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Article: Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication.

Thiele, Ines / Fleming, Ronan M T

Computational and structural biotechnology journal

2022 Volume 20, Page(s) 4098–4109

Abstract: We aimed at investigating host-virus co-metabolism during SARS-CoV-2 infection. Therefore, we extended comprehensive sex-specific, whole-body organ resolved models of human metabolism with the necessary reactions to replicate SARS-CoV-2 in the lung as ... ...

Abstract	We aimed at investigating host-virus co-metabolism during SARS-CoV-2 infection. Therefore, we extended comprehensive sex-specific, whole-body organ resolved models of human metabolism with the necessary reactions to replicate SARS-CoV-2 in the lung as well as selected peripheral organs. Using this comprehensive host-virus model, we obtained the following key results: 1. The predicted maximal possible virus shedding rate was limited by isoleucine availability. 2. The supported initial viral load depended on the increase in CD4+ T-cells, consistent with the literature. 3. During viral infection, the whole-body metabolism changed including the blood metabolome, which agreed well with metabolomic studies from COVID-19 patients and healthy controls. 4. The virus shedding rate could be reduced by either inhibition of the guanylate kinase 1 or availability of amino acids, e.g., in the diet. 5. The virus variants differed in their maximal possible virus shedding rates, which could be inversely linked to isoleucine occurrences in the sequences. Taken together, this study presents the metabolic crosstalk between host and virus and emphasises the role of amino acid metabolism during SARS-CoV-2 infection, in particular of isoleucine. As such, it provides an example of how computational modelling can complement more canonical approaches to gain insight into host-virus crosstalk and to identify potential therapeutic strategies.
Language	English
Publishing date	2022-07-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.07.019
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Article ; Online: MetaboAnnotator: an efficient toolbox to annotate metabolites in genome-scale metabolic reconstructions.

Thiele, Ines / Preciat, German / Fleming, Ronan M T

Bioinformatics (Oxford, England)

2022 Volume 38, Issue 20, Page(s) 4831–4832

Abstract: Motivation: Genome-scale metabolic reconstructions have been assembled for thousands of organisms using a wide range of tools. However, metabolite annotations, required to compare and link metabolites between reconstructions, remain incomplete. Here, we ...

Abstract	Motivation: Genome-scale metabolic reconstructions have been assembled for thousands of organisms using a wide range of tools. However, metabolite annotations, required to compare and link metabolites between reconstructions, remain incomplete. Here, we aim to further extend metabolite annotation coverage using various databases and chemoinformatic approaches. Results: We developed a COBRA toolbox extension, deemed MetaboAnnotator, which facilitates the comprehensive annotation of metabolites with database independent and dependent identifiers, obtains molecular structure files, and calculates metabolite formula and charge at pH 7.2. The resulting metabolite annotations allow for subsequent cross-mapping between reconstructions and mapping of, e.g., metabolomic data. Availability and implementation: MetaboAnnotator and tutorials are freely available at https://github.com/opencobra. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Databases, Factual ; Genome ; Metabolic Networks and Pathways ; Metabolomics ; Software
Language	English
Publishing date	2022-09-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btac596
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Article: Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication

Thiele, Ines / Fleming, Ronan M.T.

