Competitive, multi‐objective, and compartmented Flux Balance Analysis for addressing tissue‐specific inborn errors of metabolism

Abstract

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.

‘Social’ versus ‘asocial’ cells—dynamic competition flux balance analysis

“…Another example may reside in the competition between astrocytes and neurons for amino acid uptake during brain development. In a previous paper 37 , we developed another mode of competitive FBA to demonstrate implications of the amino acid competition for uptake across the blood-brain barrier. One may now fruitfully combine the two new types of FBA and include neurotransmitter cross-talk and metabolism.…”

“…However, one could try various objective functions (as Supplementary Figs. 27, 28) and utilize a more suitable and precise objective function for the specific FBA calculation as our previous paper did, for a different circumstance 37 . In multicellular organisms the specific growth rate of the various cell types is known to be controlled tightly.…”

Gear Shifting in Biological Energy Transduction

“…Second, few kinetic models are explicit on the thermodynamic implications they have and are subject to [37,38]. Third, although flux balance analysis models do accommodate the participation of hundreds of enzymes, they lack thermodynamics [39,40]. Consequently, we had to restrict our analysis to the existing linear non-equilibrium approaches.…”

‘Social’ versus ‘Asocial’ cells--- Dynamic Competition Flux Balance Analysis

“…for amino acids uptake during brain development. In a previous paper 39 , we developed another mode of competitive FBA to demonstrate implications of the amino acid competition for uptake across the blood-brain barrier. One may now fruitfully combine the two new types of FBA and include neurotransmitter cross-talk and metabolism.…”