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ORGANIZING and COMPUTING METABOLIC PATHWAY DATA in TERMS of BINARY RELATIONS 1 Introduction

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ORGANIZING and COMPUTING METABOLIC PATHWAY DATA in TERMS of BINARY RELATIONS 1 Introduction yqexssxq exh gyw sxq wiefyvsg ere hee sx iw yp fsxe ivesyx F qyyD rF fyxyD rF yqeeD F p tsf grsD F xsrsyueD uF eyD wF uexirse snstitute for ghemil eserhD uyoto niversityD jiD uyoto TIID tpn e new dtse system nmed uiqq is eing orgnized to omputerize funE tionl sp ets of genes nd genomes in terms of the inry reltions of interting moleules or genesF e re urrently working on the metoli pthwy dtse tht is omp osed of three interonneted setionsX genesD moleulesD nd pthwysD whih re lso linked to num er of existing dtses through our hfqi reE trievl systemF rere we present the si onept of inry reltions nd hierE rhil lssitions to represent the metoli pthwy dtF he dtse opertions re then dened s n extension of the reltionl opertionsD nd the pth omputtion prolem is onsidered s dedution from inry reltionsF en exmple of using uiqq for the funtionl predition of genomi sequenes is preE sentedF I sntrodution I he rst omplete genome of n orgnismD 0xIURD ws determined in IWUUD whihws followed y the explosion of hxe sequene dt for sp ei genesD s well s for smll genomes of viruses nd orgnellesF he rst omplete genome of freeEliving orgnismD remophilus inuenze Dws determined in P IWWSD whihwould ertinly e followed y the explosion of omplete genomi sequenes nd omplete gene tlogs of num er of orgnisms from teri to eukryotesF heres the exp erimentl tehnologies hve een rened to systemtilly nlyze whole genomeD the omputtionl metho ds for deiE phering funtionl implitions re still sed on the nlysis of eh gene or gene pro dut t timeF e systemti omputtionl nlysis is required for funtionl predition of whole genomeF et presen tD the funtionl dt is omputerized s n ttriute of eh sequeneD for exmpleD in the fetures tles of the sequene dtses nd Q in the motif lirries suh s ysiF husD the si ide for funtionl predition is to serh similrities of eh sequene in the sequene dtses or in the motif lirries nd then to extend sequene similrities to funtionl resent ddressX qrdute shool of egriultureD uyoto niversityD kyoEkuD uyoto THTEHID tpn ermnent ddressX gry eserh tpn vhFD IPEPS riroshiEhoD uitEshiD ysk STRD tpn similritiesF he prolem here is the lk of suitle mesure for the orE retness of funtionl ssignmentD esp eilly for the similrities in the soElled twilight zoneF he sequeneEfuntion reltionships of single moleules repreE sent how individul omp onents of iologil system workD nd they do not ontin higher level informtion of how omp onents re onneted to form funtionl unitD suh s met oli pthwyD signl trnsdution nd n op eronF es long s the ssignment is mde for eh omp onent seprtelyDit will e diult to hek if suh funtionl unit is prop erly formedF ehve initited pro jet nmed uiqqD uyoto inylop edi of qenes nd qenomesD to omputerize urren t knowledge of the informtion pthwys of genes nd gene pro dutsD whihmy e onsidered s wiring digrms of iologil systemsF uiqq onsists of three typ es of dtD pthwysD genesD nd moleulesD tht re linked with eh other nd with the existing dtses d R through our hfqi integrted dtse systemF gurrentlyDwe fous our ttention to the met oli pthwys nd enzyme genesF he dtse pro jet S vsqexh for enzyme retionsD enzymesD nd met oli omp ounds is lso tightly oupled with the uiqq pro jetF sn this pp erD we presen t the si onept of the inry reltion etween twointerting moleules or genes s fundmentl element to represen t the pthwyD the mnipultion of inry reltions sed on reltionl op ertionsD nd the pth omputtion s deE dution from inry reltionsF e lso riey mention how the pthwy dt n e utilized to mke funtionl ssignment from gene tlogF P ht epresenttion PFI fsi ht stem he si dt item in uiqq is geneD gene pro dutD met oli omp oundD or ny other moleule in ellD whihmy e identied in the formX dtseXentry or orgnismXgene where dtse9 is the dtse nme suh s gennk nd swissprotD entry9 is the entry nme or the ession num erD orgnism9 is the orgnism nmeD nd gene9 is the gene nmeF his is the uniform identier oth in uiqq nd hfqiF por exmpleD igXTFQFPFQ nd httpXGGwwwFgenomeFdFjpGkeggGkeggFhtml d httpXGGwwwFgenomeFdFjpGdgetGdgetFlinksFhtml le IX ixmples of inry reltions ht item I ht item P yp e of reltion gennkXhyevg medlineXWQPUQUWT ftul dt nd referene emlXhwevg spXgxe hywi trnsltion from nuleotides to mino ids gennkXhyevg emlXhwevg sme ession p dXgHHIIV p dXgHHIII sustrte nd pro dut igXRFPFIFI igXSFQFIFI two onseutive enzymes in the met oli pthwy hFmelnogsterXdpp hFmelnogsterXsx twointerting genes @lignd nd reeptorA iFoliXtpie spXs igyvs gene pro dut s stored in puli dtse iFoliXtpie igXSFQFIFI gene nd funtion fFsutilisXtpi igXSFQFIFI gene nd funtion iFoliXtpie fFsutilisXtpi orthologous genes p dXgHHHSI represen t glutthione synthse