Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines
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 i...
Saved in:
Published in | Journal of Neural Transmission Vol. 116; no. 11; pp. 1355 - 1362 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Vienna
Springer Vienna
01.11.2009
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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 (Ser
19
, Ser
31
, and especially Ser
40
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. |
---|---|
Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Feature-3 ObjectType-Review-1 |
ISSN: | 0300-9564 1435-1463 |
DOI: | 10.1007/s00702-009-0227-8 |