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Tryptophan hydroxylase

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Title: Tryptophan hydroxylase  
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Subject: Serotonin, AGN-2979, Fenclonine, Phenylalanine hydroxylase, Tryptophan
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Tryptophan hydroxylase

tryptophan 5-monooxygenase
Identifiers
EC number 1.14.16.4
CAS number 9037-21-2
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
tryptophan hydroxylase 1 (tryptophan 5-monooxygenase)
Identifiers
Symbol TPH1
Alt. symbols TPRH, TPH
Entrez 7166
HUGO 12008
OMIM 191060
PDB 1MLW (RCSB PDB PDBe PDBj)
RefSeq NM_004179
UniProt P17752
Other data
EC number 1.14.16.4
Locus Chr. 11 p15.3-p14
tryptophan hydroxylase 2
Identifiers
Symbol TPH2
Entrez 121278
HUGO 20692
OMIM 607478
RefSeq NM_173353
UniProt Q8IWU9
Other data
Locus Chr. 12 q15

Tryptophan hydroxylase (TPH) is an enzyme (EC 1.14.16.4) involved in the synthesis of the neurotransmitter serotonin. TPH catalyzes the following chemical reaction

L-tryptophan + tetrahydrobiopterin + O2 \rightleftharpoons 5-Hydroxytryptophan + dihydrobiopterin + H2O

It employs one additional cofactor, iron.

Contents

  • Function 1
  • Isoforms 2
  • Additional images 3
  • References 4
  • Further reading 5
  • External links 6

Function

Tryptophan } 5-HTP
 
} }
 
 

It is responsible for addition of the -HO group (hydroxylation) to the 5 position to form the amino acid 5-hydroxytryptophan (5-HTP), which is the initial and rate-limiting step in the synthesis of the neurotransmitter serotonin. It is also the first enzyme in the synthesis of melatonin.

Tryptophan hydroxylase (TPH), tyrosine hydroxylase (TH) and phenylalanine hydroxylase (PAH) are members of a superfamily of aromatic amino acid hydroxylases, catalyzing key steps in important metabolic pathways.[1] Analogously to phenylalanine hydroxylase and tyrosine hydroxylase, this enzyme uses (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and dioxygen as cofactors.[2]

In humans, the stimulation of serotonin production by administration of tryptophan has an antidepressant effect and inhibition of tryptophan hydroxylase (e.g. by p-Chlorophenylalanine) may precipitate depression.[3]

The activity of tryptophan hydroxylase (i.e. the rate at which it converts L-tryptophan into the serotonin precursor L-5-hydroxytryptophan) can be increased when it undergoes phosphorylation. Protein Kinase A, for example, can phosphorylate tryptophan hydroxylase, thus increasing its activity.

Isoforms

In humans, as well as in other mammals, there are two distinct TPH genes. In humans, these genes are located on chromosomes 11 and 12 and encode two different homologous enzymes TPH1 and TPH2 (sequence identity 71%).[4]

  • TPH1 is mostly expressed in tissues that express serotonin (a neurotransmitter) in the periphery (skin, gut, pineal gland) but it is also expressed in the central nervous system.
  • On the other hand, TPH2 is exclusively expressed in neuronal cell types and is the predominant isoform in the central nervous system.

Additional images

References

  1. ^ McKinney J, Teigen K, Frøystein NA, Salaün C, Knappskog PM, Haavik J, Martínez A (December 2001). "Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity". Biochemistry 40 (51): 15591–601.  
  2. ^ "tetrahydrobiopterin". BH4 Databases. BH4.org. 2005. 
  3. ^ Wang L, Erlandsen H, Haavik J, Knappskog PM, Stevens RC (October 2002). "Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin". Biochemistry 41 (42): 12569–74.  
  4. ^ Walther DJ, Bader M (November 2003). "A unique central tryptophan hydroxylase isoform". Biochem. Pharmacol. 66 (9): 1673–80.  

Further reading

  • Friedman PA, Kappelman AH, Kaufman S (1972). "Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain". J. Biol. Chem. 247 (13): 4165–73.  
  • Hamon M, Bourgoin S, Artaud F, Glowinski J (1979). "The role of intraneuronal 5-HT and of tryptophan hydroxylase activation in the control of 5-HT synthesis in rat brain slices incubated in K+-enriched medium". J. Neurochem. 33 (5): 1031–42.  
  • Ichiyama A, Nakamura S, Nishizuka Y, Hayaishi O (1970). "Enzymic studies on the biosynthesis of serotonin in mammalian brain". J. Biol. Chem. 245 (7): 1699–709.  
  • Jequier E, Robinson DS, Lovenberg W, Sjoerdsma A (1969). "Further studies on tryptophan hydroxylase in rat brainstem and beef pineal". Biochem. Pharmacol. 18 (5): 1071–81.  
  • Wang L, Erlandsen H, Haavik J, Knappskog PM, Stevens RC (2002). "Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin". Biochemistry. 41 (42): 12569–74.  
  • Windahl MS, Petersen CR, Christensen, HEM, Harris P (2008). "Crystal Structure of Tryptophan Hydroxylase with Bound Amino Acid Substrate". Biochemistry. 47 (46): 12087–94.  

External links

See also tryptophan hydroxylase in Proteopedia

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