Phenylalanine hydroxylase
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2008-07-08T00:15:59Z
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'''Phenylalanine hydroxylase''' ({{EC number|1.14.16.1}}) is an [[enzyme]] which catalyses the reaction causing the addition of an [[hydroxyl]] group to the end of the 6-carbon aromatic ring of [[phenylalanine]], such that it becomes [[tyrosine]]:
<gallery>
Image:L-phenylalanine-skeletal.png|[[Phenylalanine]]
Image:L-tyrosine-skeletal.png|[[Tyrosine]]
</gallery>
Phenylalanine hydroxylase is the [[rate-limiting]] enzyme of the [[metabolic pathway]] which degrades excess phenylalanine.
The other substrates in the reaction are molecular oxygen and [[tetrahydrobiopterin]]. Tetrahydrobiopterin is a member of the group of redox biochemicals known as [[pteridines]]. ''[[PAH (gene)|PAH]]'' is the [[gene]] that encodes for phenylalanine hydroxylase.<br>
It was the research on phenylalanine hydroxylase by Seymour Kaufman that led to the discovery of tetrahydrobiopterin as a biological cofactor. <ref> {{cite journal | author=Kaufman, D |title=A New Cofactor Required for the Enzymatic Conversion of Phenylalanine to Tyrosine. |journal=J. Biol. Chem. |issue= 230 |pages= 931-39 |year= 1958 |url=http://www.jbc.org/cgi/reprint/230/2/931}} </ref>
==Clinical significance==
Mutations in phenylalanine hydroxylase which result in lower activity are the cause of the disease [[phenylketonuria]], or PKU.
==Related enzymes==
Phenylalanine hydroxylase is closely related to two other enzymes:
* [[tryptophan hydroxylase]] (EC number 1.14.16.4), which controls levels of [[serotonin]] in the brain and the [[gastrointestinal tract]]
* [[tyrosine hydroxylase]] (EC number 1.14.16.2), which controls levels of [[dopamine]], [[epinephrine]], and [[norepinephrine]] in the brain and the adrenal medulla.
The three enzymes are homologous, that is, are thought to have evolved from the same ancient hydroxylase.
==Structure==
Phenylalanine hydroxylase is a tetramer composed of four monomers, that is, composed of 4 identical subunits. Each subunit is in turn composed of three domains, a regulatory domain, a catalytic domain, and a tetramerization domain.
* The ''regulatory domain'' is composed of the approximately 115 [[amino acid]]s nearest the amino terminal of the subunit.
* The ''catalytic domain'' is composed of the next approximately 300 amino acids, and is responsible for all of the catalytic activity of the enzyme.
* The ''tetramerization domain'' consists of the remaining amino acids and through the formation of a [[coiled-coil]] arrangement of amino acids, holds the tetrameric structure of the [[holoenzyme]] together with a [[leucine zipper]].
Phenylalanine hydroxylase contains one bound [[iron]] atom per subunit which is necessary for catalytic activity.
==External links==
* [http://macromoleculeinsights.com/phenylalaninehydroxylase.php The Phenylalanine Hydroxylase Protein]
==References==
{{reflist}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Eisensmith RC, Woo SL |title=Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene. |journal=Hum. Mutat. |volume=1 |issue= 1 |pages= 13-23 |year= 1993 |pmid= 1301187 |doi= 10.1002/humu.1380010104 }}
*{{cite journal | author=Konecki DS, Lichter-Konecki U |title=The phenylketonuria locus: current knowledge about alleles and mutations of the phenylalanine hydroxylase gene in various populations. |journal=Hum. Genet. |volume=87 |issue= 4 |pages= 377-88 |year= 1991 |pmid= 1679029 |doi= | doi=10.1007/BF00197152}}
*{{cite journal | author=Cotton RG |title=Heterogeneity of phenylketonuria at the clinical, protein and DNA levels. |journal=J. Inherit. Metab. Dis. |volume=13 |issue= 5 |pages= 739-50 |year= 1991 |pmid= 2246858 |doi= }}
*{{cite journal | author=Erlandsen H, Fusetti F, Martinez A, ''et al.'' |title=Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria. |journal=Nat. Struct. Biol. |volume=4 |issue= 12 |pages= 995-1000 |year= 1998 |pmid= 9406548 |doi= }}
*{{cite journal | author=Waters PJ, Parniak MA, Nowacki P, Scriver CR |title=In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function. |journal=Hum. Mutat. |volume=11 |issue= 1 |pages= 4-17 |year= 1998 |pmid= 9450897 |doi= 10.1002/(SICI)1098-1004(1998)11:1<4::AID-HUMU2>3.0.CO;2-L }}
*{{cite journal | author=Waters PJ |title=How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression. |journal=Hum. Mutat. |volume=21 |issue= 4 |pages= 357-69 |year= 2003 |pmid= 12655545 |doi= 10.1002/humu.10197 }}
}}
{{refend}}
{{Oxygenases}}
{{Amino acid metabolism enzymes}}
[[Category:EC 1.14.16]]
[[Category:Genes associated with genetic disorders]]
{{1.14-enzyme-stub}}
[[de:Phenylalaninhydroxylase]]
[[fr:Phénylalanine hydroxylase]]
[[pt:Fenilalanina hidroxilase]]
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