Tyrosine hydroxylase

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Tyrosine hydroxylase
Tyrosine hydroxylase showing all four subunits.png
Tyrosine hydroxylase showing its four subunits.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TH ; DYT14; DYT5b; TYH
External IDs OMIM191290 MGI98735 HomoloGene307 ChEMBL: 1969 GeneCards: TH Gene
EC number 1.14.16.2
RNA expression pattern
PBB GE TH 208291 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7054 21823
Ensembl ENSG00000180176 ENSMUSG00000000214
UniProt P07101 P24529
RefSeq (mRNA) NM_000360 NM_009377
RefSeq (protein) NP_000351 NP_033403
Location (UCSC) Chr 11:
2.19 – 2.19 Mb
Chr 7:
142.89 – 142.93 Mb
PubMed search [1] [2]

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA).[1][2] It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene,[2] and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla.[2] Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

Reaction[edit]

tyrosine 3-monooxygenase
Tyrosine to L-DOPA reaction TH.svg
Tyrosine hydroxylase catalyzes conversion of tyrosine to L-DOPA using Fe2+, O2 and BH4
Identifiers
EC number 1.14.16.2
CAS number 9036-22-0
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Tyrosine hydroxylase catalyzes the reaction in which L-tyrosine is hydroxylated in the meta position to obtain L-3,4-dihydroxyphenylalanine (L-DOPA). The enzyme is an oxygenase which means it uses molecular oxygen to hydroxylate its substrates. One of the oxygen atoms in O2 is used to hydroxylate the tyrosine molecule to obtain L-DOPA and the other one is used to hydroxylate the cofactor. Like the other aromatic amino acid hydroxylases (AAAHs), tyrosine hydroxylase use the cofactor tetrahydrobiopterin (BH4) under normal conditions, although other similar molecules may also work as a cofactor for tyrosine hydroxylase.[3]

The AAAHs converts the cofactor 5,6,7,8-tetrahydrobiopterin (BH4) into tetrahydrobiopterin-4a-carbinolamine (4a-BH4). Under physiological conditions, 4a-BH4 is dehydrated to quinonoid-dihydrobiopterin (q-BH2) by the enzyme pterin-4a-carbinolamine dehydrase (PCD) and a water molecule is released in this reaction.[4][5] Then, the NAD(P)H dependent enzyme dihydropteridine reductase (DHPR) converts q-BH2 back to BH4.[4] Each of the four subunits in tyrosine hydroxylase is coordinated with an iron(II) atom presented in the active site. The oxidation state of this iron atom is important for the catalytic turnover in the enzymatic reaction. If the iron is oxidized to Fe(III), the enzyme is inactivated.[6]

The product of the enzymatic reaction, L-DOPA, can be transformed to dopamine by the enzyme DOPA decarboxylase. Dopamine may be converted into norepinephrine by the enzyme dopamine β-hydroxylase, which can be further modified by the enzyme phenylethanol N-methyltransferase to obtain epinephrine.[7] Since L-DOPA is the precursor for the neurotransmitters dopamine, noradrenaline and adrenaline, tyrosine hydroxylase is therefore found in the cytosol of all cells containing these catecholamines. This initial reaction catalyzed by tyrosine hydroxylase has been shown to be the rate limiting step in the production of catecholamines.[7]

The enzyme is highly specific, not accepting indole derivatives - which is unusual as many other enzymes involved in the production of catecholamines do. Tryptophan is a poor substrate for tyrosine hydroxylase, however it can hydroxylate L-phenylalanine to form L-tyrosine and small amounts of 3-hydroxyphenylalanine.[3][8][9] The enzyme can then further catalyze L-tyrosine to form L-DOPA. Tyrosine hydroxylase may also be involved in other reactions as well, such as oxidizing L-DOPA to form 5-S-cysteinyl-DOPA or other L-DOPA derivatives.[3][10]

Structure[edit]

Tyrosine hydroxylase from rat showing two of its domains, the tetramerization domain (pink) and the catalytic domain (blue). The regulatory domain (not shown) would sit somewhere on the right hand side of the image where also the enzyme's substrate would enter from.

