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1. and CornCyc proteins by relaxing the requirements to allow matches between alternate splice variants these additional matches were not included in the final import The remaining 458 gene products from MaizeCyc with EV EXP annotations do not exist in CornCyc The anno tation data for the 179 matching protein GO term anno tations were inserted into the CornCyc database using the CycTools import feature Use case creating strain specific EcoCyc databases Metabolic engineering projects lead to the generation of genetically unique strains These altered strains are metabolically similar to the parent strain but include a small number of modifications such as gene additions deletions or regulatory changes Many novel strains may be created as a result of iterative engineering interven tions performed on a parent strain One possible solution to storing this information is to generate a new BioCyc database that is synchronized to the altered metabolism of the engineered strain By using the most up to date version of EcoCyc and modifying it with information on engineering interventions a new database is cre ated which more accurately represents the engineered strain This use case focuses on modifications to the E coli organism performed for the increase of fatty acid production E coli strains Of the many strains of E coli that are represented as model organism databases in the BioCyc database collec tion EcoCyc has received the mos
2. contains examples of the Lisp format and the spreadsheet format file formats accepted by the Pathway Tools import utility Additional file 2 CycTools user s manual and installation instructions This file contains instructions for installing CycTools and its dependencies This file also includes descriptions of the options available in CycTools Additional file 3 BioCyc database copy utility This file contains a bash shell script which will copy a BioCyc database file and automatically perform the necessary renaming steps required to differentiate the new copy from the old This is required to allow both copies to be loaded in Pathway Tools memory simultaneously Additional file 4 GO term annotation data from MaizeCyc This file contains the GO term annotations that were extracted from MaizeCyc and were imported into CornCyc The file is formatted as comma delimited values Additional file 5 Predicted regulatory links for EcoCyc This file contains the transcriptional regulatory links predicted by the program GTRNetwork for the E coli network These links include a regulatory mode such that implies downregulation and implies upregulation An empty value in this column implies that the regulatory mode could not be determined Additional file 6 CycTools source code This file contains the source code for the CycTools program Competing interests The authors declare that they have no competing in
3. several of the files and folders within the copy This restriction will also prevent the user from creating and hosting several versions of a database in the same Pathway Tools instance In order to circumvent this restriction a bash script which automatically clones a Page 4 of 10 database and modifies the appropriate files was created This tool is made available in Additional file 3 Overview of import process The CycTools import function provides a graphical pipeline for importing spreadsheet data into frame objects in the Pathway Genome Database PGDB The import utility takes as input a comma separated data file maps the data to frames in the PGDB previews the resulting changes to the PGDB and performs the update of the PGDB as shown in Figure 3 CycTools must be able to connect to a server running Pathway Tools in API mode and JavaCycO Once con nected the user will select one of the available import types import slot data import slot value annotation data import GO annotations delete frames or create tran scriptional regulation frames This determines the format of the import file and how the imported data are applied to database objects Additional options are available which Using Alternate ID Find Synonym Matches Yes Unique Matches frame IDs are allowed in order to prevent ambiguity in the import process Figure 3 Import process diagram Synonym based search automatically occurs if im
4. to matching proteins in CornCyc both maize metabolic pathway databases available at MaizeGDB and by creating Strain specific databases for metabolic engineering Keywords Annotation tool BioCyc Pathway Genome database JavaCycO Background Lower costs in genomic sequencing and improved methods of generating computationally predicted func tional annotations has led to the development of many model organism databases using the BioCyc framework 1 While computationally derived draft model organ ism databases provide useful starting points for storing biological knowledge computationally predicted annota tions are known to suffer from significant false negative rates 2 The accuracy of annotations can be substan tially improved by providing manual annotations mined from literature by expert curators Unfortunately manual curation efforts have not kept up with the proliferation of Correspondence julied iastate edu 1 Bioinformatics and Computational Biology Program lowa State University Ames IA USA 2 Electrical and Computer Engineering Department lowa State University Ames IA USA Full list of author information is available at the end of the article C BioMed Central new databases There are currently over 3500 databases in the BioCyc collection however only 42 of these currently receive moderate or intensive manual review 3 Among the databases that receive manual review main taining manually curated d
