Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism

Journal of Inherited Metabolic Disease

Volumn 33, Issue 6, 2010, Pages 649-658

  Muntau, Ania C ^a   Gersting, Søren W ^a  

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CHAPERONE; ORPHAN DRUG; PHENYLALANINE; TETRAHYDROBIOPTERIN;

AMINO ACID BLOOD LEVEL; AMINO ACID SUBSTITUTION; DIET SUPPLEMENTATION; DISEASE ASSOCIATION; DRUG APPROVAL; ENZYME ACTIVITY; ENZYME DEFICIENCY; ENZYME KINETICS; ESSENTIAL FATTY ACID DEFICIENCY; FATTY ACID OXIDATION; HUMAN; INBORN ERROR OF METABOLISM; LOSS OF FUNCTION MUTATION; LYSOSOME STORAGE DISEASE; MISSENSE MUTATION; NONHUMAN; PHENOTYPE; PHENYLKETONURIA; PROTEIN AGGREGATION; PROTEIN DEGRADATION; PROTEIN FOLDING; PROTEIN HYDROLYSIS; PROTEIN STABILITY; REVIEW; UNFOLDED PROTEIN RESPONSE; ANIMAL; BIOLOGICAL MODEL; CHEMICAL STRUCTURE; DIET THERAPY; DRUG DEVELOPMENT; DRUG MANUFACTURE; ENZYME REPLACEMENT; METHODOLOGY; PATHOLOGY; PROTEOSTASIS DEFICIENCY;

ANIMALS; DIET THERAPY; DRUG DISCOVERY; ENZYME REPLACEMENT THERAPY; HUMANS; METABOLISM, INBORN ERRORS; MODELS, BIOLOGICAL; MODELS, MOLECULAR; ORPHAN DRUG PRODUCTION; PHENYLALANINE; PHENYLKETONURIAS; PROTEOSTASIS DEFICIENCIES;

EID: 79952548103     PISSN: 01418955     EISSN: 15732665     Source Type: Journal    
DOI: 10.1007/s10545-010-9185-4     Document Type: Review

References (80)

