This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Amino Acids Biosynthesis → Proteinogenic Amino Acids Biosynthesis → L-tyrosine Biosynthesis|
Some taxa known to possess this pathway include : Homo sapiens
Expected Taxonomic Range: Metazoa
In humans, L-phenylalanine is an indispensable amino acid, which may either be used for protein synthesis or be converted to the nonessential amino acid L-tyrosine, the precursor for catecholamine and thyroid hormone synthesis. L-tyrosine is not considered indispensable, despite being an essential component of body proteins, because it can be synthesized from L-phenylalanine [McGee72, Haggerty75].
phenylalanine hydroxylase (EC 220.127.116.11) is responsible for the irreversible oxidation of the essential amino acid L-phenylalanine to L-tyrosine in animals. The enzyme is found mostly in the liver [Stanley85] and in the kidney [Moller00], and its subcellular location is the cytoplasm. The enzyme, whose active form is tetrameric, requires the binding of L-phenylalanine to the regulatory domain in order to promote phosphorylation of Ser16, followed by a conformational change, which allows the formation of active tetramers from inactive precursor dimers. Once the active tetrameric form of the enzyme has been produced, L-phenylalanine and the cofactor tetrahydrobiopterin can bind to the active site domain initiating catalysis.
In addition, phenylalanine hydroxylase is tightly coupled to pterin-4α-carbinolamine dehydratase (EC 18.104.22.168), the key enzyme that is responsible for the recycling of the cofactor tetrahydrobiopterin. It has been shown that pterin-4α-carbinolamine dehydratase increases the rate of phenylalanine hydroxylase 7-fold, and converts the product 4α-hydroxy-tetrahydrobiopterin to 7,8-dihydrobiopterin by dehydration, which is further reduced to tetrahydrobiopterin in the presence of NADH by dihydropteridine reductase (EC 22.214.171.124).
Blau: Blau N, Bonafe L, Thony B "Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency." Mol Genet Metab 74(1-2);172-85. PMID: 11592814
Cho98: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1998). "Tepidopterin, 1-O-(L-threo-biopterin-2'-yl)-beta-N-acetylglucosamine from Chlorobium tepidum." Biochim Biophys Acta 1379(1);53-60. PMID: 9468332
Chung00: Chung HJ, Kim YA, Kim YJ, Choi YK, Hwang YK, Park YS (2000). "Purification and characterization of UDP-glucose:tetrahydrobiopterin glucosyltransferase from Synechococcus sp. PCC 7942." Biochim Biophys Acta 1524(2-3);183-8. PMID: 11113566
Maier95: Maier J, Ninnemann H (1995). "Biosynthesis of pteridines in Neurospora crassa, Phycomyces blakesleeanus and Euglena gracilis: detection and characterization of biosynthetic enzymes." Photochem Photobiol 61(1);43-53. PMID: 7899493
Mataga91: Mataga N, Imamura K, Watanabe Y (1991). "6R-tetrahydrobiopterin perfusion enhances dopamine, serotonin, and glutamate outputs in dialysate from rat striatum and frontal cortex." Brain Res 551(1-2);64-71. PMID: 1680529
McGee72: McGee MM, Greengard O, Knox WE (1972). "Liver phenylalanine hydroxylase activity in relation to blood concentrations of tyrosine and phenylalanine in the rat." Biochem J 127(4);675-80. PMID: 4265522
Moller00: Moller N, Meek S, Bigelow M, Andrews J, Nair KS (2000). "The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion in adult humans: A metabolic role of the kidney." Proc Natl Acad Sci U S A 97(3);1242-6. PMID: 10655515
Schallreuter94: Schallreuter KU, Wood JM, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, Swanson NN, Hitzemann K, Ziegler I (1994). "Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin." Science 263(5152);1444-6. PMID: 8128228
Stanley85: Stanley JC, Fisher MJ, Pogson CI (1985). "The metabolism of L-phenylalanine and L-tyrosine by liver cells isolated from adrenalectomized rats and from streptozotocin-diabetic rats." Biochem J 228(1);249-55. PMID: 4004813
Tanaka89: Tanaka K, Kaufman S, Milstien S (1989). "Tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases, is synthesized by and regulates proliferation of erythroid cells." Proc Natl Acad Sci U S A 86(15);5864-7. PMID: 2762302
Wang11d: Wang H, Yang B, Hao G, Feng Y, Chen H, Feng L, Zhao J, Zhang H, Chen YQ, Wang L, Chen W (2011). "Biochemical characterization of the tetrahydrobiopterin synthesis pathway in the oleaginous fungus Mortierella alpina." Microbiology 157(Pt 11);3059-70. PMID: 21852350
Andersen01a: Andersen OA, Flatmark T, Hough E (2001). "High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin." J Mol Biol 314(2);279-91. PMID: 11718561
Kwok85: Kwok SC, Ledley FD, DiLella AG, Robson KJ, Woo SL (1985). "Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase." Biochemistry 24(3);556-61. PMID: 2986678
Miranda05: Miranda FF, Kolberg M, Andersson KK, Geraldes CF, Martinez A (2005). "The active site residue tyrosine 325 influences iron binding and coupling efficiency in human phenylalanine hydroxylase." J Inorg Biochem 99(6);1320-8. PMID: 15917086
Solstad03: Solstad T, Stokka AJ, Andersen OA, Flatmark T (2003). "Studies on the regulatory properties of the pterin cofactor and dopamine bound at the active site of human phenylalanine hydroxylase." Eur J Biochem 270(5);981-90. PMID: 12603331
vanSpronsen98: van Spronsen FJ, Reijngoud DJ, Smit GP, Nagel GT, Stellaard F, Berger R, Heymans HS (1998). "Phenylketonuria. The in vivo hydroxylation rate of phenylalanine into tyrosine is decreased." J Clin Invest 101(12);2875-80. PMID: 9637722
Volner03: Volner A, Zoidakis J, Abu-Omar MM (2003). "Order of substrate binding in bacterial phenylalanine hydroxylase and its mechanistic implication for pterin-dependent oxygenases." J Biol Inorg Chem 8(1-2);121-8. PMID: 12459906
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