5. 11520_P01 1G0 0044464 120089766 EV EXP IDA 04 25 2014 12 00 00 MaizeGDB DQC 105215 MONO GRMZM2G339699_P01 G0 0009536 20089766 EV EXP IDA 04 25 2014 12 00 00 MaizeGDB Sete eee GRMZM2G372297_P01 GO 0009536 20089766 EV EXP IDA 04 25 2014 12 00 00 MaizeGDB GDQC 112427 MONO _ GRMZM2G030494_P01 GO 0042651 20089766 EV EXP IDA 04 25 2014 12 00 00 _ MaizeGDB MONOMER 872 mdh6 GO 0009532 20089766 GDQC 108548 MONO GRMZM2G030628_P01 G0 0009536 20089766 EV EXP IDA I EV EXP IDA 04 25 2014 12 00 00 _ MaizeGDB 04 25 2014 12 00 00 _ MaizeGDB GDOC 108839 MONO _ GRMZM2G116258_P01 GO 0009532 20089766 at at at ay ay at ati EV EXP IDA 04 25 2014 12 00 00 MaizeGDB GDQC 108384 MONO GRMZM2G113325_P01 1G0 0009536 GDQC 110998 MONO GRMZM2G107089_P01 GO 0009532 20089766 20089766 EV EXP IDA EV EXP IDA 04 25 2014 12 00 00 MaizeGDB 04 25 2014 12 00 00 _ MaizeGDB GDOQC 110945 MONO GRMZM2G025031_P01 G0 0009532 20089766 EV EXP IDA 04 25 2014 12 00 00 _ MaizeGDB GDOQC 114372 MONO _ GRMZM2G149751_P05 GO 0044464 20089766 EV EXP IDA 04 25 2014 12 00 00 _ MaizeGDB GDOQC 113616 MONO _ GRMZM2G148769_P01 GO 0009532 GDQC 113976 MONO__ GRMZM2G036921_P01 GO 0009532 20089766 20089766 EV EXP IDA EV EXP IDA 04 25 2014 12 00 00 _ MaizeGDB 04 25 2014 12 00 00 GDOQC 114119 MONO _ GRMZM2G090722_P01 GO 0009532 20089766 EV E
6. DB the maize model organism database for basic translational and applied research nt J Plant Genom 2008 2008 496957 Accessed 2014 06 04 18 Metabolic Pathways at MaizeGDB http alpha maizegdb org metabolic_pathways compare Accessed 2014 05 08 19 Royce LA Liu P Stebbins MJ Hanson BC Jarboe LR The damaging effects of short chain fatty acids on escherichia coli membranes App Microbiol Biotechnol 2013 97 18 831 7 8327 Accessed 2014 04 17 20 FuY Jarboe LR Dickerson JA Reconstructing genome wide regulatory network of e coli using transcriptome data and predicted transcription factor activities BMC Bioinformatics 2011 12 1 233 Accessed 2012 08 09 21 Pathway Tools Download http biocyc org download bundle shtml Accessed 2014 05 08 doi 10 1186 s12918 014 01 15 1 Cite this article as Walsh et al A computational platform to maintain and migrate manual functional annotations for BioCyc databases BMC Systems Biology 2014 8 115 Submit your next manuscript to BioMed Central and take full advantage of e Convenient online submission e Thorough peer review e No space constraints or color figure charges e Immediate publication on acceptance e Inclusion in PubMed CAS Scopus and Google Scholar e Research which is freely available for redistribution Submit your manuscript at www biomedcentral com submit C BioMed Central
7. O provides remote access to the Pathway Tools API to Java CycO clients CycTools depends on the JavaCycO library Mol GO T j Weight Evidence Figure 2 Structure of Frames in a PGDB A Frames describe objects in the database Slots contain information about the frame object and annotations contain meta information about slot information B a protein is represented by a frame in the database Examples of slots which describe the protein include the protein name molecular weight and GO Term assignments Annotations of the GO term information include citations evidence codes and information on the person who curated this GO term assignment Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 to provide access to the Pathway Tools API in order to read and write to a BioCyc database More details on installing these dependencies can be found in Additional file 2 Cloning a database Generally speaking CycTools can modify any BioCyc database hosted by Pathway Tools Two notable excep tions to this are the MetaCyc and EcoCyc databases which are integrated into Pathway Tools and flagged as read only Since these databases can not be removed or modified the only way to edit them is to edit a copy Pathway Tools will also refuse to load two databases with the same name which prevents the user from simply installing a second copy of a database without first renam ing and modifying
8. Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 BMC Systems Biology SOFTWARE Open Access A computational platform to maintain and migrate manual functional annotations for BioCyc databases Jesse R Walsh Taner Z Sen 4 and Julie A Dickerson Abstract Background BioCyc databases are an important resource for information on biological pathways and genomic data Such databases represent the accumulation of biological data some of which has been manually curated from literature An essential feature of these databases is the continuing data integration as new knowledge is discovered As functional annotations are improved scalable methods are needed for curators to manage annotations without detailed knowledge of the specific design of the BioCyc database Results We have developed CycTools a software tool which allows curators to maintain functional annotations in a model organism database This tool builds on existing software to improve and simplify annotation data imports of user provided data into BioCyc databases Additionally CycTools automatically resolves synonyms and alternate identifiers contained within the database into the appropriate internal identifiers Conclusions Automating steps in the manual data entry process can improve curation efforts for major biological databases The functionality of CycTools is demonstrated by transferring GO term annotations from MaizeCyc