Tyrosine hydroxylase is a tetramer of four identical subunits (homotetramer). Each subunit consists of three domains. At the carboxyl terminal of the peptide chain there's a short alpha helix domain that allows tetramerization.[11] The central ~300 amino acids make up a catalytic core, in which all the residues necessary for catalysis are located, along with a non-covalently bound iron atom.[8] The iron is held in place by two histidine residues and one glutamate residue, making it a non-heme, non-iron-sulfur iron-containing enzyme.[12] The amino terminal ~150 amino acids make up a regulatory domain, thought to control access of substrates to the active site.[13] In humans there are thought to be four different versions of this regulatory domain, and thus four versions of the enzyme, depending on alternative splicing,[14] though none of their structures have yet been properly determined.[15] It has been suggested that this domain might be an intrinsically unstructured protein, which has no clearly defined tertiary structure, but so far no evidence has been presented supporting this claim.[15] It has however been showed that the domain has a low occurrence of secondary structures, which doesn't weaken suspicions of it having a disordered overall structure.[16] As for the tetramerization and catalytic domains their structure was found with rat tyrosine hydroxylase using X-ray crystallography.[17][18] This has shown how its structure is very similar to that of phenylalanine hydroxylase and tryptophan hydroxylase; together the three make up a family of homologous aromatic amino acid hydroxylases.[19][20]

Regulation[edit]

Tyrosine hydroxylase catalyzes the rate limiting step in catecholamine biosynthesis

Tyrosine hydroxylase activity is increased in the short term by phosphorylation. The regulatory domain of tyrosine hydroxylase contains multiple serine (Ser) residues, including Ser8, Ser19, Ser31 and Ser40, that are phosphorylated by a variety of protein kinases.[8][21] Ser40 is phosphorylated by the cAMP-dependent protein kinase.[22] Ser19 (and Ser40 to a lesser extent) is phosphorylated by the calcium-calmodulin-dependent protein kinase.[23] MAPKAPK2 (mitogen-activated-protein kinase-activating protein kinase) has a preference for Ser40, but also phosphorylates Ser19 about half the rate of Ser40.[24][25] Ser31 is phosphorylated by ERK1 and ERK2 (extracellular regulated kinases 1&2),[26] and increases the enzyme activity to a lesser extent than for Ser40 phosphorylation.[24] The phosphorylation at Ser19 and Ser8 has no direct effect on tyrosine hydroxylase activity. But phosphorylation at Ser19 increases the rate of phosphorylation at Ser40, leading to an increase in enzyme activity. Phosphorylation at Ser19 causes a two-fold increase of activity, through a mechanism that requires the 14-3-3 proteins.[27] Phosphorylation at Ser31 causes a slight increase of activity, and here the mechanism is unknown. Tyrosine hydroxylase is somewhat stabilized to heat inactivation when the regulatory serines are phosphorylated.[24][28]

Tyrosine hydroxylase is mainly present in the cytosol, although it also is found in some extent in the plasma membrane.[29] The membrane association may be related to catecholamine packing in vesicles and export through the synaptic membrane.[29] The binding of tyrosine hydroxylase to membranes involves the N-terminal region of the enzyme, and may be regulated by a three-way interaction between 14-3-3 proteins, the N-terminal region of tyrosine hydroxylase, and negatively charged membranes.[30]

Tyrosine hydroxylase can also be regulated by inhibition. Phosphorylation at Ser40 relieves feedback inhibition by the catecholamines dopamine, epinephrine, and norepinephrine.[31][32] The catecholamines trap the active-site iron in the Fe(III) state, inhibiting the enzyme.[3]

It has been shown that the expression of tyrosine hydroxylase can be affected by the expression of SRY. The down regulation of the SRY gene in the substantia nigra can result in a decrease in tyrosine hydroxylase expression. [33]

