Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of dopamine. Recently, we described a point mutation in hTH (Q381K) in a family of two siblings suffering from progressive L-DOPA-responsive dystonia (DRD), representing the first reported mutation in this gene. We here describe the cloning, expression and steady-state kinetic properties of the recombinant mutant enzyme. When expressed by a coupled in vitro transcription-translation system and in E. coli, the mutant enzyme represents a kinetic variant form, with a reduced affinity for L-tyrosine. The 'residual activity' of about 15% of the corresponding wild-type hTH (isoform hTH1), at substrate concentrations prevailing in vivo, is compatible with the clinical phenotype of the two Q381K homozygote patients carrying this recessively inherited mutation.
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PMID:Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. 852 10

TH is a tetrahydrobiopterin-requiring, iron-containing monooxygenase. It catalyses the conversion of L-tyrosine to L-dopa, which is the first, rate-limiting step in the biosynthesis of catecholamines (dopamine, noradrenaline and adrenaline), the central and sympathetic neurotransmitters and adrenomedullary hormones. The cofactor of TH is tetrahydrobiopterin, which is synthesized from GTP in three steps. The TH gene consists of 14 exons only in humans and 13 exons in animals. Human TH exists in four isoforms (hTH1-4) that are produced by alternative mRNA splicing from a single gene. A single mRNA and protein corresponding to hTH1 exists in non-primates. Monkey TH exists in two isoforms, corresponding to hTH1 and hTH2. TH activity is regulated in the short term by feedback inhibition of catecholamines in competition with tetrahydrobiopterin, and by activation and deactivation due to phosphorylation and dephosphorylation, mainly at Ser-19 and Ser-40 of hTH1. The multiple TH isoforms in humans and monkeys have additional phosphorylation, resulting in more subtle regulation. In long-term regulation under stress conditions, TH protein is induced. CRE and AP1 in the 5' flanking region of the TH gene may be the main functional elements for TH gene expression. TH may be closely related to the pathogenesis of neurological diseases, such as dystonia and Parkinson's disease, psychiatric diseases, such as affective disorders and schizophrenia, as well as cardiovascular diseases. The TH gene may prove useful in gene therapy to compensate for decreased levels of catecholamines in neurological diseases, for example, for supplementation of dopamine in Parkinson's disease.
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PMID:Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology. 882 46

Neurodegenerative diseases that afflict nervous system are characterized by progressive nervous system dysfunction and associated with the one-set of many diseases like Segawa's syndrome (recessive form), autosomal recessive L-dopa-responsive dystonia, L-dopa non-responsive dystonia or progressive early-onset encephalopathy and recessive L-dopa-responsive parkinsonism. It has been reported that a number of mutations in coding regions, splice sites and promoter regions of tyrosine hydroxylase (TH) are associated with many such diseases. TH is responsible for catalyzing the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine. This reaction is considered as rate-limiting step in the biosynthesis of catecholamines, dopamine, norepinephrine and epinephrine, which has made TH an important target for drug development. In our previous study using comparative molecular docking approach, it was concluded that [4-(Propan-2-yl) Phenyl]Carbamic acid (PPCA) may serve as a potential inhibitor. By further extending, our focus is to determine the binding affinities of PPCA and mutated TH. 3D structures of mutated TH were predicted and subjected to molecular docking studies. PPCA was found to bind in the deep narrow groove lined with polar and aromatic amino acids in 14 out of 17 mutants under study (R202H, L205P, H215Y, G216S, T245P, F278P, T283M, R297W, R306H, C328F, A345V, L356M, T368M, Q381K, P461L, T463M and D467G). Our results corroborate efficient binding of PPCA with normal and mutated TH, indicating that PPCA might be a strong therapeutic candidate for the management of Parkinson's disease and other related disorders. It may be a valuable target for evaluation in preclinical models.
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PMID:Computational study of human tyrosine hydroxylase mutants to uphold [4-(Propan-2-yl) Phenyl]Carbamic acid as a potential inhibitor. 2523 Feb 30

Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH-p.R233H), often unresponsive to l-DOPA treatment. The Th knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated with a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard l-DOPA treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum.
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PMID:Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency. 2627 13

Parkinson's disease (PD) is an aging-related movement disorder mainly caused by a deficiency of neurotransmitter dopamine (DA) in the striatum of the brain and is considered to be due to progressive degeneration of nigro-striatal DA neurons. Most PD is sporadic without family history (sPD), and there are only a few percent of cases of young-onset familial PD (fPD, PARKs) with the chromosomal locations and the genes identified. Tyrosine hydroxylase (TH), tetrahydrobiopterin (BH4)-dependent and iron-containing monooxygenase, catalyzes the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the initial and rate-limiting step in the biosynthesis of catecholamines (DA, noradrenaline, and adrenaline). PD affects specifically TH-containing catecholamine neurons. The most marked neurodegeneration in patients with DA deficiency is observed in the nigro-striatal DA neurons, which contain abundant TH. Accordingly, TH has been speculated to play some important roles in the pathophysiology in PD. However, this decrease in TH is thought to be secondary due to neurodegeneration of DA neurons caused by some as yet unidentified genetic and environmental factors, and thus, TH deficiency may not play a direct role in PD. This manuscript provides an overview of the role of human TH in the pathophysiology of PD, covering the following aspects: (1) structures of the gene and protein of human TH in relation to PD; (2) similarity and dissimilarity between the phenotypes of aging-related sPD and those of young-onset fPD or DOPA-responsive dystonia due to DA deficiency in the striatum with decreased TH activity caused by mutations in either the TH gene or GTP cyclohydrolase I (GCH1) gene; and (3) genetic variants of the TH gene (polymorphisms, rare variants, and mutations) in PD, as discovered recently by advanced genome analysis.
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PMID:Human tyrosine hydroxylase in Parkinson's disease and in related disorders. 2999 72