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In blue = Isolated reactions in the Reactome pathway . Reproduces the situation in ECOCYC

Problem with generic compounds+Unconnected pathway in ECOCYC ( i.e. : ECOCYC: PWY-2161 = Folate polyglutamylation ) Problem in reaction compartment association in ECOCYC ( i.e. : ECOCYC: 2PHENDEG-PWY: Phenylethylamine degradation I)

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In blue = Isolated reactions in the Reactome pathway . Reproduces the situation in ECOCYC

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  1. Problemwithgenericcompounds+Unconnectedpathway in ECOCYC (i.e.: ECOCYC: PWY-2161 = Folatepolyglutamylation) • Problem in reactioncompartmentassociation in ECOCYC (i.e.: ECOCYC: 2PHENDEG-PWY: Phenylethylaminedegradation I) • Problemswithpathwaydiagramrepresentation: Multipleconnectivity of commonintermediates (H+, H2O, ATP, etc), whichdifficultspathwaydiagramvisualization (i.e.: ANARESP1-PWY: respiration (anaerobic)) • Problemswithdifferentcytosol/cytoplasmcompartmentassociationforthesamecompound in differentreactions of thepathway = Twodifferententitiesforthesamecompound, generatingconnectivityproblems in thecorrespondingreactions (i.e.: ANARESP1-PWY: respiration (anaerobic)) • Problemwithdifferentreferenceentitiesusedforthesamecompound in differentreactions = Connectivityproblem (i.e.: ECOCYC: PEPTIDOGLYCANSYN-PWY) • Problem of connectivitybetweensubpathways in superpathways (i.e.: ECOCYC: DENOVOPURINE2-PWY) • Problemwithdifferent CHEBI referenceentitiesforthesamecompound in differentreactions (i.e.: ECOCYC: OXIDATIVEPENT-PWY) • Additionalproblemwithlack of BIGG xreferences in ECOCYC reversible reactions

  2. ECOCYC: PWY-2161 = Folatepolyglutamylation: Problemwithgenericcompounds+Unconnectedpathway in ECOCYC In blue = Isolatedreactions in theReactomepathway. Reproduces thesituation in ECOCYC

  3. Blue reactions in previousslide FOLYLPOLYGLUTAMATESYNTH-RXN RXN0-2921 FORMYLTHFGLUSYNTH-RXN Genericreactionsdealingwithpolymers (addition of L-glutamatesubunitstotetrahydrofolateprecursors). Problems in ECOCYC reactions at compound ID forgenericcompounds

  4. i.e.: FORMYLTHFGLUSYNTH-RXN: Samecompound ID forbothgenericcompoundsincluded in thereactiondespiterepresented as differentcompounds (n/n+1) COMPOUND ID: FORMYL-THF-GLU-N ECOCYC:FORMYL-THF-GLU-N = Classcompound COMPOUND ID: FORMYL-THF-GLU-N In micromerepository, thecorrespondingreactionshavethesamecompound as substrate and product in thepathwaydiagram

  5. Samecompoundentity as reactant and product

  6. Simple entity (CHEBI compound) as referenceEntity of thedefinedSet DefinedSetentity in Microme Howtosolvethisproblem in pathwaydiagrams??

  7. ECOCYC: 2PHENDEG-PWY: Phenylethylaminedegradation I:Problem in reactioncompartmentassociation in ECOCYC Connectedreactions in ECOCYC pathwaydiagramdespitetheassociatedcompartmentisdifferent (periplasmicspace in firstreaction and cytoplasm in secondreaction). Thisyieldsunconnectedpathwaydiagrams in Micromerepository

  8. Unconnectedmetabolites

  9. Samereferenceentityforphenylacetaldehyde in bothreactions (CHEBI:16424) butdifferentcompartment = 2 differentdatabaseentities Whatshouldbe done in this case???