Long term regulation of tyrosine hydroxylase can also be mediated by phosphorylation mechanisms. Hormones (e.g. glucocorticoids), drugs (e.g. cocaine), or second messengers such as cAMP increase tyrosine hydroxylase transcription. Increase in tyrosine hydroxylase activity due to phosphorylation can be sustained by nicotine for up to 48 hours.[3][34] Tyrosine hydroxylase activity is regulated chronically (days) by protein synthesis.[34]

Clinical significance[edit]

Since tyrosine hydroxylase catalyses the rate limiting step in the biosynthesis of catecholamines, alterations in the enzyme activity may be involved in disorders such as Segawa's dystonia, Parkinson's disease and schizophrenia.[17][35] Tyrosine hydroxylase is activated by phosphorylation dependent binding to 14-3-3 proteins.[30] Since the 14-3-3 proteins also are likely to be associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, it makes an indirect link between tyrosine hydroxylase and these diseases.[36] The activity of tyrosine hydroxylase in the brains of patients with Alzheimer’s disease has been shown to be significantly reduced compared to healthy individuals.[37] Tyrosine hydroxylase is also an autoantigen in Autoimmune Polyendocrine Syndrome (APS) type I.[38]

A consistent abnormality in Parkinson's disease is degeneration of dopaminergic neurons in the substantia nigra, leading to a reduction of stratial dopamine levels. As tyrosine hydroxylase catalyzes the formation of L-DOPA, the rate-limiting step in the biosynthesis of dopamine, tyrosine hydroxylase-deficiency does not cause Parkinson's disease, but typically gives rise to infantile parkinsonism, although the spectrum extends to a condition resembling dopamine-responsive dystonia. A direct pathogenetic role of tyrosine hydroxylase has also been suggested, as the enzyme is a source of H2O2 and other reactive oxygen species (ROS), and a target for radical-mediated injury. It has been demonstrated that L-DOPA is effectively oxidized by mammalian tyrosine hydroxylase, possibly contributing to the cytotoxic effects of L-DOPA.[3] Like other cellular proteins, tyrosine hydroxylase is also a possible target for damaging alterations induced by ROS. This suggests that some of the oxidative damage to tyrosine hydroxylase could be generated by the tyrosine hydroxylase system itself.[3]

Tyrosine hydroxylase can be inhibited by the drug α-methyl-para-tyrosine (metirosine). This inhibition can lead to a depletion of dopamine and norepinepherine in the brain due to the lack of the precursor L-Dopa (L-3,4-dyhydroxyphenylalanine) which is synthesized by tyrosine hydroxylase. This drug is rarely used and can cause depression, but it is useful in treating pheochromocytoma and also resistant hypertension. Older examples of inhibitors mentioned in the literature include oudenone[39] and aquayamycin.[40]

References[edit]

