ecocyc , metacyc, and the pathway tools software

1 SRI International Bioinformatics

EcoCyc, MetaCyc, and the Pathway Tools Software

Peter D. Karp, Ph.D.Bioinformatics Research Group

SRI [email protected]

http://www.ai.sri.com/pkarp/talks/

BioCyc.orgEcoCyc.org, MetaCyc.org

mailto:[email protected]


MetaCyc Family ofPathway/Genome Databases

1,700+ databases from multiple institutionsCover all domains of life with microbial emphasis

All DBs derived from MetaCyc via computational pathway prediction

Common schemaCommon controlled

vocabulariesCommon methodologies

Archives of Toxicology 2011


Curated Databases Within the MetaCyc Family

Database Organism Organization Curated From

MetaCyc Multiorganism SRI 26,000

EcoCyc E. coli SRI 21,000

HumanCyc H. sapiens SRI

AraCyc A. thaliana Carnegie Instit. 2,282

YeastCyc S. cerevisiae Stanford Univ 565

MouseCyc M. musculus Jackson Labs


BioCyc Collection of 1,100 Pathway/Genome Databases

Pathway/Genome Database (PGDB) – combines information about

Pathways, reactions, substrates Enzymes, transporters Genes, replicons Transcription factors/sites, promoters,

operons

Tier 1: Literature-Derived PGDBs MetaCyc EcoCyc -- Escherichia coli K-12

Tier 2: Computationally-derived DBs, Some Curation -- 28 PGDBs

HumanCyc, BsubCyc Mycobacterium tuberculosis

Tier 3: Computationally-derived DBs, No Curation -- The remainder


EcoCyc Project – EcoCyc.org E. coli Encyclopedia

Review-level Model-Organism Database for E. coli Tracks evolving annotation of the E. coli genome and cellular networks The two paradigms of EcoCyc

“Multi-dimensional annotation of the E. coli K-12 genome” Positions of genes; functions of gene products – 76% / 66% exp Gene Ontology terms; MultiFun terms Gene product summaries and literature citations Evidence codes Multimeric complexes Metabolic pathways Regulation of gene expression and of protein activity

Nuc. Acids Res. 35:7577 2007 ASM News 70:25 2004 Science 293:2040

Karp, Gunsalus, Collado-Vides, Paulsen


EcoCyc = E.coli Dataset + Pathway/Genome Navigator

Genes: 4,489

Proteins: 4,479Complexes: 895

RNAs: 285

Reactions: Metabolic: 1446 Transport: 287

Pathways: 260

Compounds: 1,830

URL: EcoCyc.org

Regulation: Operons: 3,409 Trans Factors: 206 Promoters: 1,878 TF Binding Sites: 2,394 Reg Interactions: 5345

EcoCyc v15.0

Citations: 21,000


EcoCyc on the iPhone


PortEco.org

EcoCyc + PortEco = E. coli model-organism database

Query multiple E. coli databases simultaneouslyE. coli gene expression archiveE. coli Wiki~40 E. coli and Shigella databases available at

BioCyc.org


MetaCyc: Metabolic Encyclopedia Describe a representative sample of every experimentally

determined metabolic pathway Describe properties of metabolic enzymes

Literature-based DB with extensive references and commentary

Pathways, reactions, enzymes, substrates

MetaCyc vs BioCyc: Experimentally elucidated pathways

Jointly developed by P. Karp, R. Caspi, C. Fulcher, SRI International L. Mueller, A. Pujar, Boyce Thompson Institute S. Rhee, P. Zhang, Carnegie Institution

Nucleic Acids Research 2010


Applications of MetaCyc

Reference source on metabolic pathways and enzymes

Predict pathways from genomes

Metabolic engineering Find desired metabolic pathways and reactions Find enzymes with desired activities, regulatory properties Determine cofactor requirements


