The RAVEN Toolbox 2.0: a versatile platform for metabolic network - - PowerPoint PPT Presentation

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The RAVEN Toolbox 2.0: a versatile platform for metabolic network reconstruction and simulation Hao Wang Ph.D. hao.wang@chalmers.se Division of Systems and Synthetic Biology Department of Biology and Biological Engineering Chalmers University

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The RAVEN Toolbox 2.0: a versatile platform for metabolic network reconstruction and simulation

Hao Wang Ph.D.

hao.wang@chalmers.se Division of Systems and Synthetic Biology Department of Biology and Biological Engineering Chalmers University of Technology, Sweden Pathway Tools Workshop 2018, Feb 12-14th

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Genome-scale models (GEMs) for Systems biology research

Genome-scale metabolic model reconstruction Simulation of metabolic capabilities

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Various packages/solutions

to aid reconstruction – Kbase – CoReCo – ModelSEED – merlin

Automated draft GEM reconstruction

PLOS Comp Biol. 2013, 9:e1002980

RAVEN (Reconstruction,

Analysis and Visualization of Metabolic Networks) Matlab-based Toolbox

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GEM reconstruction for Penicillium chrysogenum

iAL1006 # Rxn: 1471 # Met: 1235 # Gene: 1006 PLOS Comp Biol. 2013, 9:e1002980

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Task-driven Model Reconstruction Algorithm (tINIT)

Mol Syst Biol. 2014, 10:721 metabolicatlas.org

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RAVEN Toolbox ver 2.0

A wide range of biological pathway databases HMR database Template models HMMs & BLAST tINIT algorithm Import/Export GEMs Model simulation COBRA toolbox

Matlab RAVEN COBRA XML SBML FBCv2 SBML level2 YAML Excel sheet

FBA FSEOF

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Features of RAVEN Toolbox ver 2.0

MEMOSys FAME Microbes Flux CoReCo Pathway Tools RAVEN 1.0 COBRA 2.0 Model SEED merlin RAVEN 2.0 Prokaryotic models Tissues/organ models Eukaryotic models Uses KEGG Uses MetaCyc Uses template model Mass and charge balance Assign sub-cellular localization Transporters annotation Spontaneoues reaction Simulation analysis Pathways visualisation Export to SBML Export to Excel OS independent

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MetaCyc reconstruction module in RAVEN 2.0

Proteins Enzrxns Reactions Pathway-links Compounds MetaCyc Data files getEnzymesFromMetaCyc getRxnsFromMetaCyc getMetsFromMetaCyc getModelFromMetaCyc metaCycEnzrxns metaCycRxns metaCycMets getMetaCycModelForOrganism Query Proteome Super MetaCycModel

GEM

Protseq.fsa

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Streptomyces coelicolor

Nature. 2002 417:141-7.
Model organism of

Actinomycete for antibiotic production

Produce a number of

different types of compounds with antibiotic properties

A good candidate of cell

factory for novel antibiotic production

Soil-dwelling, filamentous, Gram-positive

Actinorhodin

CDA NRP ACT PK II RED NRP/PK CPK PK I

Calcium-dependent antibiotic Prodiginines Coelimycin

GC 72%

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GEMs of Streptomyces coelicolor A3(2)

Biotechnol J. 2014, 9:1185-94

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Secondary metabolites produced by S. coelicolor

Nature. 2002 417:141-7.

iIB711 iMA789 iMK1208 : 25 (12 + 8 + 3) : 33 (10 + 10 + 13) : 83 (22 + 19 + 42)

CDA ACT RED

SCO2782-2785 SCO0489-0499 SCO7681-7691 SCO6073 SCO6264-6267 SCO6759-6771 SCO1206-1208 SCO0185-0191 SCO5314-5321

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J Ind Microbiol Biotechnol 2014, 41:219–32

ACT RED

1 2 3 4 6 5 8 7 9 12 11 10 13

Ex Exper erimen entally y el elucidated ed secondary metabolic pathways

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iMK1208 Rxns 1643 Mets 1246 Genes 1208