  1. ^ Kaufman S (1995). "Tyrosine hydroxylase". Adv. Enzymol. Relat. Areas Mol. Biol. Advances in Enzymology - and Related Areas of Molecular Biology 70: 103–220. doi:10.1002/9780470123164.ch3. ISBN 978-0-470-12316-4. PMID 8638482. 
  2. ^ a b c Nagatsu T (1995). "Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology". Essays Biochem. 30: 15–35. PMID 8822146. 
  3. ^ a b c d e f g Haavik J, Toska K (June 1998). "Tyrosine hydroxylase and Parkinson's disease". Mol. Neurobiol. 16 (3): 285–309. doi:10.1007/BF02741387. PMID 9626667. 
  4. ^ a b Teigen K, McKinney JA, Haavik J, Martínez A (2007). "Selectivity and affinity determinants for ligand binding to the aromatic amino acid hydroxylases". Curr. Med. Chem. 14 (4): 455–67. doi:10.2174/092986707779941023. PMID 17305546. 
  5. ^ Thöny B, Auerbach G, Blau N (April 2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions". Biochem. J. 347 (1): 1–16. doi:10.1042/0264-6021:3470001. PMC 1220924. PMID 10727395. 
  6. ^ Ramsey AJ, Hillas PJ, Fitzpatrick PF (October 1996). "Characterization of the active site iron in tyrosine hydroxylase. Redox states of the iron". J. Biol. Chem. 271 (40): 24395–400. doi:10.1074/jbc.271.40.24395. PMID 8798695. 
  7. ^ a b Nagatsu T, Levitt M, Udenfriend S (September 1964). "Tyrosine Hydroxylase. The Initial Step in Norepinephrine Biosynthesis". J. Biol. Chem. 239: 2910–7. PMID 14216443. 
  8. ^ a b c Fitzpatrick PF (1999). "Tetrahydropterin-dependent amino acid hydroxylases". Annu. Rev. Biochem. 68: 355–81. doi:10.1146/annurev.biochem.68.1.355. PMID 10872454. 
  9. ^ Fitzpatrick PF (1994). "Kinetic Isotope Effects on Hydroxylation of Ring-Deuterated Phenylalanines by Tyrosine Hydroxylase Provide Evidence against Partitioning of an Arene Oxide Intermediate". Journal of the American Chemical Society 116 (3): 1133–1134. doi:10.1021/ja00082a046. 
  10. ^ Haavik J, Flatmark T (October 1987). "Isolation and characterization of tetrahydropterin oxidation products generated in the tyrosine 3-monooxygenase (tyrosine hydroxylase) reaction". Eur. J. Biochem. 168 (1): 21–6. doi:10.1111/j.1432-1033.1987.tb13381.x. PMID 2889594. 
  11. ^ Vrana KE, Walker SJ, Rucker P, Liu X; Walker; Rucker; Liu (1994). "A carboxyl terminal leucine zipper is required for tyrosine hydroxylase tetramer formation". Journal of neurochemistry 63 (6): 2014–2020. doi:10.1046/j.1471-4159.1994.63062014.x. PMID 7964718. 
  12. ^ Colette Daubner, S.; Daubner, J. I.; Ehrlich, A. J.; Fitzpatrick, P. F. (1995). "Identification of iron ligands in tyrosine hydroxylase by mutagenesis of conserved histidinyl residues". Protein Science 4 (10): 2082–2086. doi:10.1002/pro.5560041013. PMC 2142982. PMID 8535244. 
  13. ^ Daubner SC, Le T, Wang S (2011). "Tyrosine hydroxylase and regulation of dopamine synthesis". Archives of Biochemistry and Biophysics 508 (1): 1–12. doi:10.1016/j.abb.2010.12.017. PMC 3065393. PMID 21176768. 
  14. ^ Kobayashi k, K. N.; Kaneda, N.; Ichinose, H.; Kishi, F.; Nakazawa, A.; Kurosawa, Y.; Fujita, K.; Nagatsu, T. (1988). "Structure of the human tyrosine hydroxylase gene: Alternative splicing from a single gene accounts for generation of four mRNA types". Journal of Biochemistry 103 (6): 907–912. PMID 2902075. 
  15. ^ a b Nakashima, A.; Hayashi, N.; Kaneko, Y. S.; Mori, K.; Sabban, E. L.; Nagatsu, T.; Ota, A. (2009). "Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines". Journal of Neural Transmission 116 (11): 1355–1362. doi:10.1007/s00702-009-0227-8. PMID 19396395. 
