Journal of Inherited Metabolic Disease

, Volume 37, Issue 5, pp 735–743 | Cite as

Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU)

  • Cary O. Harding
  • Shelley R. Winn
  • K. Michael Gibson
  • Erland Arning
  • Teodoro Bottiglieri
  • Markus Grompe
Original Article


Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU.


Tyrosine Hydroxylase Serotonin Synthesis Large Neutral Amino Acid NTBC Nitisinone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Phenylalanine hydroxylase










Large neutral amino acids






L-3,4-dihydroxyphenylacetic acid




Homovanillic acid




5-hydroxyindoleacetic acid



This work was supported in part by NIH Grants R01 DK059371 and R01 NS080866 and a grant from the National PKU Alliance (NPKUA,

We thank Gloria Baca, Baoyu Lin, Lindsey Stetson, and Katie Cobb for able technical assistance and Dr. Melanie Gillingham for critical review of the manuscript.

Conflict of interest

None declared.


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Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Cary O. Harding
    • 1
  • Shelley R. Winn
    • 1
  • K. Michael Gibson
    • 2
  • Erland Arning
    • 3
  • Teodoro Bottiglieri
    • 3
  • Markus Grompe
    • 4
  1. 1.Department of Molecular and Medical GeneticsOregon Health & Science UniversityPortlandUSA
  2. 2.Section of Clinical Pharmacology, College of PharmacyWashington State UniversitySpokaneUSA
  3. 3.Institute of Metabolic DiseaseBaylor Research InstituteDallasUSA
  4. 4.Department of PediatricsOregon Health & Science UniversityPortlandUSA

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