  10. ECOCYC: ANARESP1-PWY: respiration (anaerobic):Problemswith: Pathwaydiagramrepresentation: Multipleconnectivity of commonintermediates (H+, H2O, ATP, etc), whichdifficultspathwaydiagramvisualization Differentcytosol/cytoplasmcompartmentassociationforthesamecompound in differentreactions of thepathway= Twodifferententitiesforthesamecompound, generatingconnectivityproblems in thecorrespondingreactions

  11. ECOCYC: ANARESP1-PWY: respiration (anaerobic) Micromediagram: Multipleconnectionsbetweencommonmetabolitesdifficultspathwayrepresentation ECOCYC diagram (linear) H20 metabolite (6 reactionsassociated)

  12. This can besolvedbyduplicatingthismetaboliteentities in thepathway editor of Reactomecuratortool(1 metaboliteentityforeachreaction in thediagram) Duplicatedentities conserve samedatabaseidentifier (same DB_ID) InitialMicromediagram EditedMicromediagram 2nd problem: Connectivity

  13. Samereferenceentity (CHEBI:29806) butdifferentcompartment (GO term) = 2 differententities = Connectivityproblem Possiblesolution: Unification of cytosol/cytoplasmwith single GO compartment

  14. ECOCYC: PEPTIDOGLYCANSYN-PWY: Problemwithdifferentreferenceentitiesusedforthesamecompound in differentreactions = Connectivityproblem Connectivityproblem Unconnectedreactions in ECOCYC pathway (same case as firstexample of thepresentation)

  15. DB_ID: 23436; RefEntity=CHEBI:61386 DB_ID: 45118; RefEntity=PubChemcompound

  16. Bothreactionscross-referenced in RHEA; RHEA reactionsconnectedthrough CHEBI:61386 RHEA:28375 RHEA:28388 Wrong RHEA xref (oppositedirection). Correctxreferenceis RHEA:28387 (In ObiWarehouse iAF1260:PAPPT3 and in RHEA, with RHEA:28387 xreferencedto ECOCYC reactions)

  17. Whythishappens (differentreferenceentityforthesamecompound in differentreactions) Whatshouldwe do in this case??

  18. ECOCYC: DENOVOPURINE2-PWY: Superpathway of purinenucleotidesbiosynthesiswith 4 nestedpathways. Problem of connectivitybetweensubpathways 5-phospho-D-ribose-diphosphate (DB_ID:39069; PubChemreferenceEntity) RHEA:14907; iAF1260:GLUPRT Connectedpathwayswith RHEA reactions (through CHEBI:58592 in bothreactions) PWY-6122 RHEA:23033; iAF1260:PRAIS 5-aminoimidazole ribonucleotide (DB_ID:45283; PubChemreferenceEntity) Unconnectedpathways in Microme 5-aminoimidazole ribonucleotide (DB_ID:36474; CHEBI:58592 referenceEntity) RHEA:19318; iAF1260:AIRC2 PWY-6123 RHEA:18447; Iaf1260:IMPC Unconnectedpathways in Microme IMP (DB_ID:1557; CHEBI:58053 referenceEntity) IMP (DB_ID:13357; PubChemreferenceEntity) IMP (DB_ID:13357; PubChemreferenceEntity) RHEA:11709; iAF1260:IMPD RHEA:15754; iAF1260:ADDS PWY-6125 PWY-6126 Connectedpathways (PWY-6123/PWY-6125) with RHEA reactions (RHEA:18447-11709) through CHEBI:58053 in bothreactions) Connectedpathways (PWY-6123/PWY-6126) with RHEA reactions (RHEA:18447-11709) through CHEBI:58053 in bothreactions)

  19. ECOCYC: OXIDATIVEPENT-PWY: Problemwithdifferent CHEBI referenceentitiesforthesamecompound in differentreactions Micromepathway ECOCYC pathway Unconnectedreactions