9. XP IDA MaizeGDB 04 25 2014 12 00 00 EV EXP IDA MaizeGDB 04 25 2014 12 00 00 GDQC 107750 MONO _ GRMZM2G048085_P01 GO 0009532 20089766 JEV EXP IDA iMaizeGDB IF LEYP_InA nd 25 2N44 12 00 00 _ MaizaCne v Connected Figure 5 GO term annotation import into CornCyc GO term annotations obtained from MaizeCyc are imported into CornCyc User provided gene model identifiers are resolved to database frame IDs before import Copy EcoCyc It is important to retain as much known information from the parent strain as possible therefore the first step is to create a clone of the database representing the parent strain Once the copy has been prepared further modifi cations are necessary to align it to the altered metabolism of the engineered strain In this case the EcoCyc E coli MG1655 database is downloaded available free to aca demic users requires registration 21 and a copy is made to represent our strain specific database Strain specific updates to EcoCyc Three types of data were added to the base EcoCyc database in order to represent changes in the engineered strains metabolism A gene deletion in the strain is rep resented in EcoCyc by a deletion of the associated gene object and the gene object s functionality If the gene prod uct is an enzyme then that protein product is deleted and any reactions it catalyzes have that enzyme associa tion removed from them If the reac
10. a into the newly created regulation frames Conclusions Managing and migrating manual annotations in model organism databases are essential to maintaining high quality biological data In this work we present a software tool which provides a simple pipeline for the mainte nance and transfer of manual annotations within and between BioCyc databases CycTools improves user con trol over the import process by providing users with methods to edit slot values or slot value annotations for any frame in a BioCyc database CycTools also provides methods which allow users to create transcriptional reg ulatory frames or to delete frames through the import process CycTools provides methods that can make small or large scale edits to a BioCyc database Databases using the BioCyc framework typically contain between a few frames and several thousand frames CycTools is capa ble of processing and displaying several thousand entries but is limited to a single object type for each import This means that CycTools is best suited to making many changes to a BioCyc database of a specific type rather than making many small changes to various object types Tracking the changes made to a BioCyc database is made easier with CycTools The BioCyc framework provides methods to credit an author or organization for frame edits CycTools allows users to provide curator informa tion which is stored in the BioCyc framework during the import process CycTools also
11. abases the manually curated GO annotations needed to be transferred from MaizeCyc to CornCyc All GO term assignments and their annotations were exported from MaizeCyc using a query to the Path way Tools API and are provided in Additional file 4 GO term Annotation pairs with an evidence code begin ning with EV EXP i e experimentally verified anno tations were retained while all others were removed This represents the GO term annotations which have been manually verified by curators Source protein objects were identified by their gene model name e g GRMZM2G136161_P01 with the splice variant suffix attached i e the _P01 This identifier was chosen as it is provided as a synonym in both MaizeCyc and Corn Cyc which allows for accurate mapping between objects in both databases Although MaizeCyc and CornCyc were built using the same gene model set the internal frame IDs of the protein objects in Pathway Tools were generated Page 7 of 10 with different syntax rules i e most proteins in MaizeCyc begin with GBWI while the equivalent proteins in CornCyc begin with GDQC In order to ensure the most faithful mapping between MaizeCyc and CornCyc proteins protein identifiers from MaizeCyc were used as query terms in a substring synonym search in CornCyc Exactly matching splice variants provided 179 matches between MaizeCyc and CornCyc as seen in Figure 5 While an additional 5 matches can be made between this group of MaizeCyc
12. ata can present a challenge When an improved reference sequence is released for an organism the BioCyc database representing that organ ism must be recreated in order to incorporate the new sequence data While computationally predicted annota tions within the database should be updated using the new input data it is usually preferred to keep existing man ual annotations even if the computational annotations are more recent There is a need for tools which can assist curators in persisting manually curated data through the update process either through automation or by providing pipelines for the transfer of manual annotations of these databases Additionally when several distinct databases host biological data for the same organism it is desir able to share manually curated annotations between these 2014 Walsh et al licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License http creativecommons org licenses by 4 0 which permits unrestricted use distribution and reproduction in any medium provided the original work is properly credited The Creative Commons Public Domain Dedication waiver http creativecommons org publicdomain zero 1 0 applies to the data made available in this article unless otherwise stated Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 databases in order to improve data accuracy with
