| Structural highlights
Disease
PH4H_HUMAN Defects in PAH are the cause of phenylketonuria (PKU) [MIM:261600. PKU is an autosomal recessive inborn error of phenylalanine metabolism, due to severe phenylalanine hydroxylase deficiency. It is characterized by blood concentrations of phenylalanine persistently above 1200 mumol (normal concentration 100 mumol) which usually causes mental retardation (unless low phenylalanine diet is introduced early in life). They tend to have light pigmentation, rashes similar to eczema, epilepsy, extreme hyperactivity, psychotic states and an unpleasant 'mousy' odor.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] Defects in PAH are the cause of non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA) [MIM:261600. Non-PKU HPA is a mild form of phenylalanine hydroxylase deficiency characterized by phenylalanine levels persistently below 600 mumol, which allows normal intellectual and behavioral development without treatment. Non-PKU HPA is usually caused by the combined effect of a mild hyperphenylalaninemia mutation and a severe one. Defects in PAH are the cause of hyperphenylalaninemia (HPA) [MIM:261600. HPA is the mildest form of phenylalanine hydroxylase deficiency.[39] [40] [41] [42] [43] [44] [45] [46]
Function
PH4H_HUMAN
Publication Abstract from PubMed
Phenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH4) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH4 in the precatalytic state. Crystal structures, solved at 3.18-A resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH4 BH4 forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic Fe(II) Upon BH4 binding a polar and salt-bridge interaction network links the three PAH domains, explaining the stability conferred by BH4 Importantly, BH4 binding modulates the interaction between subunits, providing information about PAH allostery. Moreover, we also show that the cryo-EM structure of hPAH in absence of BH4 reveals a highly dynamic conformation for the tetramers. Structural analyses of the hPAH:BH4 subunits revealed that the substrate-induced movement of Tyr138 into the active site could be coupled to the displacement of BH4 from the precatalytic toward the active conformation, a molecular mechanism that was supported by site-directed mutagenesis and targeted molecular dynamics simulations. Finally, comparison of the rat and human PAH structures show that hPAH is more dynamic, which is related to amino acid substitutions that enhance the flexibility of hPAH and may increase the susceptibility to PKU-associated mutations.
Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin.,Flydal MI, Alcorlo-Pages M, Johannessen FG, Martinez-Caballero S, Skjaerven L, Fernandez-Leiro R, Martinez A, Hermoso JA Proc Natl Acad Sci U S A. 2019 May 22. pii: 1902639116. doi:, 10.1073/pnas.1902639116. PMID:31118288[47]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Bosco P, Cali F, Meli C, Mollica F, Zammarchi E, Cerone R, Vanni C, Palillo L, Greco D, Romano V. Eight new mutations of the phenylalanine hydroxylase gene in Italian patients with hyperphenylalaninemia. Hum Mutat. 1998;11(3):240-3. PMID:9521426 doi:<240::AID-HUMU9>3.0.CO;2-L 10.1002/(SICI)1098-1004(1998)11:3<240::AID-HUMU9>3.0.CO;2-L
- ↑ Yang Y, Drummond-Borg M, Garcia-Heras J. Molecular analysis of phenylketonuria (PKU) in newborns from Texas. Hum Mutat. 2001 Jun;17(6):523. PMID:11385716 doi:10.1002/humu.1141
- ↑ Muntau AC, Roschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002 Dec 26;347(26):2122-32. PMID:12501224 doi:10.1056/NEJMoa021654
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- ↑ Chen KJ, Chao HK, Hsiao KJ, Su TS. Identification and characterization of a novel liver-specific enhancer of the human phenylalanine hydroxylase gene. Hum Genet. 2002 Mar;110(3):235-43. Epub 2002 Feb 5. PMID:11935335 doi:10.1007/s00439-002-0677-7
- ↑ Flydal MI, Alcorlo-Pages M, Johannessen FG, Martinez-Caballero S, Skjaerven L, Fernandez-Leiro R, Martinez A, Hermoso JA. Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin. Proc Natl Acad Sci U S A. 2019 May 22. pii: 1902639116. doi:, 10.1073/pnas.1902639116. PMID:31118288 doi:http://dx.doi.org/10.1073/pnas.1902639116
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