SRI International
Bioinformatics
 2,500+ databases from multiple institutions
 Cover all domains of life with microbial emphasis
 All DBs derived from MetaCyc via computational pathway prediction
 Common schema
 Common controlled vocabularies
 Common methodologies

SRI International
Bioinformatics
Database
MetaCyc
EcoCyc
HumanCyc
AraCyc
YeastCyc
MouseCyc
Organism
Multiorganism
E. coli
H. sapiens
A. thaliana
S. cerevisiae
M. musculus
Organization
SRI
SRI
SRI
Curated From
34,000
23,000
Carnegie Instit.
2,282
Stanford Univ 565
Jackson Labs

 Pathway/Genome Database (PGDB) – combines information about
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Pathways, reactions, substrates
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Enzymes, transporters
Genes, replicons
Transcription factors/sites, promoters, operons
 Tier 1: Literature-Derived PGDBs
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MetaCyc, HumanCyc, YeastCyc
EcoCyc -- Escherichia coli K-12
AraCyc – Arabidopsis thaliana
 Tier 2: Computationally-derived DBs,
Some Curation -- 34 PGDBs
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Bacillus subtilis, Mycobacterium tuberculosis
 Tier 3: Computationally-derived DBs, No
Curation -- The remainder
SRI International
Bioinformatics

SRI International
Bioinformatics
Pathways
Reactions
Proteins
RNAs
Genes
Chromosomes
Plasmids
Compounds
Sequence Features
Operons
Promoters
DNA Binding Sites
Regulatory Interactions
CELL

SRI International
Bioinformatics
 3,000+ licensees: 250+ groups applying software to 1,700 organisms
 Saccharomyces cerevisiae , SGD project, Stanford University
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135 pathways / 565 publications – BioCyc.org
 FungiCyc, Broad Institute
 Candida albicans, CGD project, Stanford University
 dictyBase, Northwestern University
 Mouse , MGD, Jackson Laboratory -- BioCyc.org
 Drosophila , FlyBase, Harvard University -- BioCyc.org
 Under development:
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C. elegans, WormBase
 Arabidopsis thaliana, TAIR, Carnegie Institution of Washington
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288 pathways / 2282 publications – BioCyc.org
 ChlamyCyc, GoFORSYS
 PlantCyc, Carnegie Institution of Washington
 Six Solanaceae species, Cornell University
 GrameneDB, Cold Spring Harbor Laboratory
 Medicago truncatula, Samuel Roberts Noble Foundation

SRI International
Bioinformatics
 G. Serres, MBL, Shewanella oneidensis
 M. Bibb, John Innes Centre, Streptomyces coelicolor
 TBDB Project, Mycobacterium tuberculosis
 F. Brinkman, Simon Fraser Univ, Pseudomonas aeruginosa
 Genoscope, Acinetobacter
 R.J.S. Baerends, University of Groningen, Lactococcus
lactis IL1403, Lactococcus lactis MG1363, Streptococcus
pneumoniae TIGR4, Bacillus subtilis 168, Bacillus cereus
ATCC14579
 Matthew Berriman, Sanger Centre, Trypanosoma brucei,
Leishmania major
 Sergio Encarnacion, UNAM, Sinorhizobium meliloti
 Mark van der Giezen, University of London, Entamoeba histolytica, Giardia intestinalis

SRI International
Bioinformatics
 Large scale users:
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C. Medigue, Genoscope, 500+ PGDBs
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J. Zucker, Broad Inst, 94 PGDBs
G. Sutton, J. Craig Venter Institute, 80+ PGDBs
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G. Burger, U Montreal, 60+ PGDBs
E. Uberbacher, ORNL 33 Bioenergy-related organisms
Bart Weimer, UC Davis , Lactococcus lactis, Brevibacterium linens,
Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus johnsonii,
Listeria monocytogenes
 Partial listing of outside PGDBs at http://biocyc.org/otherpgdbs.shtml

SRI International
Bioinformatics
 Comprehensive software environment spanning computational genomics and systems biology
 Create and maintain an organism database integrating genome, pathway, regulatory information
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Computational inference tools
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Interactive editing tools
 Query and visualize that database
 Interpret genome-scale datasets
 Comparative analysis tools
 Generate flux-balance models

Annotated
Genome
+ PathoLogic
SRI International
Bioinformatics
Genome-Scale
Flux Model
Pathway/Genome
Database
Pathway/Genome
Navigator
Pathway/Genome
Editors
Briefings in Bioinformatics 11:40-79 2010

SRI International
Bioinformatics
 Computational creation of new Pathway/Genome
Databases
 Transforms genome into Pathway Tools schema and layers inferred information above the genome
 Predicts operons
 Predicts metabolic network
 Predicts which genes code for missing enzymes in metabolic pathways
 Infers transport reactions from transporter names
Bioinformatics 18:S225 2002

 Interactively update PGDBs with graphical editors
 Support geographically distributed teams of curators with object database system
 Gene editor
 Protein editor
 Reaction editor
 Compound editor
 Pathway editor
 Operon editor
 Publication editor
SRI International
Bioinformatics

SRI International
Bioinformatics
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Ongoing updating and refinement of a PGDB
Correcting false-positive and false-negative predictions
Incorporating information from experimental literature
Authoring of comments and citations
Updating database fields
Gene positions, names, synonyms
Protein functions, activators, inhibitors
Addition of new pathways, modification of existing pathways
Defining TF binding sites, promoters, regulation of transcription initiation and other processes