1. Aguado C, Pérez B, Ugarte M, Desviat LR (2006) Analysis of the effect of tetrahydrobiopterin on PAH gene expression in hepatoma cells. FEBS Lett 580:1697-1701
2. Allen SJ, Crown SE, Handel TM (2007) Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25:787-820 (Pubitemid 46697924)
3. Andersen O, 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 314:279-291 (Pubitemid 33105093)
4. Andersen OA, Stokka AJ, Flatmark T, Hough E (2003) 2.0A resolution crystal structures of the ternary complexes of human phenylalanine hydroxylase catalytic domain with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine or L-norleucine: substrate specificity and molecular motions related to substrate binding. J Mol Biol 333:747-757 (Pubitemid 37268016)
5. Baric I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD, James SJ, Mejaski-Bosnjak V, Pazanin L, Pogribny IP, Rados M, Sarnavka V, Scukanec-Spoljar M, Allen RH, Stabler S, Uzelac L, Vugrek O, Wagner C, Zeisel S, Mudd SH (2004) Sadenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci USA 101:4234-4239 (Pubitemid 38405912)
6. Beluzic R, Cuk M, Pavkov T, Fumic K, Baric I, Mudd SH, Jurak I, Vugrek O (2006) A single mutation at Tyr143 of human Sadenosylhomocysteine hydrolase renders the enzyme thermosensitive and affects the oxidation state of bound cofactor nicotinamide-adenine dinucleotide. Biochem J 400:245-253 (Pubitemid 44852038)
7. Bernegger C, Blau N (2002) High frequency of tetrahydrobiopterin- responsiveness among hyperphenylalaninemias: a study of 1, 919 patients observed from 1988 to 2002.Mol GenetMetab 77:304-313 (Pubitemid 36027137)
8. Bickel H, Gerrard J, Hickmans EM (1953) Influence of phenylalanine intake on phenylketonuric. Lancet 265:812-813
9. Bickel H, Gerrard J, Hickmans EM (1954) The influence of phenylalanine intake on the chemistry and behaviour of a phenylketonuric child. Acta Paediatr 43:64-77
10. Bjørgo E, Knappskog PM, Martinez A, Stevens RC, Flatmark T (1998) Partial characterization and three-dimensional-structural localization of eight mutations in exon 7 of the human phenylalanine hydroxylase gene associated with phenylketonuria. Eur J Biochem 257:1-10 (Pubitemid 28462574)
11. Brodsky JL (2007) The protective and destructive roles played by molecular chaperones during ERAD (endoplasmic-reticulum-associated degradation). Biochem J 404:353-363
12. Bross P, Jespersen C, Jensen TG, Andresen BS, Kristensen MJ, Winter V, Nandy A, Krautle F, Ghisla S, Bolundi L et al (1995) Effects of two mutations detected in medium chain acyl-CoA dehydrogenase (MCAD)-deficient patients on folding, oligomer assembly, and stability of MCAD enzyme. J Biol Chem 270:10284-10290
13. Bross P, Pedersen P, Winter V, Nyholm M, Johansen BN, Olsen RK, Corydon MJ, Andresen BS, Eiberg H, Kolvraa S, Gregersen N (1999) A polymorphic variant in the human electron transfer flavoprotein alpha-chain (alpha-T171) displays decreased thermal stability and is overrepresented in very-long-chain acyl-CoA dehydrogenase-deficient patients with mild childhood presentation. Mol Genet Metab 67:138-147 (Pubitemid 29393241)
14. Cohen FE, Kelly JW (2003) Therapeutic approaches to proteinmisfolding diseases. Nature 426:905-909
15. Cooper DN, Ball EV, Stenson PD, Phillips AD, Howells K, Mort ME (2010) The Human Gene Mutation Database. http://www.hgmd.cf.ac.uk/ac/index.php
16. Daily MD, Gray JJ (2007) Local motions in a benchmark of allosteric proteins. Bioinformatics 399:385-399 (Pubitemid 46449415)
17. Daily MD, Upadhyaya TJ, Gray JJ (2008) Contact rearrangements form coupled networks from local motions in allosteric proteins. Proteins 71:455-466 (Pubitemid 351358624)
18. DePristo MA, Weinreich DM, Hartl DL (2005) Missense meanderings in sequence space: a biophysical view of protein evolution. Nat Rev Genet 6:678-687 (Pubitemid 41192319)
19. Erlandsen H, Pey AL, Gamez A, Perez B, Desviat LR, Aguado C, Koch R, Surendran S, Tyring S, Matalon R, Scriver CR, Ugarte M, Martinez A, Stevens RC (2004) Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Natl Acad Sci USA 101:16903-16908 (Pubitemid 39601336)
