title: Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism.
abstract: The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life. Important milestones were the successful development of a low-phenylalanine diet for phenylketonuria patients, the recognition of tetrahydrobiopterin as an option to treat these individuals pharmacologically, and finally market approval of this drug. The work related to the discovery of a pharmacological treatment led metabolic researchers and pediatricians to new insights into the molecular processes linked to mutations in the phenylalanine hydroxylase gene at the cellular and structural level. Again, phenylketonuria became a prototype disorder for a previously underestimated but now rapidly expanding group of diseases: protein misfolding disorders with loss of function. Due to potential general biological mechanisms underlying these disorders, the door may soon open to a systematic development of a new class of pharmaceutical products. These pharmacological chaperones are likely to correct misfolding of proteins involved in numerous genetic and nongenetic diseases.
authors.affiliation: Dr von Hauner Children's Hospital, Department of Molecular Pediatrics, Ludwig Maximilians University, Lindwurmstrasse 4, 80337 Munich, Germany. Ania.Muntau@med.uni-muenchen.de
authors.forename: Ania C
authors.initials: AC
authors.lastname: Muntau
authors.forename: Søren W
authors.initials: SW
authors.lastname: Gersting
mesh_terms: D000818:Animals; D004035:Diet Therapy / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D056947:Enzyme Replacement Therapy / Q000379:methods; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000188:drug therapy* / Q000473:pathology; D008954:Models, Biological; D008958:Models, Molecular; D009965:Orphan Drug Production; D010649:Phenylalanine / Q000009:adverse effects; D010661:Phenylketonurias / Q000178:diet therapy / Q000188:drug therapy* / Q000473:pathology; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000473:pathology
chemical_list: D010649:Phenylalanine
references.citation: Annu Rev Genomics Hum Genet. 2006;7:103-24
references.pmid: 16722804
references.citation: J Inherit Metab Dis. 2010 Oct;33(5):547-53
references.pmid: 20151199
references.citation: Mol Genet Metab. 2000 Feb;69(2):101-10
references.pmid: 10720436
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4234-9
references.pmid: 15024124
references.citation: Pediatr Res. 2004 Mar;55(3):425-30
references.pmid: 14681498
references.citation: Biochem J. 2006 Dec 1;400(2):245-53
references.pmid: 16872278
references.citation: FEBS Lett. 2006 Mar 20;580(7):1697-701
references.pmid: 16504182
references.citation: J Mol Biol. 2001 Nov 23;314(2):279-91
references.pmid: 11718561
references.citation: Genetics. 1993 Aug;134(4):1205-10
references.pmid: 8375656
references.citation: Eur J Pediatr. 2002 Jul;161(7):403-5
references.pmid: 12174822
references.citation: Mol Ther. 2007 Mar;15(3):508-14
references.pmid: 17213836
references.citation: J Biol Chem. 1994 Feb 11;269(6):4401-8
references.pmid: 7905878
references.citation: J Biol Chem. 2003 Nov 28;278(48):47449-58
references.pmid: 14506246
references.citation: Annu Rev Biochem. 2009;78:959-91
references.pmid: 19298183
references.citation: FEBS Lett. 2009 Aug 20;583(16):2581-6
references.pmid: 19545568
references.citation: Nat Med. 1999 Jan;5(1):112-5
references.pmid: 9883849
references.citation: J Biol Chem. 1995 Apr 28;270(17):10284-90
references.pmid: 7730333
references.citation: FEBS J. 2007 Oct;274(19):4944-50
references.pmid: 17894779
references.citation: Biochem J. 2007 Jun 15;404(3):353-63
references.pmid: 17521290
references.citation: Hum Mutat. 2003 Apr;21(4):357-69
references.pmid: 12655545
references.citation: Int J Biochem Cell Biol. 2005 Nov;37(11):2310-20
references.pmid: 15982918
references.citation: N Engl J Med. 2002 Dec 26;347(26):2122-32
references.pmid: 12501224
references.citation: J Pediatr. 2009 May;154(5):700-7
references.pmid: 19261295
references.citation: Nat Chem Biol. 2007 Feb;3(2):101-7
references.pmid: 17187079
references.citation: Mol Genet Metab. 2001 Feb;72(2):132-43
references.pmid: 11161839
references.citation: Nat Rev Genet. 2005 Sep;6(9):678-87
references.pmid: 16074985
references.citation: Lancet. 2007 Aug 11;370(9586):504-10