  16. ^ Obsilova V, Nedbalkova E, Silhan J, Boura E, Herman P, Vecer J, Sulc M, Teisinger J, Dyda F, Obsil T (2008). "The 14-3-3 Protein Affects the Conformation of the Regulatory Domain of Human Tyrosine Hydroxylase†". Biochemistry 47 (6): 1768–1777. doi:10.1021/bi7019468. PMID 18181650. 
  17. ^ a b Goodwill KE, Sabatier C, Marks C, Raag R, Fitzpatrick PF, Stevens RC; Sabatier; Marks; Raag; Fitzpatrick; Stevens (1997). "Crystal structure of tyrosine hydroxylase at 2.3 a and its implications for inherited neurodegenerative diseases". Nature structural biology 4 (7): 578–585. doi:10.1038/nsb0797-578. PMID 9228951. 
  18. ^ Goodwill KE, Sabatier C, Stevens RC (1998). "Crystal Structure of Tyrosine Hydroxylase with Bound Cofactor Analogue and Iron at 2.3 Å Resolution:  Self-Hydroxylation of Phe300 and the Pterin-Binding Site†,‡". Biochemistry 37 (39): 13437–13445. doi:10.1021/bi981462g. PMID 9753429. 
  19. ^ Ledley FD, DiLella AG, Kwok SC, Woo SL (1985). "Homology between phenylalanine and tyrosine hydroxylases reveals common structural and functional domains". Biochemistry 24 (14): 3389–3394. doi:10.1021/bi00335a001. PMID 2412578. 
  20. ^ Grenett HE, Ledley FD, Reed LL, Woo SL (1987). "Full-length cDNA for rabbit tryptophan hydroxylase: Functional domains and evolution of aromatic amino acid hydroxylases". Proceedings of the National Academy of Sciences of the United States of America 84 (16): 5530–5534. doi:10.1073/pnas.84.16.5530. PMC 298896. PMID 3475690. 
  21. ^ Haycock JW (1990). "Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31, and 40". The Journal of biological chemistry 265 (20): 11682–11691. PMID 1973163. 
  22. ^ Roskoski R Jr, Roskoski LM; Roskoski (1987). "Activation of tyrosine hydroxylase in PC12 cells by the cyclic GMP and cyclic AMP second messenger systems". Journal of neurochemistry 48 (1): 236–242. doi:10.1111/j.1471-4159.1987.tb13153.x. PMID 2878973. 
  23. ^ Lehmann IT, Bobrovskaya L, Gordon SL, Dunkley PR, Dickson PW (2006). "Differential Regulation of the Human Tyrosine Hydroxylase Isoforms via Hierarchical Phosphorylation". Journal of Biological Chemistry 281 (26): 17644–17651. doi:10.1074/jbc.M512194200. PMID 16644734. 
  24. ^ a b c Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW (2004). Journal of Neurochemistry 91 (5): 1025–1043. doi:10.1111/j.1471-4159.2004.02797.x. PMID 15569247. 
  25. ^ Sutherland C, Alterio J, Campbell DG, Le Bourdellès B, Mallet J, Haavik J, Cohen P (1993). "Phosphorylation and activation of human tyrosine hydroxylase in vitro by mitogen-activated protein (MAP) kinase and MAP-kinase-activated kinases 1 and 2". European journal of biochemistry / FEBS 217 (2): 715–722. doi:10.1111/j.1432-1033.1993.tb18297.x. PMID 7901013. 
  26. ^ Haycock JW, Ahn NG, Cobb MH, Krebs EG (1992). "ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ". Proceedings of the National Academy of Sciences of the United States of America 89 (6): 2365–2369. doi:10.1073/pnas.89.6.2365. PMC 48658. PMID 1347949. 
  27. ^ Ichimura T, Isobe T, Okuyama T, Takahashi N, Araki K, Kuwano R, Takahashi Y (1988). "Molecular cloning of cDNA coding for brain-specific 14-3-3 protein, a protein kinase-dependent activator of tyrosine and tryptophan hydroxylases". Proceedings of the National Academy of Sciences of the United States of America 85 (19): 7084–7088. doi:10.1073/pnas.85.19.7084. PMC 282128. PMID 2902623. 
  28. ^ Royo M, Fitzpatrick PF, Daubner SC (2005). "Mutation of regulatory serines of rat tyrosine hydroxylase to glutamate: Effects on enzyme stability and activity". Archives of Biochemistry and Biophysics 434 (2): 266–274. doi:10.1016/j.abb.2004.11.007. PMID 15639226. 
