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Phenylalanine hydroxylase
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| predicted 3D structure of phenylalanine hydroxylase | |||||||||||
| Available structures: 1dmw, 1j8t, 1j8u, 1kw0, 1lrm, 1mmk, 1mmt, 1pah, 1phz, 1tdw, 1tg2, 2pah, 2phm, 3pah, 4pah, 5pah, 6pah | |||||||||||
| Identifiers | |||||||||||
| Symbols | PAH; PKU; PKU1 | ||||||||||
| External IDs | OMIM: 261600 MGI: 97473 HomoloGene: 234 | ||||||||||
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| RNA expression pattern | |||||||||||
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| Orthologs | |||||||||||
| Human | Mouse | ||||||||||
| Entrez | 5053 | 18478 | |||||||||
| Ensembl | ENSG00000171759 | ENSMUSG00000020051 | |||||||||
| Uniprot | P00439 | Q3UEH8 | |||||||||
| Refseq | NM_000277 (mRNA) NP_000268 (protein) |
NM_008777 (mRNA) NP_032803 (protein) |
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| Location | Chr 12: 101.76 - 101.84 Mb | Chr 10: 86.95 - 87.01 Mb | |||||||||
| Pubmed search | [1] | [2] | |||||||||
Phenylalanine hydroxylase (EC 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:
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 is the gene that encodes for phenylalanine hydroxylase.
It was the research on phenylalanine hydroxylase by Seymour Kaufman that led to the discovery of tetrahydrobiopterin as a biological cofactor. [1]
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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 acids 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
- The Phenylalanine Hydroxylase Protein
- PAHdb - online locus-specific mutation database of the human phenylalanine hydroxylase gene
References
- ^ Kaufman, D (1958). "A New Cofactor Required for the Enzymatic Conversion of Phenylalanine to Tyrosine.". J. Biol. Chem. (230): 931-39.
Further reading
- Eisensmith RC, Woo SL (1993). "Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.". Hum. Mutat. 1 (1): 13-23. doi:. PMID 1301187.
- Konecki DS, Lichter-Konecki U (1991). "The phenylketonuria locus: current knowledge about alleles and mutations of the phenylalanine hydroxylase gene in various populations.". Hum. Genet. 87 (4): 377-88. doi:. PMID 1679029.
- Cotton RG (1991). "Heterogeneity of phenylketonuria at the clinical, protein and DNA levels.". J. Inherit. Metab. Dis. 13 (5): 739-50. PMID 2246858.
- Erlandsen H, Fusetti F, Martinez A, et al. (1998). "Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria.". Nat. Struct. Biol. 4 (12): 995-1000. PMID 9406548.
- Waters PJ, Parniak MA, Nowacki P, Scriver CR (1998). "In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function.". Hum. Mutat. 11 (1): 4-17. doi:. PMID 9450897.
- Waters PJ (2003). "How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression.". Hum. Mutat. 21 (4): 357-69. doi:. PMID 12655545.
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Wikipedia content modification information:
- This page was last modified on 9 October 2008, at 07:01.
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