references.pmid: 17693179
references.citation: J Pediatr. 1999 Sep;135(3):375-8
references.pmid: 10484807
references.citation: Nat Rev Mol Cell Biol. 2004 Jul;5(7):554-65
references.pmid: 15232573
references.citation: Hum Mutat. 2003 Apr;21(4):370-8
references.pmid: 12655546
references.citation: J Clin Invest. 2008 Aug;118(8):2858-67
references.pmid: 18596920
references.citation: Cell. 2008 Sep 5;134(5):769-81
references.pmid: 18775310
references.citation: J Inherit Metab Dis. 2004;27(4):449-53
references.pmid: 15303001
references.citation: FEBS J. 2005 Sep;272(17):4549-57
references.pmid: 16128823
references.citation: Mol Syst Biol. 2009;5:321
references.pmid: 19888216
references.citation: Proteins. 2010 Aug 15;78(11):2469-81
references.pmid: 20602461
references.citation: Annu Rev Biochem. 2005;74:739-89
references.pmid: 15952902
references.citation: Prog Clin Biol Res. 1990;340C:407-13
references.pmid: 2381939
references.citation: J Inherit Metab Dis. 2002 Feb;25(1):65-70
references.pmid: 11999982
references.citation: Mol Genet Metab. 1999 Jun;67(2):138-47
references.pmid: 10356313
references.citation: Mol Genet Metab. 2005 Dec;86 Suppl 1:S153-5
references.pmid: 16290004
references.citation: Am J Hum Genet. 2007 Nov;81(5):1006-24
references.pmid: 17924342
references.citation: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6560-5
references.pmid: 18443291
references.citation: Clin Chim Acta. 2006 Mar;365(1-2):279-87
references.pmid: 16253218
references.citation: Nat Rev Mol Cell Biol. 2008 Dec;9(12):944-57
references.pmid: 19002207
references.citation: J Mol Biol. 2003 Oct 31;333(4):747-57
references.pmid: 14568534
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15428-33
references.pmid: 12434014
references.citation: Eur J Biochem. 1998 Oct 1;257(1):1-10
references.pmid: 9799096
references.citation: J Inherit Metab Dis. 2001 Jun;24(3):352-8
references.pmid: 11486900
references.citation: J Biol Chem. 2004 Jun 18;279(25):26571-80
references.pmid: 15060071
references.citation: Mol Genet Metab. 2005 Dec;86 Suppl 1:S86-90
references.pmid: 16051511
references.citation: Hum Mol Genet. 2010 May 15;19(10):2039-49
references.pmid: 20179079
references.citation: Mol Genet Metab. 2005 Dec;86 Suppl 1:S11-6
references.pmid: 16091306
references.citation: J Biol Chem. 2007 Mar 23;282(12):9150-61
references.pmid: 17237499
references.citation: Hum Mutat. 2003 Apr;21(4):400
references.pmid: 12655554
references.citation: Clin Pharmacokinet. 2008;47(12):817-25
references.pmid: 19026037
references.citation: FEBS Lett. 2004 Nov 19;577(3):507-11
references.pmid: 15556637
references.citation: Genet Test. 2007 Summer;11(2):174-8
references.pmid: 17627389
references.citation: Eur J Pediatr. 2001 May;160(5):315
references.pmid: 11388602
references.citation: Annu Rev Immunol. 2007;25:787-820
references.pmid: 17291188
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16903-8
references.pmid: 15557004
references.citation: Am J Hum Genet. 2008 Jul;83(1):5-17
references.pmid: 18538294
references.citation: Hum Mol Genet. 2009 May 1;18(9):1612-23
references.pmid: 19224950
references.citation: Hum Mutat. 2008 Jan;29(1):167-75
references.pmid: 17935162
references.citation: Proteins. 2007 May 1;67(2):385-99
references.pmid: 17295319
references.citation: Lancet. 1953 Oct 17;265(6790):812-3
references.pmid: 13098090
references.citation: Proteins. 2008 Apr;71(1):455-66
references.pmid: 17957766
references.citation: Acta Paediatr. 1954 Jan;43(1):64-77
references.pmid: 13138177
references.citation: J Inherit Metab Dis. 2002 Aug;25(4):321-2
references.pmid: 12227464
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15912-7
references.pmid: 14676316
references.citation: Biochemistry. 2003 Apr 1;42(12):3419-28
references.pmid: 12653545
references.citation: Nature. 2003 Dec 18;426(6968):905-9
references.pmid: 14685252
references.citation: Mol Genet Metab. 2001 Jul;73(3):230-8
references.pmid: 11461190
references.citation: Hum Mutat. 2004 Nov;24(5):388-99
references.pmid: 15459954
references.citation: Traffic. 2004 Nov;5(11):821-37
references.pmid: 15479448
references.citation: Mol Genet Metab. 2002 Dec;77(4):304-13
references.pmid: 12468276
references.citation: Am J Med Genet A. 2008 Nov 15;146A(22):2851-9
references.pmid: 18932221