The Pathway Tools software provides a suite of capabilities for storing and analyzing collections of genomic and metabolic information .
Peter Karp
SRI Author
Metabolic Modeling with MetaFlux
The MetaFlux software supports creating, executing, and solving quantitative metabolic flux models using flux balance analysis (FBA).
The EcoCyc Database in 2021
The EcoCyc model-organism database collects and summarizes experimental data for Escherichia coli K-12. EcoCyc is regularly updated by the manual curation of individual database entries, such as genes, proteins, and metabolic pathways, and by the programmatic addition of results from select high-throughput analyses. Updates to the Pathway Tools software that supports EcoCyc and to the web interface that enables user access have continuously improved its usability and expanded its functionality. This article highlights recent improvements to the curated data in the areas of metabolism, transport, DNA repair, and regulation of gene expression. New and revised data analysis and visualization tools include an interactive metabolic network explorer, a circular genome viewer, and various improvements to the speed and usability of existing tools.
The BioCyc Metabolic Network Explorer
Background: The Metabolic Network Explorer is a new addition to the BioCyc.org website and the Pathway Tools software suite that supports the interactive exploration of metabolic networks. Any metabolic network visualization tool must by necessity show only a subset of all possible metabolite connections, or the results will be visually overwhelming. Existing tools, even those that purport to show an organism’s full meta- bolic network, limit the set of displayed connections based on predefined pathways or other preselected criteria. We sought instead to provide a tool that would give the user dynamic control over which connections to follow.
Results: The Metabolic Network Explorer is an easy-to-use, web-based software tool that allows the user to specify a starting metabolite of interest and interactively explore its immediate metabolic neighborhood in either or both directions to any desired depth, letting the user select from the full set of connected reactions. Although, as for other tools, only a small portion of the metabolic network is visible at a time, that portion is selected by the user, based on the full reaction complement, and it is easy to switch among alternate paths of interest. The display is intuitive, customizable, and provides copious links to more detailed information pages.
Conclusions: The Metabolic Network Explorer fills a gap in the set of metabolic network visualization tools and complements other modes of exploration. Its primary strengths are its ease of use, diagrams that are intuitive to biologists, and its integration with the broader corpus of data provided by a BioCyc Pathway/Genome Database.
Pathway Size Matters: The Influence of Pathway Granularity on Over-Representation (Enrichment) Statistics
Background: Enrichment or over-representation analysis is a common method used in bioinformatics studies of transcriptomics, metabolomics, and microbiome datasets. The key idea behind enrichment analysis is: given a set of significantly expressed genes (or metabolites), use that set to infer a smaller set of perturbed biological pathways or processes, in which those genes (or metabolites) play a role. Enrichment computations rely on collections of defined biological pathways and/or processes, which are usually drawn from pathway databases. Although practitioners of enrichment analysis take great care to employ statistical corrections (e.g., for multiple testing), they appear unaware that enrichment results are quite sensitive to the pathway definitions that the calculation uses.
Results: We show that alternative pathway definitions can alter enrichment p -values by up to nine orders of magnitude, whereas statistical corrections typically alter enrichment p -values by only two orders of magnitude. We present multiple examples where the smaller pathway definitions used in the EcoCyc database produces stronger enrichment p -values than the much larger pathway definitions used in the KEGG database; we demonstrate that to attain a given enrichment p -value, KEGG-based enrichment analyses require 1.3–2.0 times as many significantly expressed genes as does EcoCyc-based enrichment analyses. The large pathways in KEGG are problematic for another reason: they blur together multiple (as many as 21) biological processes. When such a KEGG pathway receives a high enrichment p -value, which of its component processes is perturbed is unclear, and thus the biological conclusions drawn from enrichment of large pathways are also in question.
Conclusions: The choice of pathway database used in enrichment analyses can have a much stronger effect on the enrichment results than the statistical corrections used in these analyses.
Leveraging Curation Among Escherichia coli Pathway/Genome Databases Using Ortholog-Based Annotation Propagation
Abstract Updating genome databases to reflect newly published molecular findings for an organism was hard enough when only a single strain of a given organism had been sequenced. With multiple sequenced strains now available for many organisms, the challenge has grown significantly because of the still-limited resources available for the manual curation that corrects errors […]
Pathway Tools Visualization of Organism-Scale Metabolic Networks
Abstract Metabolomics, synthetic biology, and microbiome research demand information about organism-scale metabolic networks. The convergence of genome sequencing and computational inference of metabolic networks has enabled great progress toward satisfying that demand by generating metabolic reconstructions from the genomes of thousands of sequenced organisms. Visualization of whole metabolic networks is critical for aiding researchers in […]
A Comparison of the Pathway Tools Software with the Reactome Software
This document compares SRI’s Pathway Tools (PTools) software with the Reactome software. Both software systems serve the pathway bioinformatics area, including representation and analysis of metabolic pathways and signaling pathways. The comparison covers pathway bioinformatics capabilities, but does not cover other major facets of Pathway Tools that are completely absent from the Reactome software: Pathway Tools genome-informatics capabilities, regulatory informatics capabilities, and table-based analysis tools (SmartTables).
Our overall findings are as follows. (1) PTools is significantly ahead of Reactome in its basic information pages. For example, PTools pathway layout algorithms have been developed to an advanced state over several decades, whereas Reactome pathway layouts are illegible, omit important information, and are created manually and therefore cannot scale to thousands of genomes. (2) PTools is far ahead of Reactome in omics analysis. PTools includes all of the omics-analysis methods that Reactome provides, and includes multiple methods that Reactome lacks. (3) PTools contains a metabolic route search tool (searching for paths through the metabolic network), which Reactome lacks. (4) PTools is significantly ahead of Reactome in inference of metabolic pathways from genome information to create new metabolic databases. (5) PTools has an extensive complement of metabolic-modeling tools whereas Reactome has none. (6) PTools is more scalable than Reactome, handling 18,000 genomes versus 90 genomes for Reactome. (7) PTools has a larger user base than Reactome. PTools powers 17 websites versus two for Reactome. PTools has been licensed by 10,800 users (Reactome licensed user count is unknown).
The MetaCyc Database of Metabolic Pathways and Enzymes – A 2019 Update
MetaCyc (MetaCyc.org) is a comprehensive reference database of metabolic pathways and enzymes from all domains of life. It contains 2749 pathways derived from more than 60 000 publications, making it the largest curated collection of metabolic pathways. The data in MetaCyc are evidence-based and richly curated, resulting in an encyclopedic reference tool for metabolism. MetaCyc is also used as a knowledge base for generating thousands of organism-specific Pathway/Genome Databases (PGDBs), which are available in BioCyc.org and other genomic portals. This article provides an update on the developments in MetaCyc during September 2017 to August 2019, up to version 23.1. Some of the topics that received intensive curation during this period include cobamides biosynthesis, sterol metabolism, fatty acid biosynthesis, lipid metabolism, carotenoid metabolism, protein glycosylation, antibiotics and cytotoxins biosynthesis, siderophore biosynthesis, bioluminescence, vitamin K metabolism, brominated compound metabolism, plant secondary metabolism and human metabolism. Other additions include modifications to the GlycanBuilder software that enable displaying glycans using symbolic representation, improved graphics and fonts for web displays, improvements in the PathoLogic component of Pathway Tools, and the optional addition of regulatory information to pathway diagrams.