  29. ^ a b Chen R, Wei J, Fowler SC, Wu JY (2003). "Demonstration of Functional Coupling between Dopamine Synthesis and Its Packaging into Synaptic Vesicles". Journal of Biomedical Science 10 (6): 774–781. doi:10.1159/000073965. PMID 14631117. 
  30. ^ a b Halskau Ø Jr, Ying M, Baumann A, Kleppe R, Rodriguez-Larrea D, Almås B, Haavik J, Martinez A (2009). "Three-way Interaction between 14-3-3 Proteins, the N-terminal Region of Tyrosine Hydroxylase, and Negatively Charged Membranes". Journal of Biological Chemistry 284 (47): 32758–32769. doi:10.1074/jbc.M109.027706. PMC 2781693. PMID 19801645. 
  31. ^ Daubner SC, Lauriano C, Haycock JW, Fitzpatrick PF (1992). "Site-directed mutagenesis of serine 40 of rat tyrosine hydroxylase. Effects of dopamine and cAMP-dependent phosphorylation on enzyme activity". The Journal of biological chemistry 267 (18): 12639–12646. PMID 1352289. 
  32. ^ Ramsey AJ, Fitzpatrick PF (1998). "Effects of Phosphorylation of Serine 40 of Tyrosine Hydroxylase on Binding of Catecholamines:  Evidence for a Novel Regulatory Mechanism†". Biochemistry 37 (25): 8980–8986. doi:10.1021/bi980582l. PMID 9636040. 
  33. ^ Dewing P, Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, Vilain E (February 2006). "Direct regulation of adult brain function by the male-specific factor SRY". Curr. Biol. 16 (4): 415–20. doi:10.1016/j.cub.2006.01.017. PMID 16488877. 
  34. ^ a b Bobrovskaya L, Gilligan C, Bolster EK, Flaherty JJ, Dickson PW, Dunkley PR (2007). "Sustained phosphorylation of tyrosine hydroxylase at serine 40: A novel mechanism for maintenance of catecholamine synthesis". Journal of Neurochemistry 100 (2): 479–489. doi:10.1111/j.1471-4159.2006.04213.x. PMID 17064352. 
  35. ^ Thibaut F, Ribeyre JM, Dourmap N, Meloni R, Laurent C, Campion D, Ménard JF, Dollfus S, Mallet J, Petit M; Ribeyre, J. M.; Dourmap, N; Meloni, R; Laurent, C; Campion, D; Ménard, J. F.; Dollfus, S; Mallet, J; Petit, M (1997). "Association of DNA polymorphism in the first intron of the tyrosine hydroxylase gene with disturbances of the catecholaminergic system in schizophrenia". Schizophrenia research 23 (3): 259–264. doi:10.1016/s0920-9964(96)00118-1. PMID 9075305. 
  36. ^ Steinacker P, Aitken A, Otto M (2011). "14-3-3 proteins in neurodegeneration". Seminars in Cell & Developmental Biology 22 (7): 696–704. doi:10.1016/j.semcdb.2011.08.005. PMID 21920445. 
  37. ^ Sawada M, Hirata Y, Arai H, Iizuka R, Nagatsu T; Hirata; Arai; Iizuka; Nagatsu (March 1987). "Tyrosine hydroxylase, tryptophan hydroxylase, biopterin, and neopterin in the brains of normal controls and patients with senile dementia of Alzheimer type". Journal of neurochemistry 48 (3): 760–4. doi:10.1111/j.1471-4159.1987.tb05582.x. PMID 2879891. 
  38. ^ Hedstrand H, Ekwall O, Haavik J, Landgren E, Betterle C, Perheentupa J, Gustafsson J, Husebye E, Rorsman F, Kämpe O (2000). "Identification of Tyrosine Hydroxylase as an Autoantigen in Autoimmune Polyendocrine Syndrome Type I". Biochemical and Biophysical Research Communications 267 (1): 456–461. doi:10.1006/bbrc.1999.1945. PMID 10623641. 
  39. ^ Ono M, Okamoto M, Kawabe N, Umezawa H, Takeuchi T (1971). "Oudenone, a novel tyrosine hydroxylase inhibitor from microbial origin". Journal of the American Chemical Society 93 (5): 1285–1286. doi:10.1021/ja00734a054. PMID 5545929. 
  40. ^ Ayukawa S, Takeuchi T, Sezaki M, Hara T, Umezawa H (1968). "Inhibition of tyrosine hydroxylase by aquayamycin". The Journal of antibiotics 21 (5): 350–353. PMID 5726288. 

Further reading[edit]

External links[edit]