  20. RHEA:12557 CHEBI:48928 as referenceentity; DB_ID:2367 RHEA:10117 CHEBI:58759 as referenceentity; DB_ID:5050 Both RHEA reactions uses CHEBI:58759 as 6-phospho-D-gluconate (majormirospecie at ph 7.3). CHEBI:48928 isthe CHEBI xreference of 6-phospho-D-gluconate in ECOCYC, whichiswrong (neutral compound)

  21. Whythishappens (Samecompound in onereactiontake as refEntity CHEBI ID from RHEA and in other CHEBI ID from ECOCYC, whichiswrong in several cases)??? Whatshouldwe do in this case?? Normallychangethewrong CHEBI xreference, buthow, manuallyoritcouldbepossibleanautomaticsolution??

  22. Additionalproblem: BIGG crossreferences are notreportedfor: • BIGG reversible reactions VS ECOCYC reversible reactions: Same RHEA xreference in iAF1260-ECOCYC in RHEA. i.e.:iAF1260:ASAD Bidireactional ECOCYC rxnsdecomposed in twodirectedreactions in Microme; xrefto RHEA and ECOCYC; notto BIGG:ASAD

  23. Additionalproblem:Pathwayswithconnectivityproblems in thedatabaseversionpresented in thejamboree (microme_prerelease_eco_meta_cyc_14_5_iaf1260) differs in thecurrentdatabase (microme_prerelease_ecocyc_15_0_iaf1260). i.e.: GDP-mannosebiosynthesis, wherethetwoinitialreactionsappearedunconnected in theinitialdatabaseduetodifferent CHEBI ID forfructose 6P in RHEA reactionsbut in thecurrentversionthereis no connectivityproblem: RHEA comp RefEntityMicrome Chebixref ECOCYC CHEBI:57584 CHEBI:17719 CHEBI:17719 Wrongxref ECOCYC (neutral comp; notmajormicrospph 7.3) Connectivityproblem iAF1260:PGI; RHEA:11819 CHEBI:57579 (RHEA:11819); racemic+linear CHEBI:57634 (RHEA:12359); beta+cyclic CHEBI:57634 CHEBI:57634 iAF1260:MAN6PI RHEA:12359 CHEBI:58735 CHEBI:58735 CHEBI:60332 iAF1260:PMAMNRHEA:12359 CHEBI:58409 CHEBI:58409 CHEBI:58049 iAF1260:MAN1PT2 RHEA:12906 CHEBI:57527 No Chebixref CHEBI:57527

  24. Additionalproblem:Pathwayswithconnectivityproblems in thedatabaseversionpresented in thejamboree (microme_prerelease_eco_meta_cyc_14_5_iaf1260) differs in thecurrentdatabase (microme_prerelease_ecocyc_15_0_iaf1260). • i.e.: GDP-mannosebiosynthesis, wherethetwoinitialreactionsappearedunconnected in theinitialdatabaseduetodifferent CHEBI ID forfructose 6P in RHEA reactionsbut in thecurrentversionthereis no connectivityproblem: • WhichisthecriteriausedtoassignreferenceEntityID´stomicromecompounds (some times PubChemcompounds, CHEBI compoundsfrom ECOCYC, CHEBI compoundsfrom RHEA, KEGG compounds in some cases) • Whatshouldwe do in these cases of connectivityproblems in RHEA reactionsliketheone of GDP-mannosebiosynthesis: • Edit RHEA reactiontosolvetheproblem of connectivity, i.e.changing CHEBI:57579 by CHEBI:57634 in RHEA:11819. Problem: Itsupposetoedit IUBMB reactions (RHEA reactionsassociatedto IUBMB EC numbers) • Create novel reactionequivalentto RHEA:11819 butwith CHEBI:57634 (beta isoformfructose 6P, cyclic) instead CHEBI:57579 (racemicfructose 6P, linear). Problem: ECOCYC xreferencesfrom RHEA:11819 (IUBMBrxnassociatedto EC:5.1.3.9) shouldbealso removed from RHEA:11819 and changedto novel RHEA reaction

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