13. enome 2013 6 1 0 Accessed 2014 06 04 10 Chae L Lee I Shin J Rhee SY Towards understanding how molecular networks evolve in plants Curr Opin Plant Biol 2012 15 2 177 184 Accessed 2014 06 04 11 Schnable PS Ware D Fulton RS Stein JC Wei F Pasternak S Liang C Zhang J Fulton L Graves TA Minx P Reily AD Courtney L Kruchowski SS Tomlinson C Strong C Delehaunty K Fronick C Courtney B Rock SM Belter E Du F Kim K Abbott RM Cotton M Levy A Marchetto P Ochoa K Jackson SM Gillam B et al The b73 maize genome complexity diversity and dynamics Science 2009 326 5956 1 112 1115 PMID 19965430 Accessed 2014 01 20 12 MaizeCyc Database Home Metabolic Pathways in Maize or Corn http pathway gramene org maizecyc html Accessed 2014 06 04 13 MaizeCyc Database Home Metabolic Pathways in Maize http maizecyc maizegdb org Accessed 2014 05 08 14 Summary of Zea mays Subspecies mays version 4 0 1 http omn plantcyc org organism summary object CORN Accessed 2014 05 08 15 CornCyc Database Home Metabolic Pathways in Maize http corncyc maizegdb org Accessed 2014 05 08 Page 10 of 10 16 Sen TZ Andorf CM Schaeffer ML Harper LC Sparks ME Duvick J Brendel VP Cannon E Campbell DA Lawrence CJ MaizeGDB becomes sequence centric Database J Biol Databases Curation 2009 2009 Accessed 2014 06 04 17 Lawrence CJ Harper LC Schaeffer ML Sen TZ Seigfried TE Campbell DA MaizeG
14. etylformic acid pyroracemic acid 2 oxopropanoic acid pyruvic acid 2 oxopropanoate and 2 oxo propionic acid Despite the availability of these CycBrowser File Edit About Home Step2 Step3 View File Match IDs Select Import Type Proteins Select Input File Multiple value delimiter I Update Author Credits Only applied if frame is modified a Append values or overwrite existing V Append new data to existing values Check if this value exists before importing v Ignore Duplicates oie x N Step 4 Step5 Preview Commit Finished Always backup your database file before modifying it z j Browse Select file format Comma separated values CSV v Choose Individual Author Jesse Walsh v Choose Organization MaizeGDB X Back J Open A Figure 4 CycTools import screen CycTools provides a multi step process for importing user data Several options are available for users to interact with existing data Users can also specify an author or organization to assign credit for the revision of a database frame object Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 alternate identifiers all queries to the database must resolve to valid frame IDs A key benefit of CycTools is support for automatically resolving alternate identifiers into frame IDs removing the need for researchers to per form the conve
15. for the matching object Thus while substring search will match a partial identifier to a frame CycTools enforces a stricter match ing policy by filtering out matches that do not contain complete matches to an alternate identifier Additionally CycTools requires that only one such matching object be found in the database If the search returns only a single frame that frame s ID is substituted for the searched term If multiple matches or no match is found the user is given the option to ignore that data during import or to cancel the import process altogether Create transcriptional regulation frames Importing novel transcriptional regulatory interactions requires creating regulation frames within the BioCyc database to represent the interaction Since this import type generates new frames rather than modifying existing ones the user does not provide frame identifiers with the import data As a result no frame ID search is necessary CycTools instead requests unique sequential identifiers for each new regulation object created CycTools is not able to recognize if an equivalent regulatory interaction exists in another regulation frame and therefore relies on the user to ensure that regulatory interactions are not duplicated Page 6 of 10 Delete frames CycTools implements frame deletion using the Pathway Tools API method delete frame and dependents This method detects the object type of the frame which is being deleted a
16. kD experimental Relationship Credits Date Curators Organizations none yet Select Change Create Select Change Create Current selection s Current selection s Update Last Curated Date J Cancel Figure 1 Screenshot of pathway tools protein editor Editing database objects through the Pathway Tools software editors is done by entering information into forms which describe information specific to the type of object being edited Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 Pathway Tools supports data imports through two file formats spreadsheet format or Lisp format Exam ples are provided in Additional file 1 The spread sheet format imports are limited in that some data cannot be imported using this method including GO term annotations stoichiometry and cellular localiza tion While the Lisp format supports the import of these data types it requires users to have an understanding of the Lisp data structure implemented in the BioCyc framework and is not easily converted to other standard formats A final import option provided by Pathway Tools is through an application programming interface API which exposes low level access to the BioCyc data struc ture The API is very flexible in that users can design queries to suit their specific needs but they must have a detailed understanding of the internal structure of a BioCyc da