Draft GEM reconstruction for

S. coelicolor by RAVEN 2.0

MetaCyc Rxns 1501 Mets 1940 Genes 1893 KEGG annotation Rxns 1309 Mets 1456 Genes 1076 KEGG HMMs Rxns 1565 Mets 1769 Genes 1279

Identifier association Metabolite mapping

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Model comparison

43 54 35 52 224 95 166 663 2 3 589 146 190 39 20 Genes Metabolites KEGG Annotation 442 KEGG HMMs MetaCyc 153 213 587 2 70 5 297 5 6 28 59 2 213 48 iMK1208

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Sco4 model generation by RAVEN 2.0

iMK1208 Rxns 1859 Mets 1436 Genes 1208 Annotation Rxns 1309 Mets 1456 Genes 1076 HMMs Rxns 1565 Mets 1769 Genes 1279 Merged KEGG Rxns 1662 Mets 1830 Genes 1396 MetaCyc Rxns 1501 Mets 1940 Genes 1893 Rxns 2605 Mets 3005 Genes 2175 Combined Rxns 2304 Mets 1927 Genes 1522

Sco4

MetaCyc: 958 KEGG: 1104 Both: 543

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Gapfilling by RAVEN 2.0

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Compositional distribution of the newly included reactions from RAVEN 2.0

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Stoichiometric network curation

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List of updated metabolite identifiers

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No gene-annotated, still present!

Spontaneous reaction

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Lists of MetaCyc reaction and metabolite identifiers as query

retrieveSpontaneous

1 1 1 1 1 1 1 1 1 1 1

pathway spontaneous reaction

A total of 34 spontaneous Reactions were retrieved into Sco4

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Flux Scanning based on Enforced Objective Flux (FSEOF)

Appl. Environ. Microbiol. 2010 76(10):3097-3105

Biomass formation rate Vbiomass (h-1) Target product formation rate Vproduct (mmol/gDCW/h)

max Product enforced product enforced product enforced product enforced product enforced product initial product

V V V V V V V Enforce the

bjective flux of

production formation

A RAVEN function implementing the FSEOF algorithm has been added

Increased flux Decreased flux Unchanged flux

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Over-expression targets predicted by FSEOF using Sco4

Actinorhodin

Polyketides Non-ribosomal peptides Sesquiterpene derived

All classes

Flaviolin 16 2 3 65 56 24 32 4 6 15 24 5 21 2 49 Undecylprodigiosin Calcium-dependent antibiotic Geosmin Albaflavenone 2-methylisoborneol

Polyketides Non-ribosomal peptides

BCAA met. Histidine degradation Propanoate met. Cofactor biosynthesis Nucleotide salvage

Sesquiterpene-derived

Glycolysis FA elongation Benzoate degradation Catechol degradation Tyr, Try and Phe met. AcCoA carboxylase Try degradation

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Gene essentiality analysis

Appl Environ Microbiol. 2017, 83(6):e02889-16

53,900 mutants identified by global mutagenesis study on S.

coelicolor

79 large insertion gaps (>1.9 kb), amount to 203 kb with 132
genes. They reflect either cold regions of transposition

insertion suggesting putative essential genes

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RAVEN on GitHub

1. https://github.com/SysBioChalmers/RAVEN
2. Clone or Download
Under active development
Detail help message availabe for all functions
Comments and bug reports are highly welcome

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GEMs on GitHub

https://github.com/SysBioChalmers/Streptomyces_coelicolor-GEM

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Summary

RAVEN Matlab Toolbox on GitHub
Combines multiple data sources (MetaCyc, KEGG)
Mass and charge balance
An efficient platform for high quality draft model reconstruction
Transport and spontaneous reactions
A wide range of flux analysis functions
Improved compatibility (Import/Export, COBRA)
Useful in updating existing GEMs

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Acknowledgements

Sysbio: Eduard Kerkhoven Simonas Marcišauskas Daniel Hermansson Sylvain Prigent Rasmus Ågren Jens Nielsen SRI: Ron Caspi Peter Karp