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'''Phenylalanine Hydroxylase''' (also known as Phenylalanine-4-monooxygenase or simply PAH) is the enzyme that catalyzes the conversion of L-phenylalanine into L-tyrosine by hydroxylation (addition of an -OH group) of the aromatic side chain of phenyalanine. This reaction is the initial and rate-limiting step in the phenylalanine catabolism pathway. The tyrosine product (a non-essential amino acid) can then serve as a precursor to the synthesis of important neurotransmitters.<ref name= "flydal"> Flydal, Marte, and Aurora Martinez. "Phenylalanine Hydroxylase: Function, Structure, and Regulation." International Union of Biochemistry and Molecular Biology Journal 65.4 (2013): 341-349. Web. </ref>. PAH uses tetrahydrobiopterin (BH4)as a cofactor and has a nonheme iron atom bound to its active site. PAH is classified as an oxidoreductase, specifically enzyme class EC 1.14 since its mechanism of action involves the oxidation/reduction of its substrate. <ref name= "pdb"> http://www.rcsb.org/pdb/explore/explore.do?structureId=1J8U </ref>. | |||
== Phenylalanine Hydroxylase == | |||
'''Phenylalanine Hydroxylase''' (also known as Phenylalanine-4-monooxygenase or simply PAH) is the enzyme that catalyzes the conversion of L-phenylalanine into L-tyrosine by hydroxylation (addition of an -OH group) of the aromatic side chain of phenyalanine. This reaction is the initial and rate-limiting step in the phenylalanine catabolism pathway. | |||
<Structure load='2pah' size='500' frame='true' align='right' caption='Dimeric Unit of Phenylalanine Hydroxylase with the iron atom in the active sites in brown. ' scene='Insert optional scene name here' />The tyrosine product (a non-essential amino acid) can then serve as a precursor to the synthesis of important neurotransmitters.<ref name= "flydal"> Flydal, Marte, and Aurora Martinez. "Phenylalanine Hydroxylase: Function, Structure, and Regulation." International Union of Biochemistry and Molecular Biology Journal 65.4 (2013): 341-349. Web. </ref>. | |||
PAH uses tetrahydrobiopterin (BH4) as a cofactor and has a nonheme iron atom bound to its active site. PAH is classified as an oxidoreductase, specifically enzyme class EC 1.14 since its mechanism of action involves the oxidation/reduction of its substrate. <ref name= "pdb"> http://www.rcsb.org/pdb/explore/explore.do?structureId=1J8U </ref>. | |||
PAH enzyme is present in the liver cells of humans and other mammals. It is also present in non-mammalian eukaryote organisms and some bacteria such as ''E.coli''. <ref name= "pdb"/>. Recently, it has been identified in some protozoans and slime molds, and even in nonflowering plants such as spinach from which it has been extracted and studied. <ref> Nair, P, and L Vining. "Phenylalanine Hydroxylase from Spinach Leaves." Phytochemistry 4.3 (1965): 401-411. Web. </ref>. | PAH enzyme is present in the liver cells of humans and other mammals. It is also present in non-mammalian eukaryote organisms and some bacteria such as ''E.coli''. <ref name= "pdb"/>. Recently, it has been identified in some protozoans and slime molds, and even in nonflowering plants such as spinach from which it has been extracted and studied. <ref> Nair, P, and L Vining. "Phenylalanine Hydroxylase from Spinach Leaves." Phytochemistry 4.3 (1965): 401-411. Web. </ref>. | ||
Mammalian PAH is a homo-tetrameric enzyme of 50 kDa subunits composed of two asymmetric dimeric units. The four subunits are connected to each other via a coiled-coil motif as shown in the diagram below. | Mammalian PAH is a homo-tetrameric enzyme of 50 kDa subunits composed of two asymmetric dimeric units. The four subunits are connected to each other via a coiled-coil motif as shown in the diagram below. | ||
[[Image:PAH tetramer complex.jpg]] | [[Image:PAH tetramer complex.jpg]] | ||
Each monomeric subunit is composed of three sites: the N-terminal, the catalytic site, and the C-terminal. <ref name= " flydal"/>. | Each monomeric subunit is composed of three sites: the N-terminal, the catalytic site, and the C-terminal. <ref name= " flydal"/>. | ||
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Mutations and changes in the β-ribbon region have major detrimental effects on the enzyme stability. The mutations that lead | Mutations and changes in the β-ribbon region have major detrimental effects on the enzyme stability. The mutations that lead | ||
to Phenylketonuria are most likely due to mutations in the PAH gene that cause changes at the junction between the catalytic and tetramerization domains of the enzyme. This leads to loss of enzyme stability and extensive misfolding which subsequently results in enzyme malfunction. The monomeric image below highlights the regions in the active site that, if mutated, would destroy enzyme activity and lead to phenylketonuria. | to Phenylketonuria are most likely due to mutations in the PAH gene that cause changes at the junction between the catalytic and tetramerization domains of the enzyme. <ref name= "fusetti"/>. This leads to loss of enzyme stability and extensive misfolding which subsequently results in enzyme malfunction. <ref name= "flydal"/>. The monomeric image below highlights the regions in the active site that, if mutated, would destroy enzyme activity and lead to phenylketonuria. The yellow atom is iron, the green structure is the BH4 cofactor, | ||
and the red sites are a few examples of mutation regions. | |||
[[Image:mutation sites.jpg]] | [[Image:mutation sites.jpg]] | ||
== Phenylketonuria == | |||
Dysfunctional PAH consequently prevents the conversion of L-phenylalanine into L-tyrosin. This leads to the accumulation of phenylalanine in the blood. The increased concentration | |||
