Susan LM Coort, PhD

​

susan.coort@maastrichtuniversity.nl

​

Department of Bioinformatics-BiGCaT

NUTRIM School of Nutrition and Translational Research in Metabolism

Maastricht University

​

5 July 2022

Pathway resources �Pathway databases, WikiPathways and PathVisio

Content

• Introduction
• Biological pathways
• Pathway resources
• WikiPathways
• WP portals
• Pathway visualization
• PathVisio
• Research examples

What are biological pathways?

​

Definition on Wikipedia (August 2015):

​

“A biological pathway is a series of interactions among molecules in a cell that leads to a certain product or a change in a cell.”

​

Types of biological pathways

• Metabolic pathways
• Gene regulation pathways
• Signal transduction pathways

Metabolic pathways

• Series of chemical reactions occurring within a cell
• Enzymes are catalyzing these conversions
• Example: Glycolysis

breaks down glucose and forms pyruvate with the production of two molecules of ATP

​

http://www.wikipathways.org/instance/WP534

Metabolic pathways

http://www.wikipathways.org/instance/WP534

Metabolic pathways

© 1993 Boehringer Mannheim GmbH - Biochemica.

Gene regulation pathways

• Pathways that regulate the level of gene expression
• Often sub-pathways of larger pathways
• Transcription factors

​

http://www.bio.miami.edu/dana/250/250SS11_13.html

Signal transduction pathways

• Extracellular signaling molecule
• Activation of a specific receptor
• Triggers a biochemical chain of events inside the cell
• Eventually eliciting a response

​

http://www.nature.com/nature/journal/v414/n6865/images/414799a-f2.2.jpg

Pathway databases

Commonly used pathway databases:

• WikiPathways (www.wikipathways.org)
• Reactome (www.reactome.org)
• KEGG (www.genome.jp/kegg)
• BioCyc (www.biocyc.org)

​

2018

Domingo-Fernández, D et al. ComPath: an ecosystem for exploring, analyzing, and curating mappings across pathway databases Systems Biology and Applications volume 4, Article number: 43 (2018)

Pathway databases

Be aware!

• Only about 60% of the human protein coding genes are present in biological pathways.
• A lot of information is hidden in literature and researchers’ minds.

​

​

​

​

​

​

• Detailed functions and mechanisms for many proteins still unknown.

WikiPathways

Biological pathway database

www.wikipathways.org

Founded in 2008 by Gladstone Institutes and the Department of Bioinformatics at Maastricht University

​

​

WikiPathways - What is a wiki?�“A wiki is an application, typically a web application, which allows collaborative modification, extension, or deletion of its content and structure.”

​

Definition Wikipedia 2017

Kutmon M et al. WikiPathways: capturing the full diversity of pathway knowledge.

Nucleic Acids Research. 2015 Oct 19;44(D1):D488-94. doi:10.1093/nar/gkv1024

​

WikiPathways

A Wikipedia for pathways

• Collection and curation of knowledge
• Community curated
• Everybody can contribute pathways
• Everybody can edit and curate pathways
• Everybody can use the pathway collections
• Tools
• Not just images but fully annotated models
• Interactive pathway viewer
• Full pathway editor software: PathVisio
• New findings can be added immediately - fast!
• Collaboration with Reactome

​

Pathway pages

http://www.wikipathways.org/instance/WP4846

Pathway pages

http://www.wikipathways.org/instance/WP4846

Pathway pages

http://www.wikipathways.org/instance/WP4846

WikiPathways community portals

• Adverse outcome pathways
• Inherited metabolic disorders
• CIRM
• COVID-19
• CPTAC
• Diseases
• ExRNA
• Lipids
• Micronutrients
• Nanomaterials
• NetPaths
• Plants
• Rare Disease
• Renal Genomics
• Reactome
• Skeletal Dysplasia
• Wormbase

​

https://www.wikipathways.org/index.php/Portal:COVID-19

Pathway Visualization

https://www.wikipathways.org/instance/:WP4912

https://www.wikipathways.org/instance/:WP4965

Pathway Visualization

​

​

​

​

​

​

​

​

​

​

​

​

​

https://www.wikipathways.org/index.php/Help:Guidelines_EditorPalette

PathVisio

PathVisio 3.3.0 www.pathvisio.org

​

• Draw biological pathways
• Annotate pathway molecules and interactions
• Upload pathway to WikiPathways

​

​

Kutmon M et al.PathVisio 3: an extendable pathway analysis toolbox.