17. nd attempts to also delete any frames which depend on the deleted frame For example deleting a gene frame will also delete the gene s products and potentially enzymatic reactions which depend on an enzyme pro duced by the gene Regulation frames and history note frames linked to the deleted frame are also deleted Preview changes Before any permanent modification is made to the database the user can preview the pending changes to the database A list shows all frames that will be updated as per the user data Individual frames can be viewed which will compare the original frame data to the modi fied data All changes between the original and modified frames will be highlighted to help the user more easily ver ify the import The differences are calculated using a free library called google diff match patch 8 Highlighting is inferred from the text differences reported by the diff tool Commit to database After the update is performed the results of the update can be reviewed This will provide a log of the successful and failed imports which can be used to verify the success of the import or to track down problems with the data Each individual import will be listed as either successful or failed will be time stamped and will refer to the original row of data in the spreadsheet which that update repre sents Note that it may be possible to have several updates refer to the same row of data At this point the database is in a m
18. odified but unsaved state If the user is satisfied with the update the changes can be permanently saved to the database Otherwise the user can undo all changes to the database since the last save The user will also be given the option of saving the change log to a file Import error detection CycTools checks for errors and provides user feedback at several points during the import process CycTools will directly reject syntax errors such as bad file for mats of invalid references to database objects Illegal database operations on the BioCyc database will cause failed imports in the final commit step which will be flagged to users so that they can revert the database to an unmodified state Imports with identifiers which cannot be resolved to existing database objects will be reported to the user as such Many errors in data entry are technically valid and thus cannot be differentiated from intentional input If a slot label is misspelled for example CycTools will assume the user intends to create a slot using the misspelled label Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 The preview step provides users with a frame by frame comparison of the database in a modified and an unmodi fied state Users are encouraged to browse the anticipated changes in order to detect any data entry errors that would otherwise be valid imports Results and discussion Use case MaizeCyc and CornCyc GO
19. out duplicating curator efforts In order to facilitate the trans fer of data between databases robust import and export features must be made available Pathway Tools 4 the software which supports devel opment and management of BioCyc databases provides several options for updating a BioCyc database Changes may be made manually within the pathway tools software Page 2 of 10 by first locating the object to update and then entering edit mode to make the changes to that object as shown in Figure 1 Each object type protein gene metabolite etc has a specific data entry form which can be filled out and saved While this method allows the curator to directly review and verify the changes entered into the database it is inefficient when performing large numbers of updates Edit Protein ACYLCOASYN CPLX Complex Subunits 1 Enzymatic Activity 1 Gene Modified Forms 0 Enzyme fatty acyl CoA synthetase Edit Enzyme Name Class a protein complex Evidence for non enzymatic function of this protein if any Le Evidence Code Citation Mol Fn and Biol Proc GO Terms Cellular Component GO Terms G0 0005829 cytosol Evidence Code Citation With Duplicate this term Synonyms f Citations rsd ir i__ isd Summary cits FRAME Create Search Citation Hyperlink Spel lcheck f Citation m pl Citation Links to other databases Database ID Molecular Weight
20. port file does not contain Frame IDs Only unique matches to Connect to Database _ O Q ype Select File Specify options Existing Frames w ue Q gt Search IDs in Database Creating New Frames ID s Match Objects in DB Preview Changes a w Qo E om O Commit Changes Accept Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 allow the user to specify how to handle existing data in a slot or annotation which will be modified during import shown in Figure 4 If the overwrite option is set CycTools will first delete the existing data in a slot or annotation before writing the user provided data to that slot or annotation If the ignore duplicates option is set CycTools will check each new value against each existing values in a slot or anno tation If the new value exactly matches an existing value it will not be added to the slot or annotation This option will prevent the user from adding a duplicate value to a slot or annotation but will not remove an existing duplication Thus if a protein were to be annotated with a single GO term twice this option will prevent CycTools from adding a third identical annotation using that GO term but would leave the existing annotations The author credits option allows the user to assign credit to an individual or organization for each frame updated during the impor
