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Editing Pathway/Genome Databases
Ron Caspi
Part I Compounds, Reactions and Pathways
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Why Curation is Important!

• Database curation greatly enhances the usefulness
  of the data
• in silico information less solid than
  experimental evidence

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Pathway Tools Paradigms

• Separate database from user interface
• Navigator provides one interface to the DB
• Editors provide an alternative interface to the DB

• Reuse information whenever possible!
• A PGDB should not describe the same biological or
  chemical entity more than once
• Compounds are the building blocks of reactions
• Reactions are the building blocks of pathways

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List of Editors

• Compound Editor
• Compound Structure Editor
• Reaction Editor
• Pathway Editor
• Synonym Editor
• Protein Editor
• Gene Editor
• Intron Editor (Eukaryotes only)
• Transcription Unit Editor
• Publication Editor
• Frame Editor
• Relationships Editor
• Ontology Editor

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Invoking the Editors
Use the New command

• Or Right-Click on an
• Object Handle

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Saving Changes

• The user must save changes explicitly with Save
  DB
• To discard changes made since last save
• File gt Revert Current DB

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The File Menu DB commands

• List Unsaved Changes in Current DB
• Revert Current DB
• Refresh All Current DBs
• Checkpoint Current DB
• Revert to Checkpoint in Current DB
• Delete a DB
• Save Current DB
• Attempt to Reconnect to Oracle

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Editing rules Support Policy

• Do not alter DB schema
• e.g. do not add or remove classes or slots
• Do not modify the EcoCyc or MetaCyc datasets

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Compound Editor

• Create or edit a compound
• Invoke by
• New Compound gt New
• Existing Right-Click compound name, select
  Compound Editor
• Common name and synonyms
• links to other DBs

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More Compound Editing

• Compound Structure Editor
• Mol files
• Exporting to other DBs
• Merging

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Reaction Editor

• Create or edit a reaction
• Invoke by
• New Reaction gt New
• Existing Right-Click reaction name, select
  Reaction Editor
• Entering Reaction Equation
• Compound Resolver

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Pathway Editor

• Graphically create and modify pathways
• Two tools
• Connections Editor to add reactions, remove
  reactions, alter connections
• Segment Editor to enter a linear pathway
  segment(s)
• Invoking the pathway editor
• New Pathway gt New
• Existing Right-Click pathway name,
• select Pathway Editor command

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Connections Editor Operations

• Two main display panes
• left unconnected pathway reactions
• right draws connected reactions (looks like the
  regular Pathway Tools window)
• Connecting reactions
• select initial reaction (in either pane) gt red
  and green reactions
• select a green reaction
• Additional Commands
• Exit keep changes, abort changes
• Reaction add reaction, add reaction(s) from
  history, create new reaction frame, clone a
  reaction frame, add connection, delete
  predecessor/successor link, disconnect reaction,
  delete reaction from pathway, choose main
  compounds for reaction, edit reaction frame
• Pathways enter a linear pathway segment, guess
  pathway predecessor list, disconnect all
  reactions, invoke relationships editor, add
  subpathway by name, add subpathway by substring,
  add subpathway by class, delete subpathway

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Connections Editor Limitations

• Ambiguity in some complicated situations on
  ordering
• link may be ignored
• dialog box for disambiguating
• pathway drawn in bizarre arrangement
• Fix
• try removing offending link and add links in
  different order
• Pathway editor does not handle polymerization
  pathways
• In circular pathways, Pathway editor does not
  permit specification which compound should be at
  the top

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Pathway Segment Editor

• To enter linear sequence of reactions (arguably)
  faster than with the Connections Editor
• Reactions are specified by EC numbers or reaction
  substrates
• One segment may contain up to 7 reactions

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Creating Links with External Databases

• Creating links from a pathway/genome db to an
  external database
• To define a new external database
• Tools gt Ontology Browser
• View gt Browse from new root / type Databases
• Highlight Databases
• Frame gt Create gt Instance
• Enter frame name, frame edit
• Enter Common Name, Static-Search-URL
• e.g. http/gene.pharma.com/dbquery?
• Creating links to a pathway/genome db
• see http//biocyc.org/linking.shtml

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Make sure that

• You perform all exercises on the Hb. pylori
  database, not on your own!!!

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Creating New Reactions

• Create the following five reactions
• ascorbate H2O 3-keto-L-gulonate
• 3-keto-L-gulonate ATP 3-keto-L-gulonate-6-phos
  phate ADP
• 3-keto-L-gulonate-6-phosphate
  L-xylulose-5-phosphate CO2
• L-xylulose-5-phosphate L-ribulose-5-phosphate
• L-ribulose-5-phosphate xylulose-5-phosphate

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Create a New Compound
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Define a New Pathway

• Define the pathway L-ascorbate degradation to
  xylulose-5-phosphate by connecting the reactions
  together
• Assign class
• (Pathways -gt Degradation/Utilization/Assimilation
  -gt Carboxylates, Other)
• Add a link to non-oxidative branch of the pentose
  phosphate pathway
• (Generation of precursor metabolites and energy
  gt Pentose phosphate pathways gt)
• Add a reverse link from non-oxidative branch of
  the pentose phosphate pathway to the new pathway

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Pathway Curation

• Class
• Common Name
• Synonyms
• Evidence code
• Citations
• Comments
• Links
• Hypothetical reactions

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Evidence Codes for Pathways

• http//brg.ai.sri.com/ptools/evidence-ontology.htm
  l
• EV-AS Author statement
• NAS non-traceable
• TAS - traceable
• EV-COMP Inferred from computation
• AINF - Artificial inference
• HINF - Human inference
• EV-EXP Inferred from experiment
• IDA - inferred from direct assay
• IEP - inferred from expression pattern
• IGI - inferred from genetic interaction
• IMP- inferred from mutant phenotype
• IPI - inferred from physical interaction
• EV-IC Inferred by curator

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Super Pathways

• Create more complex metabolic networks using
  superpathways
• Example superpathway of alanine biosynthesis
• composed of alanine biosynthesis I
• alanine biosynthesis II
• alanine biosynthesis III

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Pathway Export

• Export
• Edit gt Add Pathway to File Export List
• File gt Export gt Selected Pathways to File

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Constraint Checking

• General rules that constrain the valid
  relationships among instances
• Constraints are checked when new facts are
  asserted to assure that the DB remains logically
  consistent
• Constraints on slots
• Domain violation checks to make sure the slots
  are in instances of the appropriate class
• Range violation
• value type
• value cardinality
• Inverse
• Cardinality
• Lisp-predicate

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Consistency Checking (correctify-kb)

• Removes newlines from names
• Converts lt to in string citations
• Checks isozyme sequence similarity
• Fixes references from polypeptides to genes
• Changes compound names to ids in a variety of
  slots
• Matches physiological regulators to other
  regulators
• Cross-references compounds to reactions
• Checks pathways predecessors/reactions/subs
• Checks reaction balancing
• Checks compound structures
• Calculates sub- and super-pathways
• Finds missing sub-pathways links
• Verifies chromosome components and positions

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Run (correctify-kb)

• Open the database Hb. pylori (HypCyc)
• Run (correctify-kb)
• Analyze output