Supplemental Table 3. Min_max_span_internal Reactions minWT maxWTspanWTminKO maxKO spanKOspanKO/spanWTName Equation Subsystem 2HBO -2 0 2 -3 0 3 1.5 2-Hydroxybutyrate:NAD+[c] : 2hb + nad oxidoreductasePropanoate <==> 2obut Metabolism + h + nadh 2HBt2 -2 0 2 -3 0 3 1.5 2-hydroxybutyrate2hb[e] cotransport + h[e] <==>Transport, with 2hb[c] proton Extracellular + h[c] 2MCITt 0 2 2 0 3 3 1.5 2-methylcitrate2mcit[c] transport <==> via Transport,2mcit[e] diffusion Extracellular 34HPLFM 0 1 1 0 2 2 2 3-(4-hydroxyphenyl-)lactate[m] : 34hpp + Ubiquinoneh formation + nadh --> Biosynthesis34hpl + nad 3DSPHR 0 1 1 0 37.54 37.54 37.536 3-Dehydrosphinganine[c] : 3dsphgn reductase +Sphingolipid h + nadph --> Metabolism nadp + sphgn 4HOXPACDOX(NADP) 0 1 1 0 2 2 2 4-Hydroxyphenylacetaldehyde:NADP+[c] : 4hoxpacdTyrosine + h2o + nadpmetabolism oxidoreductase <==> 4hphac + (2) h + nadph AACTOOR 0 2 2 0 24.58 24.58 12.291 Aminoacetone:oxygen[c] : aact +oxidoreductase(deaminating)(flavin-containing) h2oGly, + o2 Ser, --> Thr h2o2 Metabolism + mthgxl + nh4 AACTtm 0 2 2 0 24.58 24.58 12.291 Aminoacetoneaact[m] transport --> (mitochondrial)aact[c]Transport, Mitochondrial ACACt2m -217 260.7 478.1 -219 149.7 368.6 0.771 Acetoacetate acac[c]mitochondrial + h[c] Transport,<==> transport acac[m] viaMitochondrial +H+ h[m] symport ACACtx -254 0 254.4 -130 0 129.9 0.5105 acetoacetate intracellularacac[c] <==> transport acac[x]Transport, unknown Peroxisomal mechanism ACGAMtly 0 56.44 56.44 0 5 5 0.0886 N-acetyl-glucosamineacgam[l] lysosomal --> acgam[c]Transport, efflux Lysosomal ADK3m 0 4.6 4.6 0 16.41 16.41 3.5666 adentylate kinase[m] :(GTP) amp + gtpNucleotides <==> adp + gdp ADNK1m 0 4.6 4.6 0 16.41 16.41 3.5666 adenosine kinase,[m] :mitochondrial adn + atpNucleotides --> adp + amp + h ADNtm 0 4.6 4.6 0 16.41 16.41 3.5666 adenosine facilatedadn[c] transport <==> adn[m]Transport, in mitochondria Mitochondrial ADSL2 0 2 2 0 10.51 10.51 5.2563 adenylosuccinate[c] : lyase25aics -->IMP aicar Biosynthesis + fum AHC 0 2 2 0 3 3 1.5 adenosylhomocysteinase[c] : ahcys + h2oMethionine <==> adn Metabolism+ hcys-L AICART 0 2 2 0 10.51 10.51 5.2563 phosphoribosylaminoimidazolecarboxamide[c] : 10fthf + aicarIMP <==>Biosynthesis fprica + formyltransferase thf AIRCr 0 2 2 0 10.51 10.51 5.2563 phosphoribosylaminoimidazole[c] : air + co2 <==>IMP carboxylase Biosynthesis5aizc + h AKGMALtm -708 5E+05 5E+05 -710 170 879.9 0.0018 alpha-ketoglutarate/malateakg[m] + mal-L[c]Transport, transporter <==> akg[c] Mitochondrial + mal-L[m] ALCD1 -2 0 2 -3 0 3 1.5 alcohol dehydrogenase[c] : meoh (methanol) + nadMiscellaneous <==> fald + h + nadh AOBUTDsm 0 2 2 0 24.58 24.58 12.291 L-2-amino-3-oxobutanoate[m] : 2aobut + Gly,decarboxylation, h --> Ser, aact Thr + co2Metabolism mitochondrial BETALDHxm 0 1 1 0 2 2 2 betaine-aldehyde[m] :dehydrogenase, betald + Gly,h2o Ser,+ nad mitochondrial Thr --> Metabolism glyb + (2) h + nadh BHMT 0 1 1 0 2 2 2 betaine-homocysteine[c] : glyb +S-methyltransferase hcys-LGly, --> Ser, dmgly Thr Metabolism + met-L BPNT 0 1 1 0 2 2 2 3',5'-bisphosphate[c] : h2o nucleotidase + papNucleotides --> amp + pi BUP2 0 1.3 1.3 0 27.65 27.65 21.268 beta-ureidopropionase[c] : 3uib +(D-3-amino-isobutanoate (2)Pyrimidine h + h2o --> Catabolism 3aib-D + co2 forming) + nh4 CAMPt 0 3.3 3.3 0 9.45 9.45 2.8636 cAMP transportatp[c] (ATP-dependent) + camp[c]Transport, + h2o[c] Extracellular --> adp[c] + camp[e] + h[c] + pi[c] CGMPt 0 0.15 0.15 0 9.45 9.45 63 cGMP transport35cgmp[c] (ATP-dependent) + atp[c]Transport, + h2o[c] Extracellular --> 35cgmp[e] + adp[c] + h[c] + pi[c] CHLtm 0 1 1 0 2 2 2 choline transportchol[c] via <==>diffusion chol[m]Transport, (cytosol Mitochondrialto mitochondria) CHOLD2m 0 1 1 0 2 2 2 choline dehydrogenase[m] : chol (FAD+ fadGly, acceptor),--> Ser, betald Thr + mitochondrialMetabolism fadh2 CHOLtu 0 1 1 -0.33 1 1.333 1.3333 Choline uniportchol[e] <==> chol[c]Transport, Extracellular CLFORtex 0 1 1 0 1.5 1.5 1.5 chloride transportcl[e] via+ (2) formate for[c]Transport, --> countertransport cl[c] + Extracellular (2) for[e] COAtm -108 234.8 342.7 -108 0 108.2 0.3158 CoA transportercoa[c] <==> coa[m]Transport, Mitochondrial COAtp -254 0 254.4 -130 0 129.9 0.5105 coenzyme A transport,coa[c] <==> peroxisomal coa[x]Transport, Peroxisomal CRNCARtp 0 254.4 254.4 0 129.9 129.9 0.5105 carnitine-acetylcarnitineacrn[x] + crn[c] carrier,Transport, --> acrn[c]peroxisomal Peroxisomal + crn[x] CSNATp 0 254.4 254.4 0 129.9 129.9 0.5105 carnitine O-acetyltransferase,[x] : accoa + crnFatty <==>reverse Acid acrn Metabolismdirection, + coa peroxisomal CYTDt -1.15 0.15 1.3 -13.2 0.15 13.35 10.269 cytidine facilatedcytd[e] transport <==> cytd[c] Transport,in cytosol Extracellular D-3AIBt 0 1.3 1.3 0 27.65 27.65 21.268 D-3-amino-isobutyrate3aib-D[c] transport--> 3aib-D[e]Transport, Extracellular DATPtn 0 3.3 3.3 0 9.45 9.45 2.8636 dATP diffusiondatp[c] in nucleus <==> datp[n]Transport, Nuclear DCTPtn 0 1.3 1.3 0 13.35 13.35 10.269 dCTP diffusiondctp[c] in nucleus <==> dctp[n]Transport, Nuclear DCYTt -1.3 0 1.3 -13.4 0 13.35 10.269 deoxycytidinedcyt[e] transport <==> via dcyt[c] Transport,diffusion Extracellular DGK1 -4.6 0 4.6 -16.5 0 16.46 3.5779 deoxyguanylate[c] kinase: atp + (dGMP:ATP)dgmpNucleotides <==> adp + dgdp DGK2m 0 4.6 4.6 0 16.33 16.33 3.5507 deoxyguanylate[m] kinase : datp (dGMP:dATP) + dgmpNucleotides <==> (mitochondrial)dadp + dgdp DGNSKm 0 4.6 4.6 0 16.33 16.33 3.5507 deoxyguanosine[m] kinase : atp + dgsnNucleotides --> adp + dgmp + h DGSNt -0.15 0 0.15 -9.45 0 9.45 63 deoyguanosinedgsn[e] transport <==> via dgsn[c]Transport, diffusion Extracellular DGSNtm 0 4.6 4.6 0 16.33 16.33 3.5507 deoyguanosinedgsn[c] transport <==> in dgsn[m] Transport,mitochondria Mitochondrial DGTPtn 0 0.15 0.15 0 9.45 9.45 63 dGTP diffusiondgtp[c] in nucleus <==> dgtp[n]Transport, Nuclear DHCRD1 0 1 1 0 37.31 37.31 37.309 dihydroceramide[c] : desaturasedhcrm_hsSphingolipid + nadp --> crm_hs Metabolism + h + nadph DHFR 0 1.3 1.3 0 27.65 27.65 21.268 dihydrofolate [c]reductase : dhf + h + nadphFolate <==>Metabolism nadp + thf DHPM1 0 1.3 1.3 0 47.17 47.17 36.287 dihydropyrimidinase[c] : 56dura (5,6-dihydrouracil) + Pyrimidineh2o --> cala Catabolism + h DHPM2 0 1.3 1.3 0 27.65 27.65 21.268 dihydropyrimidinase[c] : 56dthm (dihydrothymine) +Pyrimidine h2o --> 3uib Catabolism + h DMGDHm 0 1 1 0 2 2 2 dimethylglycine[m] dehydrogenase, : dmgly + fadGly, + Ser, mitochondrialh2o Thr --> Metabolismfadh2 + fald + sarcs DMGtm 0 1 1 0 2 2 2 dimethylglycinedmgly[c] transport <==> viaTransport, dmgly[m] diffusion Mitochondrial(cytosol to mitochondria) DNDPt12m 0 4.6 4.6 0 16.41 16.41 3.5666 dADP transportadp[m] via ADP + dadp[c] antiportTransport, --> adp[c] Mitochondrial + dadp[m] DNDPt13m 0 4.6 4.6 0 16.41 16.41 3.5666 dADP transportatp[m] via ATP + dadp[c] antiportTransport, --> atp[c] Mitochondrial + dadp[m] DNDPt18m 0 4.6 4.6 0 16.41 16.41 3.5666 dUDP transportadp[m] via ADP + dudp[c] antiportTransport, --> adp[c] Mitochondrial + dudp[m] DNDPt19m 0 4.6 4.6 0 16.41 16.41 3.5666 dUDP transportatp[m] via ATP + dudp[c] antiportTransport, --> atp[c] Mitochondrial + dudp[m] DNDPt1m 0 3.95 3.95 0 10.27 10.27 2.5995 dATP transportadp[m] via ADP + datp[c]antiportTransport, --> adp[c] Mitochondrial + datp[m] DNDPt20m 0 4.6 4.6 0 16.41 16.41 3.5666 dTDP transportatp[m] via ATP + dtdp[c] antiportTransport, --> atp[c] Mitochondrial + dtdp[m] DNDPt21m 0 4.6 4.6 0 16.41 16.41 3.5666 dTDP transportadp[m] via ADP + dtdp[c] antiportTransport, --> adp[c] Mitochondrial + dtdp[m] DNDPt2m 0 3.95 3.95 0 10.27 10.27 2.5995 dATP transportatp[m] via ATP + datp[c] antiportTransport, --> atp[c] Mitochondrial + datp[m] DNDPt30m 0 4.6 4.6 0 16.41 16.41 3.5666 dCDP transportadp[m] via ADP + dcdp[c] antiportTransport, --> adp[c] Mitochondrial + dcdp[m] DNDPt31m 0 4.6 4.6 0 16.41 16.41 3.5666 dCDP transportatp[m] via ATP + dcdp[c] antiportTransport, --> atp[c] Mitochondrial + dcdp[m] DNDPt32m 0 4.6 4.6 0 16.41 16.41 3.5666 dGDP transportatp[m] via ATP + dgdp[c] antiportTransport, --> atp[c] Mitochondrial + dgdp[m] DNDPt3m 0 7.9 7.9 0 20.48 20.48 2.5925 dATP transportdatp[c] via dCDP + dcdp[m] antiportTransport, --> datp[m] Mitochondrial + dcdp[c] DNDPt44m 0 1.3 1.3 0 14.91 14.91 11.472 dTTP transportatp[m] via ATP + dttp[c]antiportTransport, --> atp[c] Mitochondrial + dttp[m] DNDPt45m 0 1.3 1.3 0 14.91 14.91 11.472 dTTP transportadp[m] via ADP + dttp[c]antiportTransport, --> adp[c] Mitochondrial + dttp[m] DNDPt46m 0 1.3 1.3 0 14.91 14.91 11.472 dTTP transportdttp[c] via dUDP + dudp[m] antiportTransport, --> dttp[m] Mitochondrial + dudp[c] DNDPt47m 0 1.3 1.3 0 14.91 14.91 11.472 dTTP transportdtdp[m] via dTDP + dttp[c]antiportTransport, --> dtdp[c] Mitochondrial + dttp[m] DNDPt48m 0 1.3 1.3 0 14.91 14.91 11.472 dTTP transportdgdp[m] via dGDP + dttp[c]antiportTransport, --> dgdp[c] Mitochondrial + dttp[m] DNDPt49m 0 1.3 1.3 0 14.91 14.91 11.472 dTTP transportdadp[m] via dADP + dttp[c]antiportTransport, --> dadp[c] Mitochondrial + dttp[m] DNDPt4m 0 7.9 7.9 0 20.48 20.48 2.5925 dATP transportdatp[c] via dUDP + dudp[m] antiportTransport, --> datp[m] Mitochondrial + dudp[c] DNDPt50m 0 1.3 1.3 0 14.91 14.91 11.472 dTTP transportdcdp[m] via dCDP + dttp[c]antiportTransport, --> dcdp[c] Mitochondrial + dttp[m] DNDPt51m 0 1.3 1.3 0 13.35 13.35 10.269 dCTP transportdcdp[m] via dCDP + dctp[c]antiportTransport, --> dcdp[c] Mitochondrial + dctp[m] DNDPt52m 0 1.3 1.3 0 13.35 13.35 10.269 dCTP transportdctp[c] via dUDP + dudp[m] antiportTransport, --> dctp[m] Mitochondrial + dudp[c] DNDPt53m 0 1.3 1.3 0 13.35 13.35 10.269 dCTP transportdctp[c]