MetaCyc Data -- Version 15.4

Pathways 1,747

Reactions 9,460

Enzymes 7,424

Small Molecules

9,188

Organisms 2,170

Citations 29,900


Pathway Tools Software


Pathway Tools Software

Pathway/GenomeEditors

Pathway/GenomeDatabase

PathoLogicAnnotatedGenome

Pathway/GenomeNavigator

Briefings in Bioinformatics 11:40-79 2010

+

Genome-ScaleFlux Model


Pathway Tools Software: PathoLogic

Computational creation of new Pathway/Genome Databases

Transforms genome into Pathway Tools schema and layers inferred information above the genome

Predicts operonsPredicts metabolic networkPredicts which genes code for missing enzymes

in metabolic pathways Infers transport reactions from transporter names


Pathway Tools Software:Pathway/Genome Editors Interactively update PGDBs

with graphical editors

Support geographically distributed teams of curators with object database system

Gene and protein editor Reaction editor Compound editor Pathway editor Operon editor Publication editor


Pathway Tools Software:Pathway/Genome Navigator

Querying and visualization of: Pathways Reactions Metabolites Genes/Proteins/RNA Regulatory interactions Chromosomes

Two modes of operation: Web mode Desktop mode Most functionality shared, but each

has unique functionality


Cellular Overview Diagram

Combines metabolic map and transportersAutomatically generated for each organismZoomable, queryableWeb-based and desktop

BioCyc.org Tools Cellular Overview Tools Regulatory Overview Fastest with Safari, Chrome, Firefox


Omics Data Graphing on Cellular Overview


Genome Overview


Genome Poster


Regulatory Overview and Omics ViewerShow regulatory relationships among gene

groups


Genome BrowserChIP-Chip Data Shown in Graph Track


Enrichment Analysis

“My experiments yielded a set of genes/metabolites. What do they have in common?”

Given a set of genes: What GO terms are statistically over-represented in that set? What metabolic pathways are over-represented? What transcriptional regulators are over-represented?

Given a set of metabolites: What metabolic pathways are statistically over-represented in

that set?


Automated Generation of Metabolic Flux Models from

PGDBs

Joint work with Mario Latendresse


Goals

Decrease the time required to construct FBA models from 9-12 months to several weeks

Create richer FBA models that are tightly coupled to genome and regulatory information

Make FBA models and results more transparent


Approach: Derive FBA Models from PGDBs

Store and update metabolic model within Pathway Tools Export to constraint solver for model execution/solving

Fast generation of metabolic model from annotated genome Pathway Tools schema

Associate a wealth of information with each metabolic model Unique identifiers and controlled vocabulary for model components

Tools for querying and visualization of metabolic models Tools for model debugging and analysis

Reaction balance checking Dead-end metabolite analysis Visualize reaction flux using cellular overview Multiple gap filling


FBA Model Execution

Runs SCIP solver on .lp file Konrad-Zuse-Zentrum für Informationstechnik Berlin

Interpret SCIP output Determine if SCIP found a solution Map fluxes to PGDB reactions

Display resulting fluxes on the Cellular Overview


Model Debugging via Multiple Gap Filling

Most FBA models are not initially solvable because of incomplete or incorrect information

Use meta-optimization to postulate alterations to a model to render it solvable

Each alteration has an associated cost; minimize cost of alterations

Formulate as MILP and submit to SCIP


Multiple Gap Filling of FBA Models

Reaction gap filling (Kumar et al, BMC Bioinf 2007 8:212): Reverse directionality of selected reactions Add a minimal number of reactions from MetaCyc to the

model to enable a solution 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


Comparative Analysis

Via Cellular Overview

Comparative genome browser

Comparative pathway table

Comparative analysis reports Compare reaction complements Compare pathway complements Compare transporter complements


Advanced Query FormIntuitive construction of complex database

queries of SQL power


Work in Progress

Computation of reaction atom mappings

Program to generate metabolic pathways that synthesize target compound from feedstock compound


How to Learn More

BioCyc.org Help menu

BioCyc Webinars Biocyc.org/webinar.shtml

Publications page Biocyc.org/publications.shtml

Tutorials held at SRI Next week: FBA

ecocyc , metacyc, and the pathway tools software

Documents

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coli genome

escherichia coli

coli wiki

coli databases simultaneouslye

coli gene expression

biocyc ecocyc

ecocyc v15