids Nakagawa, Akira; Minami, Hiromichi; Kim, Ju-Sung Nature Communications, Vol. 2, Issue 1 https://doi.org/10.1038/ncomms1327	journal	May 2011
Current understanding of fatty acid biosynthesis and the acyl carrier protein Chan, David I.; Vogel, Hans J. Biochemical Journal, Vol. 430, Issue 1 https://doi.org/10.1042/BJ20100462	journal	July 2010
A directed-overflow and damage-control N-glycosidase in riboflavin biosynthesis Frelin, Océane; Huang, Lili; Hasnain, Ghulam Biochemical Journal, Vol. 466, Issue 1 https://doi.org/10.1042/BJ20141237	journal	February 2015
‘Nothing of chemistry disappears in biology’: the Top 30 damage-prone endogenous metabolites Lerma-Ortiz, Claudia; Jeffryes, James G.; Cooper, Arthur J. L. Biochemical Society Transactions, Vol. 44, Issue 3 https://doi.org/10.1042/BST20160073	journal	June 2016
Microbial production of plant benzylisoquinoline alkaloids Minami, H.; Kim, J. -S.; Ikezawa, N. Proceedings of the National Academy of Sciences, Vol. 105, Issue 21 https://doi.org/10.1073/pnas.0802981105	journal	May 2008
Fusing catalase to an alkane-producing enzyme maintains enzymatic activity by converting the inhibitory byproduct H2O2 to the cosubstrate O2 Andre, C.; Kim, S. W.; Yu, X. -H. Proceedings of the National Academy of Sciences, Vol. 110, Issue 8 https://doi.org/10.1073/pnas.1218769110	journal	February 2013
High-throughput comparison, functional annotation, and metabolic modeling of plant genomes using the PlantSEED resource Seaver, Samuel M. D.; Gerdes, Svetlana; Frelin, Océane Proceedings of the National Academy of Sciences, Vol. 111, Issue 26 https://doi.org/10.1073/pnas.1401329111	journal	June 2014
A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Morrow, J. D.; Hill, K. E.; Burk, R. F. Proceedings of the National Academy of Sciences, Vol. 87, Issue 23 https://doi.org/10.1073/pnas.87.23.9383	journal	December 1990
Formation of Highly Reactive γ-Ketoaldehydes (Neuroketals) as Products of the Neuroprostane Pathway Bernoud-Hubac, Nathalie; Davies, Sean S.; Boutaud, Olivier Journal of Biological Chemistry, Vol. 276, Issue 33 https://doi.org/10.1074/jbc.M103768200	journal	August 2001
Non-enzymatic molecular damage as a prototypic driver of aging Golubev, Alexey; Hanson, Andrew D.; Gladyshev, Vadim N. Journal of Biological Chemistry, Vol. 292, Issue 15 https://doi.org/10.1074/jbc.R116.751164	journal	March 2017
Chemical derivatization and mass spectral libraries in metabolic profiling by GC/MS and LC/MS/MS Halket, John M.; Waterman, Daniel; Przyborowska, Anna M. Journal of Experimental Botany, Vol. 56, Issue 410 https://doi.org/10.1093/jxb/eri069	journal	December 2004
HMDB 3.0—The Human Metabolome Database in 2013 Wishart, David S.; Jewison, Timothy; Guo, An Chi Nucleic Acids Research, Vol. 41, Issue D1 https://doi.org/10.1093/nar/gks1065	journal	November 2012
Data, information, knowledge and principle: back to metabolism in KEGG Kanehisa, Minoru; Goto, Susumu; Sato, Yoko Nucleic Acids Research, Vol. 42, Issue D1 https://doi.org/10.1093/nar/gkt1076	journal	November 2013
The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases Caspi, Ron; Billington, Richard; Ferrer, Luciana Nucleic Acids Research, Vol. 44, Issue D1 https://doi.org/10.1093/nar/gkv1164	journal	November 2015
METLIN: A Metabolite Mass Spectral Database Smith, Colin A.; Maille, Grace O??; Want, Elizabeth J. Therapeutic Drug Monitoring, Vol. 27, Issue 6 https://doi.org/10.1097/01.ftd.0000179845.53213.39	journal	January 2005
Identification of large linear plasmids in Arthrobacter spp. encoding the degradation of quinaldine to anthranilate Overhage, Jörg; Sielker, Sonja; Homburg, Stefan Microbiology, Vol. 151, Issue 2 https://doi.org/10.1099/mic.0.27521-0	journal	February 2005
The logic of metabolism and its fuzzy consequences: Paralogous metabolism Danchin, Antoine; Sekowska, Agnieszka Environmental Microbiology, Vol. 16, Issue 1 https://doi.org/10.1111/1462-2920.12270	journal	October 2013
Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase Marchitti, Satori A.; Deitrich, Richard A.; Vasiliou, Vasilis Pharmacological Reviews, Vol. 59, Issue 2 https://doi.org/10.1124/pr.59.2.1	journal	March 2007
Identification of Isopentenol Biosynthetic Genes from Bacillus subtilis by a Screening Method Based on Isoprenoid Precursor Toxicity Withers, S. T.; Gottlieb, S. S.; Lieu, B. Applied and Environmental Microbiology, Vol. 73, Issue 19, p. 6277-6283 https://doi.org/10.1128/AEM.00861-07	journal	August 2007
