SRI InternationalBioinformaticsUpdate your computers!

To install a patch:

Tools => Instant Patch => Download and Activate All Patches

Editing Pathway/Genome Databases

Part I: Compounds, Reactions and Pathways

Ron Caspi

SRI InternationalBioinformaticsWhy Curation is Important!

Database curation greatly enhances the usefulness of the data

“in silico” information less solid than experimental evidence

SRI InternationalBioinformaticsPathway 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

SRI InternationalBioinformaticsList 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

SRI InternationalBioinformaticsInvoking the Editors

Or: Right-Click on an

Object Handle

Use the “New” command

SRI InternationalBioinformaticsSaving Changes

The user must save changes explicitly with Save DB

To discard changes made since last save File => Revert Current DB

SRI InternationalBioinformaticsThe 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

SRI InternationalBioinformaticsEditing 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

SRI InternationalBioinformaticsCompound Editor

Create or edit a compound

Invoke by:

New: Compound => New

Existing: Right-Click compound name, select Compound Editor

Common name and synonyms

links to other DBs

SRI InternationalBioinformaticsMore Compound Editing

Compound Structure EditorMol filesExporting to other DBsMerging

SRI InternationalBioinformaticsReaction Editor

Create or edit a reaction Invoke by:

New: Reaction => New

Existing: Right-Click reaction name, select Reaction Editor

Entering Reaction Equation Compound Resolver

SRI InternationalBioinformaticsPathway 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 => NewExisting: Right-Click pathway name,

select Pathway Editor command

SRI InternationalBioinformaticsConnections 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) ===> 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

SRI InternationalBioinformatics

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

SRI InternationalBioinformaticsPathway 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

SRI InternationalBioinformaticsCreating Links with External

Databases

Creating links from a pathway/genome db to an external database

To define a new external database: Tools => Ontology Browser View => Browse from new root / type Databases Highlight Databases Frame => Create => 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 dbsee http://biocyc.org/linking.shtml

SRI InternationalBioinformaticsMake sure that…

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

SRI InternationalBioinformaticsCreating New Reactions

Create the following five reactions:

1. ascorbate + H2O = 3-keto-L-gulonate

2. 3-keto-L-gulonate + ATP = 3-keto-L-gulonate-6-phosphate + ADP

3. 3-keto-L-gulonate-6-phosphate = L-xylulose-5-phosphate + CO2

4. L-xylulose-5-phosphate = L-ribulose-5-phosphate*

5. L-ribulose-5-phosphate = xylulose-5-phosphate

SRI InternationalBioinformaticsCreate a New Compound

SRI InternationalBioinformaticsDefine a New Pathway

Define the pathway L-ascorbate degradation to xylulose-5-phosphate by connecting the reactions together

Assign class:

(Pathways -> Degradation/Utilization/Assimilation -> Carboxylates, Other)

Add a link to non-oxidative branch of the pentose phosphate pathway(Generation of precursor metabolites and energy => Pentose phosphate pathways =>)

Add a reverse link from non-oxidative branch of the pentose phosphate pathway to the new pathway

SRI InternationalBioinformaticsPathway Curation

• Class

• Common Name

• Synonyms

• Evidence code

• Citations

• Comments

• Links

• Hypothetical reactions

SRI InternationalBioinformaticsEvidence Codes for Pathways

http://brg.ai.sri.com/ptools/evidence-ontology.html

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

SRI InternationalBioinformaticsSuper Pathways

Create more complex metabolic networks using superpathways

Example: superpathway of alanine biosynthesis

composed of alanine biosynthesis I

alanine biosynthesis II

alanine biosynthesis III

SRI InternationalBioinformaticsPathway Export

Export

Edit => Add Pathway to File Export List File => Export => Selected Pathways to File

SRI InternationalBioinformaticsConstraint 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

SRI InternationalBioinformaticsConsistency Checking

(correctify-kb) Removes newlines from names Converts “<“ 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

SRI InternationalBioinformaticsRun

(correctify-kb)

Open the database Hb. pylori (HypCyc)

Run (correctify-kb)

Analyze output