21. provides a change log of actions taken during import in order to assist users in recording changes and identifying problems Page 9 of 10 In this manuscript we have demonstrated the util ity of CycTools by transferring GO annotations between two databases representing identical biology but having differing data content We have also demonstrated the ability of CycTools to make several small scale changes to a database in order to customize the content to represent a non model organism Availability and requirements Project name CycTools Project home page https github com jrwalsh CycTools Operating system s Any platform supporting Java Programming language Java Other requirements Java 1 7 Pathway Tools JavaCycO Pathway Tools must be installed and running on a Unix like server system due to use of the UnixDomainSocket class and have the relevant PGDB installed JavaCycO must be running in server mode on the same server as Pathway Tools For remote connections JavacycServer lis tens over a port connection so this user selected port must be open to outside traffic CycTools is written in Java and is thus cross platform compatible however Java must be installed on the client machine The version of Cyc Tools used in this manuscript can be found in Additional file 6 License GNU GPL Any restrictions to use by non academics None Additional files Additional file 1 Examples of file formats This file
22. rsion manually Alternate identifiers must already be annotated to the object they identify within the database and must be stored in one of the slots des ignated as a name slot in Pathway Tools These slots typically include the accession slot common name slot synonym slot and foreign database identifiers used in the dblink slot but can vary with object type During the import process CycTools attempts to resolve all user provided identifiers into frame IDs First CycTools checks if the user provided identifiers match exactly to any existing frame IDs If all identifiers are determined to be valid frame IDs no further action is needed and the ID resolution step is skipped If one or more IDs are not valid frame IDs CycTools will attempt to resolve them into valid frame IDs using an indexed text search within the database using the substring search method provided by the Pathway Tools API The substring search command can find objects with frame IDs that exactly match the search string which match to a substring of any name slot The search term provided by the user must be at least 3 characters with no commas or spaces This method requires the user to specify the object type to search and the alternate identifiers to be converted to frame IDs For each identifier in the import file CycTools requires that the searched term match exactly and entirely to at least one synonym provided by the database
23. s N Kunin V L pez Bigas N Expansion of the BioCyc collection of pathway genome databases to 160 genomes Nucleic Acids Res 2005 33 19 6083 6089 PMID 16246909 Accessed 2013 10 25 2 Schnoes AM Brown SD Dodevski Babbitt PC Annotation error in public databases Misannotation of molecular function in enzyme superfamilies PLoS Comput Biol 2009 5 12 1000605 3 Guide to the BioCyc Database Collection http biocyc org BioCycUserGuide shtml Accessed 2014 05 08 4 Paley SM Latendresse M Karp PD Regulatory network operations in the pathway tools software BMC Bioinformatics 2012 13 1 243 PMID 22998532 Accessed 2013 10 25 5 Ocelot User s Guide http www ai sri com pkarp ocelot Accessed 2014 05 08 6 Krummenacker M Paley S Mueller L Yan T Karp PD Querying and computing with BioCyc databases Bioinformatics 2005 21 16 3454 3455 Accessed 2011 12 19 7 Van Hemert JL Dickerson JA PathwayAccess CellDesigner plugins for pathway databases Bioinformatics 2010 26 18 2345 2346 Accessed 2011 07 26 8 google diff match patch Diff Match and Patch libraries for Plain Text Google Project Hosting http code google com p google diff match patch Accessed 2014 05 08 9 Monaco MK Sen TZ Dnarmawardhana PD Ren L Schaeffer M Naithani S Amarasinghe V Thomason J Harper L Gardiner J Cannon EK Lawrence CJ Ware D Jaiswal P Maize metabolic network construction and transcriptome analysis Plant G
