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Titolo:
A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis
Autore:
Martinez, A; Knappskog, PM; Haavik, J;
Indirizzi:
Univ Bergen, Dept Biochem & Mol Biol, N-5009 Bergen, Norway Univ Bergen Bergen Norway N-5009 ochem & Mol Biol, N-5009 Bergen, Norway Univ Bergen, Dept Med Genet, N-5009 Bergen, Norway Univ Bergen Bergen Norway N-5009 , Dept Med Genet, N-5009 Bergen, Norway
Titolo Testata:
CURRENT MEDICINAL CHEMISTRY
fascicolo: 9, volume: 8, anno: 2001,
pagine: 1077 - 1091
SICI:
0929-8673(200107)8:9<1077:ASAIHT>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN PHENYLALANINE-HYDROXYLASE; AMINO-ACID HYDROXYLASES; HUMAN TYROSINE-HYDROXYLASE; CRYSTAL-STRUCTURE; ACTIVE-SITE; BRAIN TRYPTOPHAN; ESCHERICHIA-COLI; RAT-BRAIN; 5-HYDROXYINDOLEACETIC ACID; CEREBROSPINAL-FLUID;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
121
Recensione:
Indirizzi per estratti:
Indirizzo: Martinez, A Univ Bergen, Dept Biochem & Mol Biol, Arstadveien 19, N-5009 Bergen, Norway Univ Bergen Arstadveien 19 Bergen Norway N-5009 ergen, Norway
Citazione:
A. Martinez et al., "A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis", CURR MED CH, 8(9), 2001, pp. 1077-1091

Abstract

Tryptophan hydroxylase (TPH) catalyzes the 5-hydroxylation of tryptophan, which is the first step in the biosynthesis of indoleamines (serotonin and melatonin). Serotonin functions mainly as a neurotransmitter, whereas melatonin is the principal hormone secreted by the pineal gland. TPH belongs to the family of the aromatic amino acid hydroxylases, including phenylalaninehydroxylase (PAH) and tyrosine hydroxylase (TH), which all have a strict requirement for dioxygen, non-heme iron (II) and tetrahydrobiopterin (BH4). During the last three years there has been a formidable increase in the amount of structural information about PAH and TH, which has provided new insights into the active site structure, the binding of substrates, inhibitors and pterins, as well as on the effect of disease-causing mutations in thesehydroxylases. Although structural information about TPH is not yet available, the high sequence homology between the three mammalian hydroxylases, notably at the catalytic domains, and the similarity of the reactions that they catalyze, indicate that they share a similar 3D-structure and a common catalytic mechanism. Thus, we have prepared a model of the structure of TPH based on the crystal structures of TH and PAH. This structural model provides a frame for understanding the specific interactions of TPH with L-tryptophan and substrate analogues, BH4 and cofactor analogues, L-DOPA and catecholamines. The interactions of these ligands with the enzyme are discussed focusing on the physiological and pharmacological regulation of serotonin biosynthesis, notably by tryptophan supplementation therapy and substitution therapy with tetrahydrobiopterin analogues positive effects), as well as the effect of catecholamines on TPH activity in L-DOPA treated Parkinson's disease patients (enzyme inhibition).

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/01/20 alle ore 14:48:39