Anaerobic degradation of 2-aminobenzoate (anthranilic acid) by denitrifying bacteria Braun, K.; Gibson, D. T. Applied and Environmental Microbiology, Vol. 48, Issue 1 https://doi.org/10.1128/aem.48.1.102-107.1984	journal	July 1984
Metabolite Damage and Metabolite Damage Control in Plants Hanson, Andrew D.; Henry, Christopher S.; Fiehn, Oliver Annual Review of Plant Biology, Vol. 67, Issue 1 https://doi.org/10.1146/annurev-arplant-043015-111648	journal	April 2016
The Biochemistry and Physiology of Mitochondrial Fatty Acid β-Oxidation and Its Genetic Disorders Houten, Sander M.; Violante, Sara; Ventura, Fatima V. Annual Review of Physiology, Vol. 78, Issue 1 https://doi.org/10.1146/annurev-physiol-021115-105045	journal	February 2016
ModEnzA: Accurate Identification of Metabolic Enzymes Using Function Specific Profile HMMs with Optimised Discrimination Threshold and Modified Emission Probabilities Desai, Dhwani K.; Nandi, Soumyadeep; Srivastava, Prashant K. Advances in Bioinformatics, Vol. 2011 https://doi.org/10.1155/2011/743782	journal	March 2011
Metabolic engineering for improving anthranilate synthesis from glucose in Escherichia coli Balderas-Hernández, Víctor E.; Sabido-Ramos, Andrea; Silva, Patricia Microbial Cell Factories, Vol. 8, Issue 1 https://doi.org/10.1186/1475-2859-8-19	journal	April 2009
Towards a Universal SMILES representation - A standard method to generate canonical SMILES based on the InChI O’Boyle, Noel M. Journal of Cheminformatics, Vol. 4, Issue 1 https://doi.org/10.1186/1758-2946-4-22	journal	September 2012
Systematic identification and analysis of frequent gene fusion events in metabolic pathways Henry, Christopher S.; Lerma-Ortiz, Claudia; Gerdes, Svetlana Y. BMC Genomics, Vol. 17, Issue 1 https://doi.org/10.1186/s12864-016-2782-3	journal	June 2016
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
Interpreting Expression Data with Metabolic Flux Models: Predicting Mycobacterium tuberculosis Mycolic Acid Production Colijn, Caroline; Brandes, Aaron; Zucker, Jeremy PLoS Computational Biology, Vol. 5, Issue 8 https://doi.org/10.1371/journal.pcbi.1000489	journal	August 2009
Identification of NAD(P)H Quinone Oxidoreductase Activity in Azoreductases from P. aeruginosa: Azoreductases and NAD(P)H Quinone Oxidoreductases Belong to the Same FMN-Dependent Superfamily of Enzymes Ryan, Ali; Kaplan, Elise; Nebel, Jean-Christophe PLoS ONE, Vol. 9, Issue 6 https://doi.org/10.1371/journal.pone.0098551	journal	June 2014
Systematic Applications of Metabolomics in Metabolic Engineering Dromms, Robert; Styczynski, Mark Metabolites, Vol. 2, Issue 4 https://doi.org/10.3390/metabo2041090	journal	December 2012
Degradation of Methyl 2-Aminobenzoate (Methyl Anthranilate) by H2O2/UV: Effect of Inorganic Anions and Derived Radicals Lanzafame, Grazia; Sarakha, Mohamed; Fabbri, Debora Molecules, Vol. 22, Issue 4 https://doi.org/10.3390/molecules22040619	journal	April 2017
Potential Biological Activities of Magnoflorine: A Compound from Aristolochia debilis Sieb. et Zucc Li, Chunmei; Wang, Myeong-Hyeon Korean Journal of Plant Resources, Vol. 27, Issue 3 https://doi.org/10.7732/kjpr.2014.27.3.223	journal	June 2014

Similar Records

Metabolite damage and repair in metabolic engineering design

Journal Article · 2017 · Metabolic Engineering · OSTI ID:1427485

Sun, Jiayi; Jeffryes, James G.; Henry, Christopher S.; +2 more

MINEs: Open access databases of computationally predicted enzyme promiscuity products for untargeted metabolomics

Journal Article · 2015 · Journal of Cheminformatics · OSTI ID:1221820

Jeffryes, James G.; Colastani, Ricardo L.; Elbadawi-Sidhu, Mona; +7 more

Curating a comprehensive set of enzymatic reaction rules for efficient novel biosynthetic pathway design

Journal Article · 2021 · Metabolic Engineering · OSTI ID:1852562

Ni, Zhuofu; Stine, Andrew E.; Tyo, Keith E. J.; +1 more

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Computational biochemistry
Metabolic engineering
Metabolite damage
Side-product
Spontaneous reaction
Synthetic biology

Title: Chemical-damage MINE: A database of curated and predicted spontaneous metabolic reactions

Citation Formats

References (57)

Similar Records

Related Subjects