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The reduced PAH activity increases blood concentration of phenylalanine and urine levels of phenylpyruvate. Flux balance analysis (FBA) of a single\u2010compartment model of PKU predicts that maximum growth rate should be reduced unless Tyr is supplemented. However, the PKU phenotype is lack of development of brain function specifically, and Phe reduction rather than Tyr supplementation cures the disease. Phe and Tyr cross the blood\u2013brain barrier (BBB) through the aromatic amino acid transporter implying that the two transport reactions interact. However, FBA does not accommodate such competitive interactions. We here report on an extension to FBA that enables it to deal with such interactions. We built a three\u2010compartment model, made the common transport across the BBB explicit, and included dopamine and serotonin synthesis as parts of the brain function to be delivered by FBA. With these ramifications, FBA of the genome\u2010scale metabolic model extended to three compartments does explain that (i) the disease is brain specific, (ii) phenylpyruvate in urine is a biomarker, (iii) excess of blood\u2010phenylalanine rather than shortage of blood\u2010tyrosine causes brain pathology, and (iv) Phe deprivation is the better therapy. The new approach also suggests (v) explanations for differences in pathology between individuals with the same PAH inactivation, and (vi) interference of disease and therapy with the functioning of other neurotransmitters.<\/jats:p>","DOI":"10.1002\/jimd.12603","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T05:10:03Z","timestamp":1678165803000},"page":"573-585","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Competitive, multi\u2010objective, and compartmented Flux Balance Analysis for addressing tissue\u2010specific inborn errors of metabolism"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8282-7404","authenticated-orcid":false,"given":"Yanhua","family":"Liu","sequence":"first","affiliation":[{"name":"Swammerdam Institute for Life Sciences, University of Amsterdam  Amsterdam The 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