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| Original file line number | Diff line number | Diff line change |
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| % This scripts applies curations to be applied on yeast-GEM release 9.0.1, to | ||
| % get to yeast-GEM release 9.0.2. | ||
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|
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| %% Load yeast-GEM 9.0.1 (requires local yeast-GEM git repository) | ||
| cd .. | ||
| codeDir=pwd(); | ||
| model = getEarlierModelVersion('9.0.1'); | ||
| model.id='yeastGEM_develop'; | ||
| model.version=''; | ||
| %dataDir=fullfile(pwd(),'..','data','modelCuration','v9.0.0'); % No dataDir required for these curations | ||
| cd modelCuration | ||
|
|
||
| %% Issue #371. Implement auxotrophy-based curation, as proposed by Han | ||
| % et al., 2024 doi:10.1016/j.synbio.2024.07.006. Not all changes are | ||
| % implemented as proposed by the authors. | ||
|
|
||
| % To resolve AAT2 causing asparate auxotrophy | ||
| model = setParam(model,'eq','r_0217',0); | ||
| rxnIdx = getIndexes(model,'r_0217','rxns'); | ||
| model.rxnNotes{rxnIdx} = 'No significant mitochondrial flux'; | ||
| model.rxnReferences{rxnIdx} = '10.1016/j.femsyr.2004.09.008'; | ||
|
|
||
| % To resolve ALD2 and ALD3 causing pantothenic acid auxotrophy | ||
| model = changeGrRules(model,'r_0172','YMR170C or YMR169C',true); | ||
| rxnIdx = getIndexes(model,'r_0172','rxns'); | ||
| model.rxnReferences{rxnIdx} = '10.1093/genetics/163.1.69'; | ||
|
|
||
| % To resolve CHO2 causing choline auxotrophy | ||
| CHO2rxns = {'r_2488','r_2489','r_2490','r_2491','r_2492','r_2493','r_2494','r_2495'}; | ||
| model = changeGrRules(model,CHO2rxns,'YGR157W',true); | ||
| rxnIdx = getIndexes(model,CHO2rxns,'rxns'); | ||
| model.rxnReferences(rxnIdx) = {'10.1016/0005-2760(90)90145-N'}; | ||
| % While the curation is correct, CHO2 and OPI3 are not strictly essential | ||
| % genes, choline auxotrophy is only in relation to the production of | ||
| % phosphocholines. If no cholines are available, the phospholipid | ||
| % composition would be different. But because of the fixed biomass | ||
| % composition in yeast-GEM, CHO2 and OPI3 act as essential genes. This | ||
| % causes false positives in the essentialGenes function, as the genes not | ||
| % truly essential. | ||
|
|
||
| % To resolve CYS3 causing cysteine auxotrophy | ||
| model = setParam(model,'eq','r_0312',0); | ||
| rxnIdx = getIndexes(model,'r_0312','rxns'); | ||
| model.rxnNotes{rxnIdx} = 'Regulatory role only'; | ||
| model.rxnReferences{rxnIdx} = '10.1111/j.1574-6968.2003.tb11531.x'; | ||
|
|
||
| % Han et al. suggest to block TUM1 reaction r_4703, to resolve CYS4 as | ||
| % causing cysteine auxotrophy. However, there is good evidence that this | ||
| % reaction is taking place (doi:10.1093/femsyr/fow100). Instead, make the | ||
| % reaction irreversible. | ||
| model = setParam(model,'lb','r_4703',0); | ||
|
|
||
| % To resolve ERG10 causing ergosterol auxotrophy | ||
| model = removeReactions(model,'r_0559',true,true); % ERG13, mitochondrial | ||
| % only, see e.g. https://www.uniprot.org/uniprotkb/P54839/entry | ||
|
|
||
| % To resolve GFA1 causing D-glucosamine auxotrophy: add chitin to | ||
| % carbohydrate pseudoreaction and adjust other reactions proportionally | ||
| rxn = getIndexes(model,'r_4048','rxns'); | ||
| met1 = getIndexes(model,'s_0509','mets');%chitin | ||
| met2 = getIndexes(model,'s_0001','mets');%(1->3)-beta-D-glucan | ||
| met3 = getIndexes(model,'s_0004','mets');%(1->6)-beta-D-glucan | ||
| met4 = getIndexes(model,'s_1107','mets');%mannan | ||
| met5 = getIndexes(model,'s_0773','mets');%glycogen | ||
| met6 = getIndexes(model,'s_1520','mets');%trehalose | ||
| model.S(met1, rxn) = -0.02361; | ||
| model.S(met2, rxn) = -0.73914; | ||
| model.S(met3, rxn) = -0.24696; | ||
| model.S(met4, rxn) = -0.70204; | ||
| model.S(met5, rxn) = -0.35689; | ||
| model.S(met6, rxn) = -0.13655; | ||
| % And change gene association | ||
| model = changeGrRules(model,'r_0477','YKL104C',true); | ||
|
|
||
| % To resolve GSH1 causing glutatione auxotrophy: add glutathione to the | ||
| % cofactor pseudoreaction | ||
| rxn = getIndexes(model,'r_4598','rxns'); | ||
| met = getIndexes(model,'s_0750','mets'); | ||
| model.S(met, rxn) = -1e-06; | ||
| % The above change will make GSH1 and GSH2 essential genes. This will be | ||
