A Multiplatform Metabolomics Approach to Characterize Plasma Levels of Phenylalanine and Tyrosine in Phenylketonuria.
BACKGROUND
Different pathophysiological mechanisms have been described in phenylketonuria (PKU) but the indirect metabolic consequences of metabolic disorders caused by elevated Phe or low Tyr concentrations remain partially unknown. We used a multiplatform metabolomics approach to evaluate the metabolic signature associated with Phe and Tyr.


METHODS
We prospectively included 10 PKU adult patients and matched controls. We analysed the metabolome profile using GC-MS (urine), amino-acid analyzer (urine and plasma) and nuclear magnetic resonance spectroscopy (urine). We performed a multivariate analysis from the metabolome (after exclusion of Phe, Tyr and directly derived metabolites) to explain plasma Phe and Tyr concentrations, and the clinical status. Finally, we performed a univariate analysis of the most discriminant metabolites and we identified the associated metabolic pathways.


RESULTS
We obtained a metabolic pattern from 118 metabolites and we built excellent multivariate models to explain Phe, Tyr concentrations and PKU diagnosis. Common metabolites of these models were identified: Gln, Arg, succinate and alpha aminobutyric acid. Univariate analysis showed an inverse correlation between Arg, alpha aminobutyric acid and Phe and a positive correlation between Arg, succinate, Gln and Tyr (p < 0.0003). Thus, we highlighted the following pathways: Arg and Pro, Ala, Asp and Glu metabolism.


CONCLUSIONS
We obtain a specific metabolic signature related to Tyr and Phe concentrations. We confirmed the involvement of different pathophysiological mechanisms previously described in PKU such as protein synthesis, energetic metabolism and oxidative stress. The metabolomics approach is relevant to explore PKU pathogenesis.
Laboratoire de biochimie et biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours cedex 1, France. helene.blasco@univ-tours.fr.|INSERM U930, Université François Rabelais Tours, Tours cedex 1, France. helene.blasco@univ-tours.fr.
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Blasco
Laboratoire de biochimie et biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours cedex 1, France.|INSERM U930, Université François Rabelais Tours, Tours cedex 1, France.
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Veyrat-Durebex
Centre de Biophysique Moléculaire, CNRS UPR4301, Orléans, France.
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Bertrand
Laboratoire de biochimie et biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours cedex 1, France.|INSERM U930, Université François Rabelais Tours, Tours cedex 1, France.
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Patin
Service de Pédiatrie, CHRU de Tours, Tours cedex 1, France.|INSERM U1069, Université François Rabelais Tours, Tours cedex 1, France.
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Labarthe
Service de médecine interne, CHRU de Tours, Tours cedex 1, France.
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Henique
INSERM U930, Université François Rabelais Tours, Tours cedex 1, France.
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Emond
Laboratoire de biochimie et biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours cedex 1, France.|INSERM U930, Université François Rabelais Tours, Tours cedex 1, France.
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Andres
Laboratoire de biochimie et biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours cedex 1, France.|INSERM U930, Université François Rabelais Tours, Tours cedex 1, France.
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Antar
Centre de Biophysique Moléculaire, CNRS UPR4301, Orléans, France.
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Landon
INSERM U930, Université François Rabelais Tours, Tours cedex 1, France.
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Nadal-Desbarats
INSERM U1069, Université François Rabelais Tours, Tours cedex 1, France.|Service de médecine interne, CHRU de Tours, Tours cedex 1, France.
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Maillot
Biomarkers; Metabolomics; NMR; Phenylketonuria