PLoS computational biology. 2015 Feb 23;11(2):e1004085. doi:10.1371/journal.pcbi.1004085

PathVisio

Annotated pathway models

Pathways are more than just images - fully annotated pathway models

• Elements (data nodes and interactions) are annotated with biological database identifiers, e.g. Ensembl, UniProt, ChEBI, HMDB, …
• Elements are linked to publication references if available
• Users can add additional comments to elements

​

​

Identifier mapping in PathVisio

Data nodes and interactions can be annotated with biological database identifiers

• Problem: Many different biological online databases → different identifiers for the same biological element
• Manual mapping of identifiers is very time-consuming and error-prone

​

​

​

• Solution: BridgeDb framework → identifier mapping databases for gene products, metabolites and interactions
• Gene products based on Ensembl
• Metabolites based on ChEBI
• Interactions based on Rhea

Biological databases

• Ensembl

A genome browser for vertebrate genomes -> gene annotation https://www.ensembl.org/

Identifier BRCA2 gene

ENSG#### (human), ENSG00000139618

ENSMUS#### (mouse), ENSMUSG00000035401

​

• ChEBI

Chemical Entities of Biological Interest (ChEBI) is a freely available dictionary of molecular entities focused on ‘small’ chemical compounds.

https://www.ebi.ac.uk/chebi/

Identifier for D Glucose-6-phosphate

CHEBI:14314:

​

• Rhea

An expert-curated knowledgebase of chemical and transport reaction

https://www.rhea-db.org/

Chorsimate = 4-hydroxybenzoate + pyruvate

Identifier bidirectional reaction:

RHEA:16508

​

​

​

Identifier mapping in PathVisio

Identifier mapping in PathVisio

• Databases can be downloaded from
• https://bridgedb.github.io/data/gene_database/

​

• Important: Load mapping database in PathVisio
• Menu: Data → Import Gene/Metabolite/Interaction Database

​

• Double click on element to add annotation
• Check “Backpage” side-tab to check annotation and mapped identifiers (cross references)

​

Identifier mapping in PathVisio

• Click at a data node
• Annotated with Xref (Identifier + Database)
• Find linkouts and cross references in “Backpage” side-tab

​

Exporting pathway diagrams

Pathway diagrams can be exported as high quality images for publication

​

PathVisio

WikiPathways

Research example – knowledge review

Siddiqa A. et al. (2017) “Visualizing the regulatory role of Angiopoietin-like protein 8 (ANGPTL8) in glucose and

lipid metabolic pathways” Genomics. 109(5-6):408-418. doi: 10.1016/j.ygeno.2017.06.006

​

Research example - data visualization

Kutmon, M, et al. "Integrative network-based analysis of mRNA and microRNA expression in 1,25-dihydroxyvitamin D3-treated cancer cells." Genes & Nutrition 10.5 (2015): 1-12

​

Downregulation of cell cycle pathways in prostate cancer cells after vitamin D�treatment

​

Research example - multi-omics data visualization

Rubio-Aliaga, I, et al. "Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention." Physiological genomics 43.8 (2011): 408-416.

​

Take home messages

• PathVisio is an open-source tool for creation and curation of pathways.
• When designing biological pathways, use PathVisio.
• Molecules and interactions in pathways are annotated with biological databases
• Newly created SARS-CoV-2 related pathways will become part of the WikiPathways COVID-19 community portal.

​

​

Thank you for your attention!