| % reported in essentialGenes as false positives, as their essentiality is | ||
| % debated (see for instance doi:10.1016/S1567-1356(02)00081-8). We here | ||
| % argue that absence of glutathione very strongly affects cell growth and | ||
| % stress tolerance. | ||
|
|
||
| % To resolve ERG13/20 causing ergosterol auxotrophy; and HEM1/2/3/4/12 | ||
| % causing heme auxotrophy. Heme transport and exchange should be present to | ||
| % allow uptake if supplemented | ||
| metsToAdd.metNames = 'heme a'; | ||
| metsToAdd.compartments = 'e'; | ||
| model = addMets(model,metsToAdd,true,'s_'); | ||
| model = addTransport(model,'c','e','heme a',true,false,'r_'); | ||
| model = addExchangeRxns(model,'out',model.mets(end)); | ||
| model.rxns(end) = generateNewIds(model,'rxns','r_',1); | ||
| model.rxnNames(end) = {'heme a exchange'}; | ||
| model.subSystems{end} = {'Exchange reaction'}; | ||
|
|
||
| % To resolve MET3 causing methionine auxotrophy | ||
| rxnIdx = getIndexes(model,{'r_0223','r_0224','r_1026'},'rxns'); | ||
| model.eccodes(rxnIdx) = {'2.7.7.53','2.7.7.53','2.7.7.5'}; | ||
| % Han et al. suggest to block APA1 reaction r_1026, but their cited | ||
| % reference (doi:10.1007/BF00264692) contains no reasoning for this. | ||
| % Instead, there is good evidence for the function of this enzyme: | ||
| % (doi:10.1128/jb.171.12.6437-6445.1989), although the reaction is assayed | ||
| % in the reverse direction. So instead, invert the reaction (and keep it | ||
| % irreversible), this has the same effect for MET3 as blocking it. | ||
| model.S(:,rxnIdx(3)) = - model.S(:,rxnIdx(3)); | ||
|
|
||
| % To resolve MET13 causing methionine auxotrophy | ||
| model = changeGrRules(model,'r_0080','(YGL125W and YPL023C) or YGL125W',true); | ||
|
|
||
| % To resolve MET17 causing methionine auxotrophy | ||
| model = setParam(model,'lb','r_0815',0); | ||
|
|
||
| % To resolve THI4 causing thiamine auxotrophy and HOM2 causing methionine | ||
| % and threonine auxotrophy | ||
| model = removeReactions(model,'r_2070',true,true); | ||
| model = removeReactions(model,'r_2071',true,true); | ||
| rxnsToAdd.rxns = generateNewIds(model,'rxns','r_',2); | ||
| rxnsToAdd.equations = {'s_3910 + s_0803 => s_0423 + s_0293 + s_0456 + s_0794', ... | ||
| 's_1003 + s_1198 + s_0841 => s_1216 + s_3910 + 3 s_0803 + s_0794'}; | ||
| rxnsToAdd.rxnNames = {'HET-P synthase (thiazole synthase)','adenylated thiazole synthase'}; | ||
| rxnsToAdd.lb = [0,0]; | ||
| rxnsToAdd.ub = [1000,1000]; | ||
| rxnsToAdd.eccodes = {'','2.4.2.60'}; | ||
| rxnsToAdd.subSystems= {'Thiamine metabolism','Thiamine metabolism'}; | ||
| rxnsToAdd.grRules = {'YGR144W','YGR144W'}; | ||
| rxnsToAdd.rxnMiriams{1} = struct('name',{{'kegg.reaction';'kegg.pathway';'metanetx.reaction'}},... | ||
| 'value',{{'R10685';'sce00730';'MNXR139808'}}); | ||
| rxnsToAdd.rxnMiriams{2} = struct('name',{{'kegg.reaction';'kegg.pathway';'metanetx.reaction'}},... | ||
| 'value',{{'R10711';'sce00730';'MNXR139812'}}); | ||
| rxnsToAdd.rxnReferences = {'10.1021/ja067606t','10.1021/ja067606t'}; | ||
| rxnsToAdd.rxnConfidenceScores = [3,3]; | ||
| model = addRxns(model,rxnsToAdd); | ||
|
|
||
| % To resolve URA2 causing uracil auxotrophy | ||
| model = changeGrRules(model,'r_0250','YJL130C or (YJR109C and YOR303W)',true); | ||
|
|
||
| %% Issue #372. Correct UniProt identifier of YCR024C and YCR024C-A | ||
| geneIdx = getIndexes(model,'YCR024C','genes'); | ||
| model.geneMiriams{geneIdx}.value = {'P25345'}; | ||
|
|
||
| %% DO NOT CHANGE OR REMOVE THE CODE BELOW THIS LINE. | ||
| % Show some metrics: | ||
| cd(fullfile(codeDir,'modelTests')) | ||
| disp('Run gene essentiality analysis') | ||
| [new.accuracy,new.tp,new.tn,new.fn,new.fp] = essentialGenes(model,true); | ||
| fprintf('Genes in model: %d\n',numel(model.genes)); | ||
| fprintf('Gene essentiality accuracy: %.4f\n', new.accuracy); | ||
| fprintf('True non-essential genes: %d\n', numel(new.tp)); | ||
| fprintf('True essential genes: %d\n', numel(new.tn)); | ||
| fprintf('False non-essential genes: %d\n', numel(new.fp)); | ||
| fprintf('False essential genes: %d\n', numel(new.fn)); | ||
| fprintf('\nRun growth analysis\n') | ||
| R2=growth(model,true); | ||
| fprintf('R2 of growth prediction: %.4f\n', R2); | ||
|
|
||
| % Save model: | ||
| cd .. | ||
| saveYeastModel(model) | ||
| cd modelCuration |
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