Definition
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine and norepinephrine. It may be involved in the pathophysiology of psychiatric disorders and positive associations have been reported for TH gene markers in mood disorders 1.
Related Peptides
The enzymes phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase constitute the family of pterin-dependent aromatic amino acid hydroxylases. Each enzyme catalyzes the hydroxylation of the aromatic side chain of its respective amino acid substrate using molecular oxygen and a tetrahydropterin as substrates 2.
Discovery
In 1965, Ikeda and co-workers reported that crude preparations of rat striatal or adrenal tyrosine hydroxylase catalyzed the hydroxylation of small amounts of phenylalanine. These authors further demonstrated that the reaction was not mediated by a liver type of phenylalanine hydroxylase but was catalyzed by a tyrosine hydroxylase which converted phenylalanine to DOPA 3.
Structural Characteristics
TH is highly homologous in terms of both protein sequence and catalytic mechanism to phenylalanine hydroxylase (PheOH) and tryptophan hydroxylase (TrpOH). The crystal structure of the catalytic and tetramerization domains of TH reveals a novel a-helical basket holding the catalytic iron and a 40 Å long anti-parallel coiled coil which forms the core of the tetramer. The catalytic iron is located 10 Å below the enzyme surface in a 17 Å deep active site pocket and is coordinated by the conserved residues His 331, His 336 and Glu 376. The structure provides a rationale for the effect of point mutations in TH that cause L-DOPA responsive parkinsonism and Segawa's syndrome. The location of 112 different point mutations in PheOH that lead to phenylketonuria (PKU) are predicted based on the TH structure 4.
Mode of Action
TH is a non-heme iron enzyme which uses molecular oxygen to hydroxylate tyrosine to form L-dihydroxyphenylalanine (L-DOPA), and tetrahydrobiopterin to form 4a-hydroxybiopterin, in the rate-limiting step of the catecholamine biosynthetic pathway 5.
Functions
TH is an important brain enzyme because it catalyzes the conversion of l-tyrosine to 3, 4-dihydroxy-l-phenylalanine, which is the first and rate-limiting step of catecholamine biosynthesis. TH is selectively expressed in catecholamine-synthesizing and secreting cells, including dopaminergic, noradrenergic, and adrenergic neurons in the central nervous system and sympathetic ganglia and adrenal chromaffin cells in the periphery 6. Profound TH deficiency, as occurs after unusual inactivating mutations (Leu205Pro or Gln381Lys) in homozygous individuals, results in widespread disturbance of neuropsychiatric function such as autosomal-recessive, L-dihydroxyphenylalanine–responsive dystonia. Complete homozygous ablation of the TH locus by homologous recombination-directed gene targeting in transgenic mice is lethal by the early postnatal period 7.
References
1. Serretti A, Macciardi F, Verga M, Cusin C, Pedrini S, Smeraldi E. 1998. Tyrosine hydroxylase gene associated with depressive symptomatology in mood disorder. Am J Med Genet., 81(2):127-130.
2. Fitzpatrick PF (2000). The aromatic amino acid hydroxylases. Adv Enzymol Relat Areas Mol Biol., 74:235-294.
3. Ribeiro P, Pigeong D, Kaufman S (1991). The hydroxylation of phenylalanine and tyrosine by tyrosine hydroxylase from cultured pheochromocytoma cells. The Journal of Biological Chemistry, 266(24):16207-16211.
4. Goodwill KE, Sabatier C, Marks C, Raag R, Fitzpatrick PF, Stevens RC (1997). Crystal structure of tyrosine hydroxylase at 2.3 Å and its implications for inherited neurodegenerative diseases. Nature Structural Biology, 4:578-585.
5. Goodwill KE, Sabatier C, Stevens RC (1998). Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site. Biochemistry, 37(39):13437-13445.
6. Tinti C, Yang C, Seo H, Conti B, Kim C, Joh TH, Kim KS (1997). Structure/Function Relationship of the cAMP Response Element in Tyrosine Hydroxylase Gene Transcription. The Journal of Biological Chemistry, 272:19158-19164.
7. Rao F, Zhang L,Wessel J,Zhang K,Wen G, Kennedy BP,. Rana BK, Das M, Rodriguez-Flores L, Smith DW, Cadman PE, Salem RM, Mahata SK, Schork; Laurent NJ, Ziegler MG, O’Connor DT (2007). Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis. Discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo. Circulation, 116:993-1006.