nd glutthioneD resp etivelyD in the vsqexh dtseD nd iFoliXtpie represen ts triosephosphte isomerse gene in iF oli F PFP finry eltions o represen t the dt of interting moleules or genesD we use the simplest form of represen ttionX the inry reltion tht orresp onds to the pirwise intertionF eny higher level intertions involving more thn two omp onents t time will e pproximted y the olletion of pirwise intertionsF he T onept of inry reltions hs lredy een utilized in the vinkhf dtse of the hfqi systemF por exmpleD the link etween two dtse entriesX dtseIXentryI A dtsePXentryP nd the link etween dtse entry nd gene nmeX dtseXentry A orgnismXgene re usully provided y eh dtse nd implemented in vinkhfGhfqiF ixmples of these nd other typ es of inry reltions re shown in le IF uiqq inorp ortes the links tht exist in vinkhfGhfqi @pigF I@AA ndD in dditionD ontins more iologil links of twointerting moleules Database:Entry Enzyme sp:TYRB_ECOLI 2.6.1.57 sp:PHHC_PSEAE 2.6.1.57 DBGET pir:XNECY 2.6.1.57 .. .. genbank:BACGTPBP 4.2.1.51 @A eltion etween dtse entry nd n enzymeF his reltion is exE T R trted from vinkhf in the hfqi systemF Enzyme Substrate Product 2.6.1.57 Prephenate Pretyrosine LIGAND 4.2.1.51 Prephenate Phenylpyruvate 4.2.1.51 Chorismate Prephenate .. .. @A finry reltion etween hemil omp ounds @sustrte nd pro dutA tht prtiipte in hemil retionF his reltion is extrted from vsqexh S ghemil htse for inzyme etionF (c-1) Map Enzyme Phe, try and trp biosynthesis 2.6.1.57 KEGG Phe, try and trp biosynthesis 4.2.1.51 .. Pathway .. Terpenoid biosynthesis 2.5.1.10 (c-2) Map Enzyme1 Enzyme2 Phe, try and trp biosynthesis 4.6.1.4 4.2.1.51 Phe, try and trp biosynthesis 4.2.1.51 2.6.1.57 ... ... Terpenoid biosynthesis 2.5.1.1 2.5.1.10 @A eltionship etween n enzyme nd its lotion @mpA in the met oli pthwys @EIAF finry reltion etween two enzymes tht pp er onseuE tively in the pthwy @EPAF hese reltions re extrted from the pthwy digrms of uiqqF Organism:Gene Enzyme KEGG H. influenzae:HI1145 4.2.1.51 Genes H. influenzae:HI0196 4.6.1.3 .. .. H. sapiens:ADCY1 4.6.1.1 @dA eltion etween gene nd n enzymeF st is extrted from the uiqq hierrhil text dt in the genes setionF pigure IX eltionl tles used in the omputtion of pthwys Enzyme Group (superfamily) 2.6.1.1 aspartate aminotransferase 2.6.1.5 aspartate aminotransferase .. .. KEGG Molecules Enzyme Group (motif) 2.6.1.1 Aminotransferase class-I 2.6.1.5 Aminotransferase class-I 2.6.1.57 Aminotransferase class-I .. .. @eA eltion etween n enzyme nd the group to whih it elongsF his reltion is derived from the uiqq hierrhil text dt in the moleules U setionF gurrentlyD there re four lssitions sed on ig num ersD s V W Q sup erfmiliesD gy QhEfolds nd ysi motifsF pigure IX eltionl tles used in the omputtion of pthwys @ontdFA or genesF por the met oli pthwysD the twotyp es of inry reltions re identiedF yne is the sustrteEpro dut reltion in the form of p dXgHHIIV A p dXgHHIII whih is extrted from the vsqexh dtse @pigF I@AAF he other is the reltion of two onseutive enzymes pp ering in the known pthwysD suh s igXRFPFIFI A igXSFQFIFI his reltion is extrted from the pthwy digrms of uiqq @pigF I@AAF PFQ rierrhil glssitions e hierrhy is often used to represen t funtionl nd struturl similrities of genes nd moleulesF he hierrhil lssition of ig num ers is sed on the nture of hemil retions tlyzed y enzymesF he degree of similrity in sequenes nd Qh strutures of proteins is used for lssifying sup erfmilies nd foldsF he txonomy is the lssition of orgnismsD whih is importnt for extending sequene nd Qh struturl similrities to funtionl similritiesF sn the urrent version of uiqqD we onstrut enzyme lssition tles U V W ording to ig num ersD s sup erfmiliesD gy QhEfoldsD nd ysi Q motifs @pigF I@eAAF yne the entire genome is sequened nd the omplete tlog of genes is otinedD it is nturl to ttempt to lssify ll genes ording to their funE IH tionsF iley9s hierrhil lssition nd tegoriztion of iF oli genes is n exmple of suh n ttemptF sn uiqqD the funtionl lssition is sed on the tul pthwy dt whihwe onsider s n o jetive riterion for tegoriztion of funtionl unitsF sn the implementtion of uiqqD the lssition tles n e viewed nd mnipulted s wht we ll hierE rhil text dtD where rnhes of the tree my e expnded or ollpsed y simply liking on the hedings nd suhedingsF PFR thwy higrms II he met oli pthwy digrms suhsy fo ehringer nd y the tpnese IP fio hemil o iety represen t onsensus view of known met oli pthE wys for humns to understndF trting from these two ompiltionsD wehve omputerized the met oli pthwy dt in the form of out VH grphil digrmsF ih digrm ontins enzyme o jets tht n e mnipulted toE gether with the reltionl op ertionsF he digrm is intended s drwing of ll hemilly fesile pthwysD rther thn onsensus of known pthwysF husD lthough the referene digrm hs to e drwn nd ontinuously upE dted mnullyD the orgnismEspei pthwys re utomtilly
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