Premium
Effect of pharmacological chaperones on brain tyrosine hydroxylase and tryptophan hydroxylase 2
Author(s) -
Calvo Ana C.,
Scherer Tanja,
Pey Angel L.,
Ying Ming,
Winge Ingeborg,
McKinney Jeffrey,
Haavik Jan,
Thöny Beat,
Martinez Aurora
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06821.x
Subject(s) - tryptophan hydroxylase , phenylalanine hydroxylase , tph2 , tyrosine hydroxylase , homovanillic acid , chemistry , aromatic amino acids , monoamine neurotransmitter , biochemistry , tryptophan , enzyme , amino acid , tyrosine , serotonin , phenylalanine , pterin , tyrosine 3 monooxygenase , dopamine , tetrahydrobiopterin , cofactor , endocrinology , biology , receptor , serotonergic
J. Neurochem. (2010) 114 , 853–863. Abstract Phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPH1 and TPH2) are structurally and functionally related enzymes that share a number of ligands, such as amino acid substrates, pterin cofactors and inhibitors. We have recently identified four compounds (I‐IV) with pharmacological chaperone effect for PAH and phenylketonuria mutants (Pey et al. (2008) J. Clin. Invest. 118 , 2858–2867). We have now investigated the effect of these compounds on the brain enzymes TH and TPH2, comparative to hepatic PAH. As assayed by differential scanning fluorimetry each of the purified human PAH, TH and TPH2 was differently stabilized by the compounds and only 3‐amino‐2‐benzyl‐7‐nitro‐4‐(2‐quinolyl)‐1,2‐dihydroisoquinolin‐1‐one (compound III) stabilized the three enzymes. We also investigated the effect of compounds II‐IV in wild‐type mice upon oral loading with 5 mg/kg/day. Significant effects were obtained by treatment with compound III – which increased total TH activity in mouse brain extracts by 100% but had no measurable effects either on TPH activity nor on monoamine neurotransmitter metabolites dopamine, dihydroxyphenylacetic acid, homovanillic acid, serotonin and 5‐hydroxyindolacetic acid – and with 5,6‐dimethyl‐3‐(4‐methyl‐2‐pyridinyl)‐2‐thioxo‐2,3‐dihydrothieno[2,3‐d]pyrimidin‐4(1H)‐one (compound IV) – which led to a 10–30% decrease of these metabolites. Our results indicate that pharmacological chaperones aiming the stabilization of one of the aromatic amino acid hydroxylases should be tested on other members of the enzyme family. Moreover, compound III stabilizes in vitro the human TH mutant R202H, associated to autosomal recessive l ‐DOPA‐responsive dystonia, revealing the potential of pharmacological chaperones for the treatment of disorders associated with TH misfolding.