24. t manual curation It is therefore desirable to leverage annotations from EcoCyc whenever possible while developing new strain databases The metabolically engineered strains for which strain specific databases were developed in this study strain ML103 and strain MLC115 1 were described in Liam et al 19 The genotype of ML103 is MG1655 AfadD The genotype of MLC115 1 is MG1655 AfadD ApoxB ackA pta cmR New regulatory links were predicted using the GTR Network software 20 These results were derived for the MG1655 network and so were applied to a copy of the wildtype EcoCyc database rather than the ML103 or MLC115 1 databases Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 Page 8 of 10 S CycBrowser File Edit About the database CORN Found 0 terms with FramelD matches in database DOQC 113208 MONO __ GRMZM2G412611_P01 GO 0009532 20089766 We were able to match 0 out of 743 based on FramelDs An additional 176 out of 743 terms were matched based on synonyms This search was performed on Proteins in Found 176 terms with Synonym matches Matched Frame GivenID GO TERMS PubMedID COR TRO HONO GRMZM2G044247_P01 GO 0009532 20089766 aes SO Ne Nore Steps S05 finished gt 7 Preview P 4 eee 613 terms with ambiguous matches or no matches in database 04 25 2014 12 00 00 MaizeGDB a EV EXP IDA 04 25 2014 12 00 00 MaizeGDB DQC 110931 MONO GRMZM2G0
25. t process CycTools autofills a list of curators and organizations described in the cur rently selected database For each frame updated during the import the frame is modified to append the curator or organization to the CREDITS slot This update is anno tated as a revision to the frame and is timestamped to the current system time Page 5 of 10 GO term annotations GO term annotation imports are handled slightly different from other annotations imports In particular Pathway Tools has specific requirements for the storage of GO term descriptions within a BioCyc database The Pathway Tools API provides a method called import go terms which automatically creates the necessary frames when provided with a valid GO term Pathway Tools is packaged with a file containing GO term information which is used by this method to populate the GO term frames it cre ates CycTools makes a call to import go terms once for each GO term that appears during a GO term annotation import Resolving alternate identifiers to database frames Each frame object in the database is uniquely identi fied by an internal identifier known as the frame ID The BioCyc framework supports annotating frames with alternate identifiers such as those which are commonly used in literature to refer to genes proteins and other biological objects For example PYRUVATE in Eco Cyc has the synonyms alpha ketopropionic acid BTS a ketopropionic acid ac
26. tabase in order to do so Certain modifica tions to a BioCyc database such as GO term annotations require additional steps in order to maintain the ref erential integrity of the database This provides further barriers to use as users must have an understanding of how Pathway Tools implements storage of these features Despite the diversity of import methods provided by Pathway Tools there remains a need for an import pipeline which is both capable of importing slot value annotation data in batch and accessible to researchers who are not experts in programming or BioCyc database structure CycTools is a graphical interface for the BioCyc family of databases which improves data management by providing methods which can import slot value annota tion data in batch Implementation CycTools dependencies BioCyc is a family of databases built using the BioCyc Framework Each member database of the BioCyc collec tion typically represents the pathway and genomic data Page 3 of 10 of a specific organism BioCyc databases are built on the Frame Representation System FRS known as Ocelot 5 which extends the Generic Frame Protocol GFP The native storage format for BioCyc data is an object oriented database representation based on frames The hierarchical nature of data represented in a frame can be seen in Figure 2 A frame is a high level container that groups information regarding either biological entities genes proteins transcrip
27. terests Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 Authors contributions TZS and JRW conceived designed and coordinated the project JRW developed and documented the software and drafted the manuscript JAD provided advice and guidance on the software development and drafting of the manuscript All authors read and approved the final manuscript Acknowledgements We thank the MaizeGDB team for sharing their insights and expertise The MaizeGDB group also created a use case for this software and provided user feedback The material presented here is based upon work supported by the National Science Foundation under Award No EEC 0813570 Any opinions findings and conclusions or recommendations expressed in this material are those of the author s and do not necessarily reflect the views of the National Science Foundation Author details 1 Bioinformatics and Computational Biology Program lowa State University Ames IA USA 7Electrical and Computer Engineering Department lowa State University Ames IA USA 7 gt USDA ARS Corn Insects and Crop Genetics Research Unit Ilowa State University Ames IA USA Department of Genetics Development and Cell Biology lowa State University Ames IA USA Received 6 June 2014 Accepted 23 September 2014 Published online 12 October 2014 References 1 Karp PD Ouzounis CA Moore Kochlacs C Goldovsky L Kaipa P Ahr n D Tsoka S Darzenta