 Querying and visualization of:
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Pathways
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Reactions
Metabolites
Proteins
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Genes
Chromosomes
 Two modes of operation:
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Web mode
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Desktop mode
Most functionality shared, but each has unique functionality
SRI International
Bioinformatics

SRI International
Bioinformatics
 Ontology classes: 1621
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Datatype classes: Define objects from genomes to pathways
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Classification systems for pathways, chemical compounds, enzymatic reactions (EC system)
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Protein Feature ontology
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Controlled vocabularies:

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Cell Component Ontology
Evidence codes
 Comprehensive set of 248 attributes and relationships

SRI International
Bioinformatics
 A connected sequence of biochemical reactions
 Occurs in one organism
 Conserved through evolution
 Regulated as a unit
 Starts or stops at one of 13 common intermediate metabolites

SRI International
Bioinformatics
 KEGG approach: Static collection of reference pathway diagrams are color-coded to produce organism-specific views
 KEGG vs MetaCyc: Resource on literature-derived pathways
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KEGG maps are not pathways Nuc Acids Res 34:3687 2006
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KEGG maps contain multiple biological pathways
KEGG maps are composites of pathways in many organisms -- do not identify what specific pathways elucidated in what organisms
KEGG has no literature citations, no comments, less enzyme detail
 KEGG vs BioCyc organism-specific PGDBs
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KEGG does not curate or customize pathway networks for each organism
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Highly curated PGDBs now exist for important organisms such as E. coli, yeast, mouse, Arabidopsis
KEGG re-annotates entire genome for each organism

SRI International
Bioinformatics
 Inference tools
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KEGG does not predict presence or absence of pathways
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KEGG lacks pathway hole filler, operon predictor
 Curation tools
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KEGG does not distribute curation tools
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No ability to customize pathways to the organism
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Pathway Tools schema much more comprehensive
 Visualization and analysis
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KEGG does not perform automatic pathway layout
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No comparative pathway analysis

SRI International
Bioinformatics
 Allegro Common Lisp
 PC/Windows, Linux, Macintosh platforms
 Ocelot object database
 600,000+ lines of code
 Lisp-based WWW server at BioCyc.org
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Manages 1,100+ PGDBs

SRI International
Bioinformatics
 Available in iTunes store
 Free
 Look up gene information while on travel, at a conference, in the library

Joint work with Mario Latendresse

SRI International
Bioinformatics
 Steady state, constraint-based quantitative models of metabolism
 Starting information for organism of interest:
Nutrients
A
Metabolic Reaction List
A B C D
X
Biomass
Secretions
D

SRI International
Bioinformatics
 Submit to linear optimization package
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Optimize biomass production, ATP production, etc
 Results
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Steady-state reaction fluxes for the metabolic network
 Remove reactions from the model to predict knock-out phenotypes
 Supply alternative nutrient sets to predict growth phenotypes

SRI International
Bioinformatics
 Store and update metabolic model within Pathway Tools
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The PGDB is the model
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All query and visualization tools applicable to FBA model
FBA model is tightly coupled to genome and regulatory information
 Export to constraint solver for model execution/solving
 Reaction balance checking
 Dead-end metabolite analysis
 Visualize reaction flux using cellular overview
 Multiple gap filling

SRI International
Bioinformatics
 Reaction gap filling
(Kumar et al, BMC Bioinf 2007 8:212)
:
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Reverse directionality of selected reactions
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Add a minimal number of reactions from MetaCyc to the model to enable a solution
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Reaction cost is a function of reaction taxonomic range
 Metabolite gap filling: Postulate additional nutrients and secretions
 Partial solutions: Identify maximal subset of biomass components for which model can yield positive production rates

SRI International
Bioinformatics
 Obtain license
 http://biocyc.org/download.shtml
 Download directory offers several configurations
 Choose platform and database configuration
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Many combinations of databases available
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All databases requires a lot of memory
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Use registry to add PGDBs to configuration you downloaded

SRI International
Bioinformatics

Pathway Tools User’s Guide
 aic-export/pathway-tools/ptools/14.0/doc/manuals/userguide.pdf
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NOTE: Location of the aic-export directory can vary across different computers
 Pathway Tools Web Site
 http://bioinformatics.ai.sri.com/ptools/
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Publications, FAQ, programming examples, etc.
 Slides from this tutorial
 http://bioinformatics.ai.sri.com/ptools/tutorial/sessions/
 BioCyc Webinars
 http://biocyc.org/webinar.shtml
 Desktop vs Web functionality in Pathway Tools
 http://biocyc.org/desktop-vs-web-mode.shtml

SRI International
Bioinformatics
 Publications

“Pathway Tools version 13.0: Integrated Software for
Pathway/Genome Informatics and Systems Biology”,
Briefings in Bioinformatics 11:40-79 2010

“A survey of metabolic databases emphasizing the MetaCyc family”, Archives of Toxicology 2011

 BioCyc Web site: Help Menu

Basic Help
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Search Help
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BioCyc Glossary
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Publications

Website User Guide

PGDB Concepts

Guide to EcoCyc

Guide to MetaCyc
SRI International
Bioinformatics