Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which the tetrahydropterin-requiring enzyme tyrosine hydroxylase (TH) activates dioxygen for substrate hydroxylation was explored. TH contains one ferrous iron per subunit and catalyzes the conversion of its tetrahydropterin cofactor to a 4a-carbinolamine concomitant with substrate hydroxylation. These results are in accord with shared mechanisms of oxygen activation by TH and the more commonly studied tetrahydropterin-dependent enzyme phenylalanine hydroxylase (PAH) and strongly suggest that a peroxytetrahydropterin is the hydroxylating species generated during TH turnover. In addition, TH can also utilize H2O2 as a cofactor for substrate hydroxylation, a result not previously established for PAH. A detailed mechanism for the reaction is proposed. While the overall pattern of tetrahydropterin-dependent oxygen activation by TH and PAH is similar, the H2O2-dependent hydroxylation performed by TH provides an indication that subtle differences in the Fe ligand field exist between the two enzymes. The mechanistic ramifications of these results are briefly discussed.
 ...
PMID:Mechanism of oxygen activation by tyrosine hydroxylase. 288 78

A cDNA clone for rabbit tryptophan hydroxylase was used as a probe to identify human tryptophan hydroxylase gene fragments in a panel of hamster-human somatic cell hybrids and determine its chromosomal location in man. A single locus was identified for tryptophan hydroxylase on chromosome 11. Tryptophan hydroxylase is a member of the superfamily of pterin-dependent aromatic amino acid hydroxylases which includes tyrosine hydroxylase, located at 11p15.5-p15, and phenylalanine hydroxylase, located at 12q22-q24.1 in human. The locations of these genes and the evolutionary distance between their sequences suggest that at least three distinct genetic events have occurred during the evolution of the aromatic amino acid hydroxylase superfamily: two sequential gene duplications giving rise to the three distinct hydroxylase loci, and a translocation which separated the tryptophan and tyrosine hydroxylase loci on chromosome 11 from the phenylalanine hydroxylase locus on chromosome 12.
 ...
PMID:Assignment of human tryptophan hydroxylase locus to chromosome 11: gene duplication and translocation in evolution of aromatic amino acid hydroxylases. 288 73

This report describes the organization of the rat tyrosine hydroxylase (TH) gene and compares its structure with the human phenylalanine hydroxylase gene. Both genes are single copy and contain 13 exons separated by 12 introns. Remarkably, the positions of 10 out of 12 intron/exon boundaries are identical for the two genes. These results support the idea that these hydroxylase genes are members of a gene family which has a common evolutionary origin. We predict that this ancestral gene would have encoded exons similar to those of TH prior to evolutionary drift to other members of this gene family.
 ...
PMID:Organization and evolution of the rat tyrosine hydroxylase gene. 288 68

A monoclonal antibody, PH8, has been isolated and shown by immunocytochemistry to bind to serotonergic and catecholaminergic neurons in sections of the rat and human brain. In human brain, obtained at autopsy, particular fixation and embedding conditions eliminate the labelling of catecholaminergic neurons while leaving intact the labelling of serotonergic neurons. This property makes the antibody of potential use for structural studies of serotonergic neurons in the normal and diseased human brain. PH8 was raised to pure monkey phenylalanine hydroxylase and has been shown to bind to the 50,000 mol. wt. phenylalanine hydroxylase polypeptide. Immunocytochemical and immunochemical evidence is presented in support of the hypothesis that the labelling of serotonergic and catecholaminergic neurons results from the binding of PH8 to tryptophan and tyrosine hydroxylase, respectively.
 ...
PMID:Identification of serotonergic neurons in human brain by a monoclonal antibody binding to all three aromatic amino acid hydroxylases. 289 7

A full-length genomic clone for human tyrosine hydroxylase (L-tyrosine, tetrahydropteridine:oxygen oxidoreductase, EC 1.14.16.2) has been isolated. A human brain genomic library constructed in EMBL3 was screened by using a rat cDNA for tyrosine hydroxylase as a probe [Brown, E. R., Coker, G. T., III, & O'Malley, K. L. (1987) Biochemistry 26, 5208-5212]. Out of one million recombinant phage, one clone was identified that hybridized to both 5' and 3' rat cDNA probes. Restriction endonuclease mapping. Southern blotting, and sequence analysis revealed that, like its rodent counterpart, the human gene is single copy, contains 13 primary exons, and spans approximately 8 kilobases (kb). In contrast to the rat gene, human tyrosine hydroxylase undergoes alternative RNA processing within intron 1, generating at least three distinct mRNAs. A comparison of the human tyrosine hydroxylase and phenylalanine hydroxylase [DiLella, A. G., Kwok, S. C. M., Ledley, F. D., Marvit, J., & Woo, S. L. C. (1986) Biochemistry 25, 743-749] genes indicates that although both probably evolved from a common ancestral gene, major changes in the size of introns have occurred since their divergence.
 ...
PMID:Isolation and characterization of the human tyrosine hydroxylase gene: identification of 5' alternative splice sites responsible for multiple mRNAs. 289 28