Computational and Structural Biotechnology Journal. 2022 July 10,

2022

Abstract	We aimed at investigating host-virus co-metabolism during SARS-CoV-2 infection. Therefore, we extended comprehensive sex-specific, whole-body organ resolved models of human metabolism with the necessary reactions to replicate SARS-CoV-2 in the lung as well as selected peripheral organs. Using this comprehensive host-virus model, we obtained the following key results: 1. The predicted maximal possible virus shedding rate was limited by isoleucine availability. 2. The supported initial viral load depended on the increase in CD4+ T-cells, consistent with the literature. 3. During viral infection, the whole-body metabolism changed including the blood metabolome, which agreed well with metabolomic studies from COVID-19 patients and healthy controls. 4. The virus shedding rate could be reduced by either inhibition of the guanylate kinase 1 or availability of amino acids, e.g., in the diet. 5. The virus variants achieved differed in their maximal possible virus shedding rates, which could be inversely linked to isoleucine occurrences in the sequences. Taken together, this study presents the metabolic crosstalk between host and virus and emphasis the role of amino acid metabolism during SARS-CoV-2 infection, in particular of isoleucine. As such, it provides an example of how computational modelling can complement more canonical approaches to gain insight into host-virus crosstalk and to identify potential therapeutic strategies.
Keywords	CD4-positive T-lymphocytes ; COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; amino acid metabolism ; biotechnology ; diet ; humans ; isoleucine ; lungs ; metabolome ; metabolomics ; models ; therapeutics ; viral load ; viruses
Language	English
Dates of publication	2022-0710
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.07.019
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Article ; Online: DEMETER: efficient simultaneous curation of genome-scale reconstructions guided by experimental data and refined gene annotations.

Heinken, Almut / Magnúsdóttir, Stefanía / Fleming, Ronan M T / Thiele, Ines

Bioinformatics (Oxford, England)

2021 Volume 37, Issue 21, Page(s) 3974–3975

Abstract: Motivation: Manual curation of genome-scale reconstructions is laborious, yet existing automated curation tools do not typically take species-specific experimental and curated genomic data into account.: Results: We developed Data-drivEn METabolic ... ...

Abstract	Motivation: Manual curation of genome-scale reconstructions is laborious, yet existing automated curation tools do not typically take species-specific experimental and curated genomic data into account. Results: We developed Data-drivEn METabolic nEtwork Refinement (DEMETER), a Constraint-Based Reconstruction and Analysis (COBRA) Toolbox extension, which enables the efficient, simultaneous refinement of thousands of draft genome-scale reconstructions, while ensuring adherence to the quality standards in the field, agreement with available experimental data and refinement of pathways based on manually refined genome annotations. Availability and implementation: DEMETER and tutorials are freely available at https://github.com/opencobra. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Software ; Molecular Sequence Annotation ; Metabolic Networks and Pathways ; Genome ; Genomics
Language	English
Publishing date	2021-09-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btab622
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Article ; Online: Cardinality optimization in constraint-based modelling: application to human metabolism.

Fleming, Ronan M T / Haraldsdottir, Hulda S / Minh, Le Hoai / Vuong, Phan Tu / Hankemeier, Thomas / Thiele, Ines

Bioinformatics (Oxford, England)

2023 Volume 39, Issue 9

Abstract: Motivation: Several applications in constraint-based modelling can be mathematically formulated as cardinality optimization problems involving the minimization or maximization of the number of nonzeros in a vector. These problems include testing for ... ...

Abstract	Motivation: Several applications in constraint-based modelling can be mathematically formulated as cardinality optimization problems involving the minimization or maximization of the number of nonzeros in a vector. These problems include testing for stoichiometric consistency, testing for flux consistency, testing for thermodynamic flux consistency, computing sparse solutions to flux balance analysis problems and computing the minimum number of constraints to relax to render an infeasible flux balance analysis problem feasible. Such cardinality optimization problems are computationally complex, with no known polynomial time algorithms capable of returning an exact and globally optimal solution. Results: By approximating the zero-norm with nonconvex continuous functions, we reformulate a set of cardinality optimization problems in constraint-based modelling into a difference of convex functions. We implemented and numerically tested novel algorithms that approximately solve the reformulated problems using a sequence of convex programs. We applied these algorithms to various biochemical networks and demonstrate that our algorithms match or outperform existing related approaches. In particular, we illustrate the efficiency and practical utility of our algorithms for cardinality optimization problems that arise when extracting a model ready for thermodynamic flux balance analysis given a human metabolic reconstruction. Availability and implementation: Open source scripts to reproduce the results are here https://github.com/opencobra/COBRA.papers/2023_cardOpt with general purpose functions integrated within the COnstraint-Based Reconstruction and Analysis toolbox: https://github.com/opencobra/cobratoolbox.
MeSH term(s)	Humans ; Algorithms ; Thermodynamics
Language	English
Publishing date	2023-09-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btad450
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Article: Quantitative systems pharmacology and the personalized drug-microbiota-diet axis.