28. term annotation migration MaizeCyc 9 and CornCyc 10 are two separate BioCyc databases both based on the Zea mays B73 RefGen_v2 gene models 11 MaizeCyc is developed by Gramene 12 in collaboration with MaizeGDB 13 and Corn Cyc is developed by Plant Metabolic Network 14 and MaizeGDB 15 17 Recent comparison between Maize Cyc and CornCyc revealed annotation differences in data content and quality despite both databases having been based on the same reference sequence 18 MaizeCyc does not contain alternative splicing information there fore each gene is only linked to a single gene product CornCyc does contain alternative splicing information where gene products linked to alternate splice variants are suffixed with a numerical identifier It is interesting to note that even though MaizeCyc does not contain alterna tive splicing information it still uses the numerical suffix convention for differentiating between alternately spliced proteins Recent curation efforts have provided GO term anno tations for several proteins in the MaizeCyc database however CornCyc version 4 0 does not currently contain any GO annotations Since MaizeCyc and CornCyc both were created using the same sequence data and represent the same biology the biological functions of MaizeCyc genes should be identical to those of CornCyc genes In an effort to update the GO term annotations of the maize genome databases and ensure consistency across both dat
29. tion has no existing enzymes which can catalyze the reaction then the reac tion is also removed If the gene is a transcription factor than the transcription factor is removed as well as any regulation objects in which that transcription factor was either a regulator or target Preprocessing for this database modification simply requires compiling the list of genes to delete CycTools automatically removes additional objects which are connected to the deleted gene as described above A thioesterase with altered specificity added to the strain improves specificity for specific fatty acid chain lengths This does not represent novel metabolic func tionality in the strain but rather changes relative activities of an existing functionality Since kinetic information and relative specificities of enzymes is not stored explicitly in current PGDBs this information is best added to the comments section of the existing enzyme Preprocessing in this case requires the user to explicitly write out the comment and provide the identifier of the enzyme to be modified The final modification made to the base EcoCyc database is the inclusion of novel computationally pre dicted transcription factor regulation These regulatory interactions were predicted using GIT RNetwork 20 and can be found in Additional file 5 Transcription factor reg ulatory interactions in EcoCyc are typically described by a regulation object which describes a transcription fac
30. tor s regulatory activity of a transcription factor binding site but can also be described as a direct interaction between the regulating entity and the regulated gene As the results produced in this computation prediction tool do not provide predicted binding sites binding site Walsh et al BMC Systems Biology 2014 8 115 http www biomedcentral com 1752 0509 8 115 information is not available for import Preprocessing in this case requires the user to assemble the list of regulator and target interactions Each type of modification to the EcoCyc database must be made separately In this case the three modifica tions gene deletions thioesterase comment and pre dicted regulation represent three types of modification Gene deletions are removed from the database by select ing the frame deletion option and loading the list of genes to be deleted CycTools automatically removes extended links to the provided genes such as their products and reactions The thioesterase comment is performed as an update to an existing frame A file with the com ments is loaded and CycTools appends the new comment to the end of any existing comments on the enzyme Importing novel predicted transcription factor regula tion requires creating new regulation frames This pro cess is performed as two steps internally to CycTools First new frames are created using the user provided unique Frame IDs An import step is then used to load the regulation dat
31. ts compounds etc or biolog ical relationships reactions pathways regulation etc Information about the object a frame represents can be stored in either slots or slot value annotations Informa tion stored in slots describes the frame i e the name of the object its physical properties or annotations assigned to it while information in slot value annotations pro vides context for the information in the slots i e pubmed citations author credits or experimental evidence codes The data stored in frames and slots in the database can be accessed programmatically through the Pathway Tools API The API exposes many of the internal functions of Path way Tools and allows low level access to the internal data structure of any BioCyc database hosted by Pathway Tools Advanced users can create third party software which can read or write to BioCyc databases using customized queries The API is designed to support the Lisp program ming language but the libraries PerlCyc 6 and JavaCycO 7 allow users to access the API through Perl and Java respectively JavaCycO is an object oriented improvement to the JavaCyc library JavaCycO contains the JavaCyc 6 class and is fully backwards compatible with it In addition to extending and improving the functionality of JavaCyc JavaCycO provides a client server model for accessing the Pathway Tools API By running the server JavaCyc Server on the same machine as Pathway Tools JavaCyc

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