A new procedure that permits large-scale purification of tyrosine 3-monooxygenase (tyrosine hydroxylase) (L-tyrosine,tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2) from the cytosolic fraction of bovine adrenal medulla is described. The homogenous enzyme revealed a subunit Mr of 60,000 and a specific activity of 425 nmol.min-1.mg-1. The N-terminal amino-acid sequence (27 residues) revealed 89% homology with the human pheochromocytoma enzyme as deduced from its cDNA sequence. The pure enzyme contained 0.66 +/- 0.09 mol iron, 0.13 mol zinc and 0.62 +/- 0.04 mol phosphate per mol subunit of Mr = 60,000. A broad light absorption band with its maximum around 700 nm (epsilon 700 nm = 1.3 (mM monomer)-1.cm-1) explains its blue-green color. EPR spectra at 3.6 K revealed high-spin Fe(III) (S = 5/2) in an environment of nearly axial symmetry (g values at 7.2-6.7, 4.7-5.3 and 1.9-2.0). A close correlation was observed between the absorbance at 700 nm and the intensity of the axial type of EPR spectrum. The absorption peak at 700 nm is compatible with a ligand-to-iron charge-transfer transition as a result of catecholate coordination to the iron. Physicochemical studies suggest that the enzyme does not undergo such major substrate- or cofactor-induced conformational changes as have been reported for the related enzyme, phenylalanine hydroxylase.
 ...
PMID:Soluble tyrosine hydroxylase (tyrosine 3-monooxygenase) from bovine adrenal medulla: large-scale purification and physicochemical properties. 289 60

Mild trypsin proteolysis of tyrosine hydroxylase (TH) produces a 34 kDa fragment which is catalytically active. To determine the structure of the trypsin-digested tyrosine hydroxylase (tTH) relative to the native enzyme and to regulatory phosphorylation sites, bovine adrenal tTH was purified to homogeneity and the sequence of 17 amino acids from the N-terminus was determined. These data indicate that the N-terminus of tTH corresponds to amino acid 158. Thus the catalytic region is contained within the central region of enzyme approximately 17 kDa from the N-terminal and 5 kDa from the C-terminal and does not include phosphorylation sites located in the N-terminus. This region of TH shares a high degree of homology with phenylalanine hydroxylase and tryptophan hydroxylase and thus reflects a selective conservation of regions required for catalysis in contrast to the non-homologous regulatory sites. Activation by proteolysis corresponds to an increase in affinity for both substrate and cofactor indicating that the region removed by proteolysis imposes additional constraints on substrate and cofactor binding. These data are consistent with the model that the catalytic core of TH is contained within a 34 kDa region in the highly conserved central portion of the molecule whereas the non-homologous N-terminus regulates cofactor binding and directs substrate specificity.
 ...
PMID:Characterization of the catalytic domain of bovine adrenal tyrosine hydroxylase. 289 48

We have employed immunohistochemical and morphometric procedures to study the distribution of monoamine-synthesizing neurons in the medulla oblongata of the adult human, utilizing antibodies to tyrosine hydroxylase (TH), phenylethanolamine N-methyltransferase (PNMT), and phenylalanine hydroxylase (PH8). In the human brain, the antigen with which PH8 reacts occurs within neurons that presumably synthesize serotonin (Haan et al., '87). Neurons containing these antigens were mapped and counted in successive coronal sections with the aid of a computer-assisted procedure. The results indicate that monoamine-synthesizing neurons are distributed in the human brain in patterns broadly similar to those described for other species. TH-immunoreactive cells extended caudorostrally for approximately 32 mm commencing at the spinomedullary junction and ending 8 mm caudal to the pontomedullary junction. In coronal sections these TH-immunoreactive neurons were seen in the lateral medulla dorsal to the inferior olive extending in a continuous band to the dorsomedial medulla. Above the obex the majority of these cells apparently synthesize adrenaline since many PNMT-immunoreactive cells were also found in this region. There were few or no PNMT-immunoreactive cells caudal to the obex, indicating that the TH-immunoreactive cells in this region synthesize either noradrenaline or dopamine. Approximately 65% of these TH-immunoreactive neurons contained melanin pigment, whereas few or no PNMT-immunoreactive cells contained melanin pigment. PH8-immunoreactive cells extended throughout the rostrocaudal extent of the medulla oblongata (approximately 40 mm). In coronal sections the majority were found in the medullary raphe nuclei. However, many cells throughout the rostrocaudal extent of the medulla were found laterally intermingled with catecholamine-synthesizing neurons. Occasional neurons in the lateral medulla appeared to contain both PH8- and TH-immunoreactivity.
 ...
PMID:Distribution of monoamine-synthesizing neurons in the human medulla oblongata. 290 64

Mouse phenylalanine hydroxylase has been localized on chromosome 10C2----D1 by in situ hybridization using a mouse phenylalanine hydroxylase cDNA clone. This locus is distinct from the hyperphenylalaninemia locus on chromosome 14 and the locus for tyrosine hydroxylase on chromosome 7.
 ...
PMID:Localization of mouse phenylalanine hydroxylase locus on chromosome 10. 337 51

A full-length cDNA for tryptophan hydroxylase was cloned from rabbit pineal body by screening an expression library with antibody against rat phenylalanine hydroxylase, which crossreacts with rabbit tryptophan hydroxylase. Clones producing immunoreactive material contain sequences homologous to, yet distinct from, phenylalanine hydroxylase. The rabbit cDNA hybridizes to mRNA in pineal body and brainstem but not in liver. Comparison of the rabbit tryptophan hydroxylase sequence with the sequences of phenylalanine hydroxylase and tyrosine hydroxylase demonstrates that these three biopterin-dependent aromatic amino acid hydroxylases are highly homologous, reflecting a common evolutionary origin from a single primordial genetic locus. The pattern of sequence homology supports the hypothesis that the carboxyl-terminal two-thirds of the molecules constitute the enzymatic activity cores, and the amino-terminal thirds of the molecules constitute domains for substrate specificity.
 ...
PMID:Full-length cDNA for rabbit tryptophan hydroxylase: functional domains and evolution of aromatic amino acid hydroxylases. 347 90


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>