Thiele, Ines / Clancy, Catherine M / Heinken, Almut / Fleming, Ronan M T

Current opinion in systems biology

2020 Volume 4, Page(s) 43–52

Abstract: Precision medicine is an emerging paradigm that aims at maximizing the benefits and minimizing the adverse effects of drugs. Realistic mechanistic models are needed to understand and limit heterogeneity in drug responses. While pharmacokinetic models ... ...

Abstract	Precision medicine is an emerging paradigm that aims at maximizing the benefits and minimizing the adverse effects of drugs. Realistic mechanistic models are needed to understand and limit heterogeneity in drug responses. While pharmacokinetic models describe in detail a drug's absorption and metabolism, they generally do not account for individual variations in response to environmental influences, in addition to genetic variation. For instance, the human gut microbiota metabolizes drugs and is modulated by diet, and it exhibits significant variation among individuals. However, the influence of the gut microbiota on drug failure or drug side effects is under-researched. Here, we review recent advances in computational modeling approaches that could contribute to a better, mechanism-based understanding of drug-microbiota-diet interactions and their contribution to individual drug responses. By integrating systems biology and quantitative systems pharmacology with microbiology and nutrition, the conceptually and technologically demand for novel approaches could be met to enable the study of individual variability, thereby providing breakthrough support for progress in precision medicine.
Language	English
Publishing date	2020-07-07
Publishing country	England
Document type	Journal Article ; Review
ISSN	2452-3100
ISSN	2452-3100
DOI	10.1016/j.coisb.2017.06.001
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Book ; Online: DEMETER

Heinken, Almut / Magnúsdóttir, Stefanía / Fleming, Ronan M. T. / Thiele, Ines

Efficient simultaneous curation of genome-scale reconstructions guided by experimental data and refined gene annotations

2021

Abstract: Motivation: Manual curation of genome-scale reconstructions is laborious, yet existing automated curation tools typically do not take species-specific experimental data and manually refined genome annotations into account. Results: We developed DEMETER, ... ...

Abstract	Motivation: Manual curation of genome-scale reconstructions is laborious, yet existing automated curation tools typically do not take species-specific experimental data and manually refined genome annotations into account. Results: We developed DEMETER, a COBRA Toolbox extension that enables the efficient simultaneous refinement of thousands of draft genome-scale reconstructions while ensuring adherence to the quality standards in the field, agreement with available experimental data, and refinement of pathways based on manually refined genome annotations. Availability: DEMETER and tutorials are available at https://github.com/opencobra/cobratoolbox. Comment: 6 pages, 1 Figure
Keywords	Quantitative Biology - Genomics ; Quantitative Biology - Molecular Networks
Publishing date	2021-06-11
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of Conserved Moieties in Metabolic Networks by Graph Theoretical Analysis of Atom Transition Networks.

Hulda S Haraldsdóttir / Ronan M T Fleming

PLoS Computational Biology, Vol 12, Iss 11, p e

2016 Volume 1004999

Abstract: Conserved moieties are groups of atoms that remain intact in all reactions of a metabolic network. Identification of conserved moieties gives insight into the structure and function of metabolic networks and facilitates metabolic modelling. All moiety ... ...

Abstract	Conserved moieties are groups of atoms that remain intact in all reactions of a metabolic network. Identification of conserved moieties gives insight into the structure and function of metabolic networks and facilitates metabolic modelling. All moiety conservation relations can be represented as nonnegative integer vectors in the left null space of the stoichiometric matrix corresponding to a biochemical network. Algorithms exist to compute such vectors based only on reaction stoichiometry but their computational complexity has limited their application to relatively small metabolic networks. Moreover, the vectors returned by existing algorithms do not, in general, represent conservation of a specific moiety with a defined atomic structure. Here, we show that identification of conserved moieties requires data on reaction atom mappings in addition to stoichiometry. We present a novel method to identify conserved moieties in metabolic networks by graph theoretical analysis of their underlying atom transition networks. Our method returns the exact group of atoms belonging to each conserved moiety as well as the corresponding vector in the left null space of the stoichiometric matrix. It can be implemented as a pipeline of polynomial time algorithms. Our implementation completes in under five minutes on a metabolic network with more than 4,000 mass balanced reactions. The scalability of the method enables extension of existing applications for moiety conservation relations to genome-scale metabolic networks. We also give examples of new applications made possible by elucidating the atomic structure of conserved moieties.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2016-11-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Metabolic and signalling network maps integration

