%%% SETUP %%%

% init cobra toolbox and set solver
currDir = pwd;

% NOTE: change the relative path to the location of cobratoolbox on your machine!
cd('cobratoolbox')
initCobraToolbox
cd(currDir);
changeCobraSolver ('gurobi', 'all');

% load yeastGEM 7.6 model
disp('loading model(s)...')

% NOTE: change the relative path to the location of the yeast model on your machine!
model = readCbModel('sbml\yeast_7.6_cobra.xml');
model = buildRxnGeneMat(model);
disp('done')

%%% Set constraints: knock out genes and define medium %%%

% SEY6210: leu2 ura3 his3 trp1 suc2 lys2
model = deleteModelGenes(model,'YCL018W');
model = deleteModelGenes(model,'YEL021W');
model = deleteModelGenes(model,'YOR202W');
model = deleteModelGenes(model,'YDR007W');
model = deleteModelGenes(model,'YIL162W');
model = deleteModelGenes(model,'YBR115C');

% SDC medium
model = changeRxnBounds(model,'r_1639',-1,'l');  % Adenine
model = changeRxnBounds(model,'r_1899',-1,'l');  % Leu
model = changeRxnBounds(model,'r_1873',-1,'l');  % Ala
model = changeRxnBounds(model,'r_1880',-1,'l');  % Asp
model = changeRxnBounds(model,'r_1889',-1,'l');  % Glu
model = changeRxnBounds(model,'r_1893',-1,'l');  % His
model = changeRxnBounds(model,'r_1897',-1,'l');  % Ile
model = changeRxnBounds(model,'r_1900',-1,'l');  % Lys
model = changeRxnBounds(model,'r_1902',-1,'l');  % Met
model = changeRxnBounds(model,'r_1903',-1,'l');  % Phe
model = changeRxnBounds(model,'r_1911',-1,'l');  % Thr
model = changeRxnBounds(model,'r_1912',-1,'l');  % Trp
model = changeRxnBounds(model,'r_2090',-1,'l');  % Uracil
model = changeRxnBounds(model,'r_1913',-1,'l');  % Tyr
model = changeRxnBounds(model,'r_1914',-1,'l');  % Val
model = changeRxnBounds(model,'r_1906',-1,'l');  % Ser


%%% FVA serine reactions %%%

% find reactions connected to serine (cytoplasmic, ER, extracellular,
% mitochondrial, and ER membrane)
serRxns = findRxnsFromMets(model,...
    {'s_1039[c_03]','s_1040[c_04]','s_1041[c_06]','s_1042[c_11]','s_3107[c_05]'});

% exclude intracellular transport reactions
serRxns([19,21:24]) = [];

% run FVA
[vMin, vMax, optSol, ret, fbaSol, fvaMin, fvaMax, statusSolMin, ...
    statusSolMax] = fastFVA(model, 99, 'max', 'ibm_cplex', serRxns);

% reaction names of the reactions as they will be displayed in the plot
rxnNames = {
    'cystathionine beta-synthase', ...
    'glycine hydroxymethyltransferase 2', ...
    'glycine hydroxymethyltransferase 1', ...
    'L-serine deaminase', ...
    'L-serine dehydrogenase', ...
    'phosphoserine phosphatase', ...
    'serine O-acetyltransferase', ...
    'serine palmitotransferase', ...
    'seryl-tRNA synthetase', ...
    'tryptophan synthase', ...
    'PS synthase', ...
    'L-serine exchange'
    };


% combine all PS synthase reactions
psFluxMin = min(sum(fvaMin(findRxnIDs(model,serRxns(11:18)),:)));
psFluxMax = max(sum(fvaMax(findRxnIDs(model,serRxns(11:18)),:)));

vMin = [vMin(1:10); psFluxMin; vMin(19)];
vMax = [vMax(1:10); psFluxMax; vMax(19)];

% change flux direction so that positive values always mean serine
% production
coefs = [-1,-1,-1,-1,-1,1,-1,-1,-1,-1,-1,-1]';

vMin = vMin .* coefs;
vMax = vMax .* coefs;