20. Fan JQ, Ishii S, Asano N, Suzuki Y (1999) Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 5:112-115 (Pubitemid 29051008)
21. Feillet F, Clarke L, Meli C, Lipson M, Morris AA, Harmatz P, Mould DR, Green B, Dorenbaum A, Giovannini M, Foehr E (2008) Pharmacokinetics of sapropterin in patients with phenylketonuria. Clin Pharmacokinet 47:817-825
22. Ficko-Blean E, Stubbs KA, Nemirovsky O, Vocadlo DJ, Boraston AB (2008) Structural and mechanistic insight into the basis of mucopolysaccharidosis IIIB. Proc Natl Acad Sci USA 105:6560-6565 (Pubitemid 351754546)
23. Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5:554-565 (Pubitemid 38868584)
24. Gersting SW, Kemter KF, Staudigl M, Messing DD, Danecka MK, Lagler FB, Sommerhoff CP, Roscher AA, Muntau AC (2008) Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am J Hum Genet 83:5-17
25. Gersting SW, Lagler FB, Eichinger A, Kemter KF, Danecka MK,Messing DD, Staudigl M, Domdey KA, Zsifkovits C, Fingerhut R, Glossmann H, Roscher AA, Muntau AC (2010) Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. Hum Mol Genet 19:2039-2049
26. Gjetting T, Petersen M, Guldberg P, Güttler F (2001) In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: correlation with metabolic phenotypes and susceptibility toward protein aggregation. Mol Genet Metab 72:132-143
27. Gregersen N, Olsen RKJ (2010) Disease mechanisms and protein structures in fatty acid oxidation defects. J Inherit Metab Dis. doi:10.1007/s10545-010- 9046-1
28. Gregersen N, Bross P, Vang S, Christensen JH (2006) Protein misfolding and human disease. Annu Rev Genomics Hum Genet 7:103-124 (Pubitemid 44627924)
29. Hennermann JB, Bührer C, Blau N, Vetter B, Mönch E (2005) Longterm treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab 86(Suppl 1):S86-S90 (Pubitemid 41771115)
30. Ignatova Z (2005) Monitoring protein stability in vivo. Microb Cell Fact 6:1-6
31. Kim S-W, Jung J, Oh H-J, Kim J, Lee K-S, Lee D-H, Park C, Kimm K, Koo SK, Jung S-C (2006) Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene. Clin Chim Acta 365:279-287 (Pubitemid 43196449)
32. Koch J (1997) Robert Guthrie - the PKU story: crusade against mental retardation. Hope Publishing House, Pasadena, CA
33. Kure S, Hou DC, Ohura T, Iwamoto H, Suzuki S, Sugiyama N, Sakamoto O, Fujii K, Matsubara Y, Narisawa K (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135:375-378 (Pubitemid 30180515)
34. Lässker U, Zschocke J, Blau N, Santer R (2002) Tetrahydrobiopterin responsiveness in phenylketonuria. Two new cases and a review of molecular genetic findings. J Inherit Metab Dis 25:65-70 (Pubitemid 34303228)
35. Lee P, Treacy EP, Crombez E, Wasserstein M, Waber L, Wolff J, Wendel U, Dorenbaum A, Bebchuk J, Christ-Schmidt H, Seashore M, Giovannini M, Burton BK, Morris AA (2008) Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet 146A:2851-2859
36. Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK, Whitley CB, Feillet F, Feigenbaum AS, Bebchuk JD, Christ-Schmidt H, Dorenbaum A (2007) Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 370:504-510 (Pubitemid 47212372)
37. Lieberman RL,Wustman BA, Huertas P, Powe AC Jr, Pine CW, Khanna R, Schlossmacher MG, Ringe D, Petsko GA (2007) Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease. Nat Chem Biol 3:101-107 (Pubitemid 46134996)
38. Lindner M, Steinfeld R, Burgard P, Schulze A, Mayatepek E, Zschocke J (2003) Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency. Hum Mutat 21:400
39. Luheshi LM, Dobson CM (2009) Bridging the gap: from protein misfolding to protein misfolding diseases. FEBS Lett 583:2581-2586
40. Maegawa GH, Tropak M, Buttner J, Stockley T Kok F, Clarke JT, Mahuran DJ (2007) Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. J Biol Chem 282:9150-9161 (Pubitemid 47093481)
41. Maier EM, Gersting SW, Kemter KF, Jank JM, Reindl M, Messing DD, Truger MS, Sommerhoff CP, Muntau AC (2009) Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum Mol Genet 18:1612-1623