Nicolas Sompairac / Jennifer Modamio / Emmanuel Barillot / Ronan M. T. Fleming / Andrei Zinovyev / Inna Kuperstein

BMC Bioinformatics, Vol 20, Iss S4, Pp 1-

application to cross-talk studies and omics data analysis in cancer

2019 Volume 14

Abstract: Abstract Background The interplay between metabolic processes and signalling pathways remains poorly understood. Global, detailed and comprehensive reconstructions of human metabolism and signalling pathways exist in the form of molecular maps, but they ... ...

Abstract	Abstract Background The interplay between metabolic processes and signalling pathways remains poorly understood. Global, detailed and comprehensive reconstructions of human metabolism and signalling pathways exist in the form of molecular maps, but they have never been integrated together. We aim at filling in this gap by integrating of both signalling and metabolic pathways allowing a visual exploration of multi-level omics data and study of cross-regulatory circuits between these processes in health and in disease. Results We combined two comprehensive manually curated network maps. Atlas of Cancer Signalling Network (ACSN), containing mechanisms frequently implicated in cancer; and ReconMap 2.0, a comprehensive reconstruction of human metabolic network. We linked ACSN and ReconMap 2.0 maps via common players and represented the two maps as interconnected layers using the NaviCell platform for maps exploration (https://navicell.curie.fr/pages/maps_ReconMap%202.html). In addition, proteins catalysing metabolic reactions in ReconMap 2.0 were not previously visually represented on the map canvas. This precluded visualisation of omics data in the context of ReconMap 2.0. We suggested a solution for displaying protein nodes on the ReconMap 2.0 map in the vicinity of the corresponding reaction or process nodes. This permits multi-omics data visualisation in the context of both map layers. Exploration and shuttling between the two map layers is possible using Google Maps-like features of NaviCell. The integrated networks ACSN-ReconMap 2.0 are accessible online and allows data visualisation through various modes such as markers, heat maps, bar-plots, glyphs and map staining. The integrated networks were applied for comparison of immunoreactive and proliferative ovarian cancer subtypes using transcriptomic, copy number and mutation multi-omics data. A certain number of metabolic and signalling processes specifically deregulated in each of the ovarian cancer sub-types were identified. Conclusions As knowledge evolves ...
Keywords	Signalling ; Metabolism ; Networks ; Comprehensive map ; Systems biology ; Cancer ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural conserved moiety splitting of a stoichiometric matrix.

Ghaderi, Susan / Haraldsdóttir, Hulda S / Ahookhosh, Masoud / Arreckx, Sylvain / Fleming, Ronan M T

Journal of theoretical biology

2020 Volume 499, Page(s) 110276

Abstract: Characterising biochemical reaction network structure in mathematical terms enables the inference of functional biochemical consequences from network structure with existing mathematical techniques and spurs the development of new mathematics that ... ...

Abstract	Characterising biochemical reaction network structure in mathematical terms enables the inference of functional biochemical consequences from network structure with existing mathematical techniques and spurs the development of new mathematics that exploits the peculiarities of biochemical network structure. The structure of a biochemical network may be specified by reaction stoichiometry, that is, the relative quantities of each molecule produced and consumed in each reaction of the network. A biochemical network may also be specified at a higher level of resolution in terms of the internal structure of each molecule and how molecular structures are transformed by each reaction in a network. The stoichiometry for a set of reactions can be compiled into a stoichiometric matrix N∈Z
MeSH term(s)	Cell Physiological Phenomena ; Mathematics
Language	English
Publishing date	2020-04-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2020.110276
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