The inborn error of metabolism phenylketonuria (PKU, OMIM 261600) is most often due to inactivation of phenylalanine hydroxylase (PAH), which converts phenylalanine (Phe) into tyrosine (Tyr). The reduced PAH activity increases blood concentration of phenylalanine and urine levels of phenylpyruvate. Flux balance analysis (FBA) of a single‐compartment 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–brain 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‐compartment 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‐scale 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‐phenylalanine rather than shortage of blood‐tyrosine 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.
In multicellular organisms, different cell types compete for resources or growth factors, endangering cellular diversity as well as co-existence. To address this, we developed ‘dynamic cell-cell competition FBA’ (dcFBA). With total biomass synthesis as objective, we found that lower-growth-yield cell types face extinction even when they synthesized mutually required metabolic commodities. Signal transduction between cells promoted co-existence, when turning the cells into mutually regulatory and responsive ‘social cells’. Mutants with specific growth rate but intact signal transduction did not outgrow others. However, loss of its social characteristics enabled a mutant to dominate the other cell types with higher specific growth rates and bring those to extinction. A corollary is that cancer arises from reduced sensitivity to regulatory factors rather than enhanced specific growth rates. Therapies reinforcing cells’ cross-regulation, perhaps through alternative signaling routes, may therefore be more effective than those targeting replication rates.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.