42. Matsuda J, Suzuki O, Oshima A, Yamamoto Y, Noguchi A, Takimoto K, Itoh M, Matsuzaki Y, Yasuda Y, Ogawa S, Sakata Y, Nanba E, Higaki K, Ogawa Y, Tominaga L, Ohno K, Iwasaki H, Watanabe H, Brady RO, Suzuki Y (2003) Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis. Proc Natl Acad Sci USA 100:15912-15917 (Pubitemid 38021089)
43. McDonald JD, Bode VC, Dove WF, Shedlovsky A (1990) The use of N-ethyl-N-nitrosourea to produce mouse models for human phenylketonuria and hyperphenylalaninemia. Prog Clin Biol Res 340C:407-413
44. Mu TW, Ong DS, Wang YJ, Balch WE, Yates JR 3rd, Segatori L, Kelly JW (2008) Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 134:769-781
45. Muntau AC, Röschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347:2122-2132 (Pubitemid 36015124)
46. O'Reilly LP, Andresen BS, Engel PC (2005) Two novel variants of human medium chain acyl-CoA dehydrogenase (MCAD). K364R, a folding mutation, and R256T, a catalytic-site mutation resulting in a well-folded but totally inactive protein. FEBS J 272:4549-4557
47. Parenti G, Zuppaldi A, Gabriela Pittis M, Rosaria Tuzzi M, Annunziata I, Meroni G, Porto C, Donaudy F, Rossi B, Rossi M, Filocamo M, Donati A, Bembi B, Ballabio A, Andria G (2007) Pharmacological enhancement of mutated alpha-glucosidase activity in fibroblasts from patients with Pompe disease. Mol Ther 15:508-514
48. Pedersen CB, Bross P, Winter VS, Corydon TJ, Bolund L, Bartlett K, Vockley J, Gregersen N (2003) Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. J Biol Chem 278:47449-47458 (Pubitemid 37523186)
49. Pérez B, Desviat LR, Gómez-Puertas P, Martínez A, Stevens RC, Ugarte M (2005) Kinetic and stability analysis of PKU mutations identified in BH4-responsive patients. Mol Genet Metab 86 (Suppl 1):S11-S16 (Pubitemid 41771105)
50. Pey AL, Desviat LR, Gámez A, Ugarte M, Pérez B (2003) Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat 21:370-378 (Pubitemid 36389826)
51. Pey AL, Perez B, Desviat LR, Martinez MA, Aguado C, Erlandsen H, Gamez A, Stevens RC, Thorolfsson M, Ugarte M, Martinez A (2004) Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations. Hum Mutat 24:388-399 (Pubitemid 39473664)
52. Pey AL, Stricher F, Serrano L, Martinez A (2007) Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Am J Hum Genet 81:1006-1024 (Pubitemid 47580253)
53. Pey AL, Ying M, Cremades N, Velazquez-Campoy A, Scherer T, Thöny B, Sancho J, Martinez A (2008) Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria. J Clin Invest 118:2858-2867
54. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959-991
55. Saijo T, Welch WJ, Tanaka K (1994) Intramitochondrial folding and assembly of medium-chain acyl-CoA dehydrogenase (MCAD). Demonstration of impaired transfer of K304E-variant MCAD from its complex with hsp60 to the native tetramer. J Biol Chem 269:4401-4408
56. Sawkar AR, Cheng WC, Beutler E, Wong CH, Balch WE, Kelly JW (2002) Chemical chaperones increase the cellular activity of N370S beta-glucosidase: a therapeutic strategy for Gaucher disease. Proc Natl Acad Sci USA 99:15428-15433 (Pubitemid 35403951)
57. Scavelli R, Ding Z, Blau N, Haavik J, Martínez A, Thöny B (2005) Stimulation of hepatic phenylalanine hydroxylase activity but not Pah-mRNA expression upon oral loading of tetrahydrobiopterin in normal mice. Mol Genet Metab 86 (Suppl 1):S153-S155 (Pubitemid 41771127)
58. Schmitz M, Alfalah M, Aerts JMFG, Naim HY, Zimmer K-P (2005) Impaired trafficking of mutants of lysosomal glucocerebrosidase in Gaucher's disease. Int J Biochem Cell Biol 37:2310-2320 (Pubitemid 41207403)
59. Schröder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739-789 (Pubitemid 40995523)
60. Shedlovsky A, McDonald JD, Symula D, Dove WF (1993) Mouse models of human phenylketonuria. Genetics 134:1205-1210 (Pubitemid 23220041)
61. Shintaku H, Kure S, Ohura T, Okano Y, Ohwada M, Sugiyama N, Sakura N, Yoshida I, Yoshino M, Matsubara Y, Suzuki K, Aoki K, Kitagawa T (2004) Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene. Pediatr Res 55:425-430 (Pubitemid 38240820)
