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 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.
Nakashima
A
A
Department of Physiology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
Hayashi
N
N
Kaneko
Y S
YS
Mori
K
K
Sabban
E L
EL
Nagatsu
Toshiharu
T
Ota
A
A
D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002395:Catecholamines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D025461:Feedback, Physiological / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D017434:Protein Structure, Tertiary / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D002395:Catecholamines; D014446:Tyrosine 3-Monooxygenase