Journal of Neural Transmission

, Volume 116, Issue 11, pp 1355–1362 | Cite as

Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines

  • A. Nakashima
  • N. Hayashi
  • Y. S. Kaneko
  • K. Mori
  • E. L. Sabban
  • Toshiharu Nagatsu
  • A. Ota
Basic Neurosciences, Genetics and Immunology - Review Article

Abstract

Tyrosine hydroxylase (TH) catalyzes the conversion of l-tyrosine to l-dopa, which is the initial and rate-limiting step in the biosynthesis of catecholamines [CA; dopamine (DA), noradrenaline, and adrenaline], and plays a central role in the neurotransmission and hormonal actions of CA. Thus, TH is related to various neuro-psychiatric diseases such as TH deficiency, Parkinson’s disease (PD), and schizophrenia. Four isoforms of human TH (hTH1–hTH4) are produced from a single gene by alternative mRNA splicing in the N-terminal region, whereas two isoforms exist in monkeys and only a single protein exist in all non-primate mammals. A catalytic domain is located within the C-terminal two-thirds of molecule, whereas the part of the enzyme controlling enzyme activity is assigned to the N-terminal end as the regulatory domain. The catalytic activity of TH is end product inhibited by CA, and the phosphorylation of Ser residues (Ser19, Ser31, and especially Ser40 of hTH1) in the N-terminus relieves the CA-mediated inhibition. Ota and Nakashima et al. have investigated the role of the N-terminus of TH enzyme in the regulation of both the catalytic activity and the intracellular stability by producing various mutants of the N-terminus of hTH1. The expression of the following three enzymes, TH, GTP cyclohydrolase I, which synthesizes the tetrahydrobiopterin cofactor of TH, and aromatic-l-amino acid decarboxylase, which produces DA from l-dopa, were induced in the monkey striatum using harmless adeno-associated virus vectors, resulting in a remarkable improvement in the symptoms affecting PD model monkeys Muramatsu (Hum Gene Ther 13:345–354, 2002). Increased knowledge concerning the amino acid sequences of the N-terminus of TH that control enzyme activity and stability will extend the spectrum of the gene-therapy approach for PD.

Keywords

Gene therapy Mutants N-terminus Parkinson’s disease Schizophrenia Tyrosine hydroxylase 

Abbreviations

AADC

Aromatic l-amino acid decarbxylase

BH4

(6R)-l-erythro-5,6,7,8-tetrahydrobiopterin

DA

Dopamine

hTH1–hTH4

Human tyrosine hydroxylase types 1–4

PD

Parkinson’s disease

TH

Tyrosine hydroxylase

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • A. Nakashima
    • 1
  • N. Hayashi
    • 3
  • Y. S. Kaneko
    • 1
  • K. Mori
    • 1
  • E. L. Sabban
    • 4
  • Toshiharu Nagatsu
    • 2
  • A. Ota
    • 1
  1. 1.Department of Physiology, School of MedicineFujita Health UniversityToyoakeJapan
  2. 2.Department of Pharmacology, School of MedicineFujita Health UniversityToyoakeJapan
  3. 3.Institute for Comprehensive Medical ScienceFujita Health UniversityToyoakeJapan
  4. 4.Department of Biochemistry and Molecular BiologyNew York Medical CollegeValharaUSA

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