62. Spaapen LJ, Bakker JA, Velter C, Loots W, Rubio-Gozalbo ME, Forget PP, Dorland L, De Koning TJ, Poll-The BT, Ploos van Amstel HK, Bekhof J, Blau N, Duran M (2001) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates. J Inherit Metab Dis 24:352-358 (Pubitemid 32677515)
63. Steinfeld R, Kohlschütter A, Zschocke J, Lindner M, Ullrich K, Lukacs Z (2002) Tetrahydrobiopterin monotherapy for phenylketonuria patients with common mild mutations. Eur J Pediatr 161:403-405 (Pubitemid 34744017)
64. Steinfeld R, Kohlschütter A, Ullrich K, Lukacs Z (2004) Efficiency of long-term tetrahydrobiopterin monotherapy in phenylketonuria. J Inherit Metab Dis 27:449-453 (Pubitemid 39140135)
65. Stokka AJ, Carvalho RN, Barroso JF, Flatmark T (2004) Probing the role of crystallographically defined/predicted hinge-bending regions in the substrate-induced global conformational transition and catalytic activation of human phenylalanine hydroxylase by single-site mutagenesis. J Biol Chem 279:26571-26580 (Pubitemid 38798813)
66. Tekpinar M, Zheng W (2010) Predicting order of conformational changes during protein conformational transitions using an interpolated elastic network model. Proteins 78:2469-2481
67. Thöny B, Ding Z, Martínez A (2004) Tetrahydrobiopterin protects phenylalanine hydroxylase activity in vivo: implications for tetrahydrobiopterin-responsive hyperphenylalaninemia. FEBS Lett 577:507-511
68. Thórólfsson M, Teigen K, Martínez A (2003) Activation of phenylalanine hydroxylase: effect of substitutions at Arg68 and Cys237. Biochemistry 42:3419-3428
69. Trefz FK, Aulela-Scholz C, Blau N (2001) Successful treatment of phenylketonuria with tetrahydrobiopterin. Eur J Pediatr 160:315
70. Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, Lipson MH, Milanowski A, Randolph LM, Vockley J, Whitley CB, Wolff JA, Bebchuk J, Christ-Schmidt H, Hennermann JB (2009) Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr 154:700-707
71. Ulloa-Aguirre A, Janovick JA, Brothers SP, Conn PM (2004) Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic 5:821-837 (Pubitemid 39433553)
72. Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat RevMol Cell Biol 9:944-957
73. Wang L, Surendran S, Michals-Matalon K, Bhatia G, Tanskley S, Koch R, Grady J, Tyring SK, Stevens RC, Guttler F, Matalon R (2007) Mutations in the regulatory domain of phenylalanine hydroxylase and response to tetrahydrobiopterin. Genet Test 11:174-178 (Pubitemid 47041936)
74. Waters PJ (2003) How PAH gene mutations cause hyperphenylalaninemia and why mechanism matters: insights from in vitro expression. Hum Mutat 21:357-369
75. Waters PJ, Parniak MA, Akerman BR, Scriver CR (2000) Characterization of phenylketonuria missense substitutions, distant from the phenylalanine hydroxylase active site, illustrates a paradigm for mechanism and potential modulation of phenotype. Mol Genet Metab 69:101-110 (Pubitemid 30180693)
76. Waters PJ, Scriver CR, Parniak MA (2001) Homomeric and heteromeric interactions between wild-type and mutant phenylalanine hydroxylase subunits: evaluation of two-hybrid approaches for functional analysis of mutations causing hyperphenylalaninemia. Mol Genet Metab 73:230-238 (Pubitemid 32709613)
77. Weglage J, Grenzebach M, van Teeffelen-Heithoff A, Marquardt T, Feldmann R, Denecke J, Gödde D, Koch HG (2002) Tetrahydrobiopterin responsiveness in a large series of phenylketonuria patients. J Inherit Metab Dis 25:321-322 (Pubitemid 34982066)
78. Yu Z, Sawkar AR, Kelly JW (2007) Pharmacologic chaperoning as a strategy to treat Gaucher disease. FEBS J 274:4944-4950 (Pubitemid 47481193)
79. Zhong Q, Simonis N, Li QR, Charloteaux B, Heuze F, Klitgord N, Tam S, Szeto D, Lin C, Hao T, Fan C, Milstein S, Dupuy D, Brasseur R, Hill DE, Cusick ME, Vidal M (2009) Edgetic perturbation models of human inherited disorders. Mol Syst Biol 5:321
80. Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N (2008) Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat 29:167-175