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Overview of The Pathway Tools Software

Overview of The Pathway Tools Software

What is a Pathway/Genome Database and What is Pathway Tools?

A PGDB is a bioinformatics DB that integrates genomic data with detailed functional annotations of the genome, such as descriptions of metabolic and signalling pathways, and of the regulatory network. The EcoCyc and HumanCyc DBs are PGDBs (see EcoCyc.org and HumanCyc.org).

A PGDB serves as a central resource for capturing, integrating, and disseminating new scientific findings about the organism. It is a vehicle for tracking the evolving annotation of the genome, metabolic network, and genetic network of the organism, and for communicating that evolving knowledge through the Web. All genome annotations produced to date are incomplete, and contain significant numbers of errors. For organisms with active experimental communities, ongoing efforts are required to update those annotations to reflect new computational inferences, and new gene identifications and pathways reported in the experimental literature.

The existence of an up-to-date genome annotation for an organism is a prerequisite for performing functional genomics studies of an organism because (a) one aim of functional genomics is to determine the functions of genes whose function is not already known, therefore, functional genomics efforts require access to the most accurate genome annotation possible; (b) the extensive new knowledge about gene function and gene regulation that will be gleaned from functional genomics studies must be integrated and disseminated to the scientific community, such as through a PGDB.

Pathway Tools supports creation, editing, querying, visualization, and analysis of PGDBs. The software also allows users to publish a PGDB on the Web for access by the scientific community. More than 250 groups have applied Pathway Tools to analyze more than 2,500 genomes from all domains of life [list of external PGDBs].

PathoLogic: Creation of PGDBs

The PathoLogic component of Pathway Tools accepts an annotated genome in Genbank format as its input. Its output is a new PGDB. PathoLogic contains several computational inference algorithms:

  • It predicts the metabolic pathways of an organism from the genome.
  • It predicts what genes code for missing enzymes within the predicted metabolic pathways, typically identifying on the order of 100 new gene functions in a microbial genome.
  • It predicts the operons of a bacterium.

Pathway/Genome Navigator: Querying and Visualization of PGDBs

The Bioinformatics datatypes supported by the Pathway/Genome Navigator component of Pathway Tools are listed below. For each of the datatypes , Pathway Tools provides querying capabilities, visualization tools (such as for drawing pathways and genome maps), and interactive editing tools to allow users to update data (such as modifying a metabolic pathway or defining a new DNA binding site for a transcription factor). The visualization and querying capabilities allow PGDBs to be published on the Web, or to be accessed as a desktop application on the PC, Mac, and Linux platforms. The desktop and Web capabilities of the software overlap substantially, with some differences [details].
  • Metabolic and signalling pathways Full-sized image

  • Metabolic enzymes, reactions, and small-molecule metabolites

  • Transcription factors, operons, promoters, and transcription-factor binding sites

  • Transport proteins

  • Genome maps for closed and unclosed genomes Full-sized image

  • Individual growth media; growth observation studies under multiple growth conditions; gene essentiality information

  • Nucleic-acid sequences, amino-acid sequences, protein features, Gene Ontology annotations

Pathway/Genome Navigator: Analysis of Large-Scale Datasets

Pathway Tools can aid analyses of gene expression, protein expression, and metabolomics experiments through the Pathway Tools Omics Viewers, which allow omics datasets to be graphically painted onto three system-level diagrams: a diagram of the full metabolic network of the organism, a diagram of the full regulatory network of the organism, and a diagram of the full genome of the organism. The software can produce animated displays of a series of omics measurements. It can also depict data from multiple omics datatypes simultaneously, such as mixing gene-expression and metabolomics data on one diagram.

Click on images to see full-size.

Other Pathway Tools capabilities for analysis of large-scale datasets include:

  • Enrichment analysis of gene sets and metabolite sets to pathways and Gene Ontology terms
  • Graphing of omics data values for selected genes or metabolites, or for entire pathways
  • Visualization of omics data on individual pathways

Other Pathway/Genome Navigator Operations

  • Interactively tracing metabolites through the metabolic network Full-sized image

  • Finding dead-end metabolites in metabolic networks

  • Identifying choke points (potential drug targets) in metabolic networks

  • Comparative operations, including comparing the full metabolic networks of two or more organisms

  • Automatic generation of posters depicting the genome and the complete metabolic network

  • BLAST searches against the genome

MetaFlux: Flux-Balance Analysis

The MetaFlux component of Pathway Tools supports development and execution of steady-state metabolic flux models using flux-balance analysis. Its gap filler module accelerates model development by suggesting improvements to a model such as addition of missing reactions. Reaction fluxes computed by MetaFlux can be painted onto the metabolic map diagram to speed understanding of modeling results. MetaFlux can simulate gene knock outs for selected genes, or for all genes in the organism.

Pathway/Genome Editors: Curation Tools

Pathway Tools includes a suite of interactive editing tools for adding new information to a PGDB, and for updating existing information. Tools such as a pathway editor, gene editor, and enzyme editor speed database development.

Other Aspects of Pathway Tools

Pathway Tools has a large user community, who have already successfully used the software to create database for many organisms.

Extensive user documentation is available, as is an online information site at http://bioinformatics.ai.sri.com/ptools.

The software is freely available to academic and government users. Users own and therefore control the PGDBs that they create.

How to Learn More

Funding Sources

The development of Pathway Tools is funded by grants GM077678, GM080746, and GM75742 from the National Institutes of Health.