% plot flux variability of serine reactions
figure
p = errorbar(1:12, mean([vMin';vMax']), vMin' - mean([vMin';vMax']), vMax' - mean([vMin';vMax']));
p.LineStyle = 'none';
p.LineWidth = 2;
set(p,'Color','black')
yline(0)
xlim([0,13])
xticks(1:12)
xticklabels(rxnNames)
set(gca, 'XTickLabelRotation', -90)
ylabel('fluxes [mmol/(gDW*h)]')



%%% FVA serine synthesis and uptake %%%

% vary serine uptake rates
uptakeRates = 0:-0.1:-1;

% prepare vectors for min and max values of fluxes
fluxMin = zeros(size(uptakeRates));
fluxMax = zeros(size(uptakeRates));

% control variable
index = 1;

% perform FVA for each uptake rate
for uptakeRate = uptakeRates 
    
    % set serine uptake rate
    tmpModel = changeRxnBounds(model,'r_1906',uptakeRate, 'l');
    
    % run FVA
    [tmpVMin, tmpVMax, tmpOptSol, tmpRet, tmpFbaSol, tmpFvaMin, tmpFvaMax]...
        = fastFVA(tmpModel, 99, 'max', 'ibm_cplex', [serRxns(2:3);serRxns(6)]');
    
    % extract min and max fluxes from reactions of SHM1, SHM2 and SER2
    tmpFvaMin = tmpFvaMin(findRxnIDs(tmpModel,[serRxns(2:3);serRxns(6)]'),:);
    tmpFvaMax = tmpFvaMax(findRxnIDs(tmpModel,[serRxns(2:3);serRxns(6)]'),:);
    
    % change flux direction so that positive values always mean serine
    % production
    coefs = [-1,-1,1]';
    
    tmpFvaMin = tmpFvaMin .* coefs;
    tmpFvaMax = tmpFvaMax .* coefs;
    
    % combine reactions to one net reaction
    fluxMin(index) = min(sum(tmpFvaMin));
    fluxMax(index) = max(sum(tmpFvaMax));
    
    index = index + 1;
    
end

% plot flux variability of SHM1, SHM2 and SER2 combined
figure
p = errorbar(-uptakeRates, mean([fluxMin;fluxMax]), fluxMin - mean([fluxMin;fluxMax]), fluxMax - mean([fluxMin;fluxMax]));
p.LineStyle = 'none';
p.LineWidth = 2;
set(p,'Color','black')
yline(0)
xlim([-0.1,1.1])
xticks(-uptakeRates)
ylabel('fluxes [mmol/(gDW*h)]')
xlabel('serine uptake rate [mmol/(gDW*h)]')


%%% SPT ACTIVITY %%%

% vary serine uptake rates
uptakeRates = 0:-0.1:-1;

% prepare vectors for min and max values of fluxes
fluxMin = zeros(size(uptakeRates));
fluxMax = zeros(size(uptakeRates));

% control variable
index = 1;

% perform FVA for each uptake rate
for uptakeRate = uptakeRates 
    
    % set serine uptake rate
    tmpModel = changeRxnBounds(model,'r_1906',uptakeRate, 'l');
    
    % run FVA
    [tmpVMin, tmpVMax, tmpOptSol, tmpRet, tmpFbaSol, tmpFvaMin, tmpFvaMax]...
        = fastFVA(tmpModel, 99, 'max', 'ibm_cplex', serRxns(8));
    
    % save min and max fluxes
    fluxMin(index) = tmpVMin;
    fluxMax(index) = tmpVMax;
    
    index = index + 1;
    
end

% plot flux variability of SPT
figure
p = errorbar(-uptakeRates, mean([fluxMin;fluxMax]), fluxMin - mean([fluxMin;fluxMax]), fluxMax - mean([fluxMin;fluxMax]));
p.LineStyle = 'none';
p.LineWidth = 2;
set(p,'Color','black')
ylim([0,0.0003])
xlim([-0.1,1.1])
xticks(-uptakeRates)
ylabel('fluxes [mmol/(gDW*h)]')
xlabel('serine uptake rate [mmol/(gDW*h)]')