Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Phenylketonuria
Homo sapiens
Disease Pathway
Created: 2022-11-01
Last Updated: 2024-05-18
Phenylketonuria, also called Folling disease, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder that affects the proper processing of phenylalanine caused by a defective phenylalanine hydroxylase. Phenylalanine hydroxylase breaks down phenylalanine from the diet. This disorder is characterized by a large accumulation of phenylalanine in the blood and other tissues. It is also characterized by an accumulation of Phenylpyruvic acid, Mandelic acid, Phenylacetic acid, Phenylacetylglutamine, and Glycine in the blood and urine. Symptoms of the disorder include behavioural problems, psychiatric disorders and seizures. Treatment eating a diet limiting the intake of phenylalanine is very effective. It is estimated that phenylketonuria affects 1 in 15,000 individuals in the United States.
References
Phenylketonuria References
Engelke, U., van der Graaf, M., Heerschap, A., Hoenderop, S., Moolenaar, S., Morava, E., Wevers, R. Handbook of 1H-NMR spectroscopy in inborn errors of metabolism: body fluid NMR spectroscopy and in vivo MR spectroscopy (2nd ed) (2007) p.80 Heilbronn: SPS Verlagsgesellschaft
Burgard P, Rupp A, Konecki DS, Trefz FK, Schmidt H, Lichter-Konecki U: Phenylalanine hydroxylase genotypes, predicted residual enzyme activity and phenotypic parameters of diagnosis and treatment of phenylketonuria. Eur J Pediatr. 1996 Jul;155 Suppl 1:S11-5. doi: 10.1007/pl00014222.
Pubmed: 8828601
Eisensmith RC, Woo SL: Gene therapy for phenylketonuria. Eur J Pediatr. 1996 Jul;155 Suppl 1:S16-9. doi: 10.1007/pl00014237.
Pubmed: 8828602
Hanley WB, Lee AW, Hanley AJ, Lehotay DC, Austin VJ, Schoonheyt WE, Platt BA, Clarke JT: "Hypotyrosinemia" in phenylketonuria. Mol Genet Metab. 2000 Apr;69(4):286-94. doi: 10.1006/mgme.2000.2985.
Pubmed: 10870846
Kalaydjieva L, Dworniczak B, Kucinskas V, Yurgeliavicius V, Kunert E, Horst J: Geographical distribution gradients of the major PKU mutations and the linked haplotypes. Hum Genet. 1991 Feb;86(4):411-3. doi: 10.1007/BF00201847.
Pubmed: 1671852
Sumaily KM, Mujamammi AH: Phenylketonuria: A new look at an old topic, advances in laboratory diagnosis, and therapeutic strategies. Int J Health Sci (Qassim). 2017 Nov-Dec;11(5):63-70.
Pubmed: 29114196
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M: KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023 Jan 6;51(D1):D587-D592. doi: 10.1093/nar/gkac963.
Pubmed: 36300620
Cannet C, Bayat A, Frauendienst-Egger G, Freisinger P, Spraul M, Himmelreich N, Kockaya M, Ahring K, Godejohann M, MacDonald A, Trefz F: Phenylketonuria (PKU) Urinary Metabolomic Phenotype Is Defined by Genotype and Metabolite Imbalance: Results in 51 Early Treated Patients Using Ex Vivo (1)H-NMR Analysis. Molecules. 2023 Jun 22;28(13):4916. doi: 10.3390/molecules28134916.
Pubmed: 37446577
Blau K: Aromatic acid excretion in phenylketonuria. Analysis of the unconjugated aromatic acids derived from phenylalanine. Clin Chim Acta. 1970 Jan;27(1):5-18. doi: 10.1016/0009-8981(70)90368-2.
Pubmed: 5412612
Wild J, Shanmuganathan M, Hayashi M, Potter M, Britz-McKibbin P: Metabolomics for improved treatment monitoring of phenylketonuria: urinary biomarkers for non-invasive assessment of dietary adherence and nutritional deficiencies. Analyst. 2019 Nov 4;144(22):6595-6608. doi: 10.1039/c9an01642b.
Pubmed: 31608347
Lukito BR, Wang Z, Sundara Sekar B, Li Z: Production of (R)-mandelic acid from styrene, L-phenylalanine, glycerol, or glucose via cascade biotransformations. Bioresour Bioprocess. 2021 Mar 4;8(1):22. doi: 10.1186/s40643-021-00374-6.
Pubmed: 38650227
Glushakov AV, Dennis DM, Morey TE, Sumners C, Cucchiara RF, Seubert CN, Martynyuk AE: Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria. Mol Psychiatry. 2002;7(4):359-67. doi: 10.1038/sj.mp.4000976.
Pubmed: 11986979
Bousquet-Lemercier B, Pol S, Pave-Preux M, Hanoune J, Barouki R: Properties of human liver cytosolic aspartate aminotransferase mRNAs generated by alternative polyadenylation site selection. Biochemistry. 1990 Jun 5;29(22):5293-9. doi: 10.1021/bi00474a011.
Pubmed: 1974457
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Deloukas P, Earthrowl ME, Grafham DV, Rubenfield M, French L, Steward CA, Sims SK, Jones MC, Searle S, Scott C, Howe K, Hunt SE, Andrews TD, Gilbert JG, Swarbreck D, Ashurst JL, Taylor A, Battles J, Bird CP, Ainscough R, Almeida JP, Ashwell RI, Ambrose KD, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Bates K, Beasley H, Bray-Allen S, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Cahill P, Camire D, Carter NP, Chapman JC, Clark SY, Clarke G, Clee CM, Clegg S, Corby N, Coulson A, Dhami P, Dutta I, Dunn M, Faulkner L, Frankish A, Frankland JA, Garner P, Garnett J, Gribble S, Griffiths C, Grocock R, Gustafson E, Hammond S, Harley JL, Hart E, Heath PD, Ho TP, Hopkins B, Horne J, Howden PJ, Huckle E, Hynds C, Johnson C, Johnson D, Kana A, Kay M, Kimberley AM, Kershaw JK, Kokkinaki M, Laird GK, Lawlor S, Lee HM, Leongamornlert DA, Laird G, Lloyd C, Lloyd DM, Loveland J, Lovell J, McLaren S, McLay KE, McMurray A, Mashreghi-Mohammadi M, Matthews L, Milne S, Nickerson T, Nguyen M, Overton-Larty E, Palmer SA, Pearce AV, Peck AI, Pelan S, Phillimore B, Porter K, Rice CM, Rogosin A, Ross MT, Sarafidou T, Sehra HK, Shownkeen R, Skuce CD, Smith M, Standring L, Sycamore N, Tester J, Thorpe A, Torcasso W, Tracey A, Tromans A, Tsolas J, Wall M, Walsh J, Wang H, Weinstock K, West AP, Willey DL, Whitehead SL, Wilming L, Wray PW, Young L, Chen Y, Lovering RC, Moschonas NK, Siebert R, Fechtel K, Bentley D, Durbin R, Hubbard T, Doucette-Stamm L, Beck S, Smith DR, Rogers J: The DNA sequence and comparative analysis of human chromosome 10. Nature. 2004 May 27;429(6990):375-81. doi: 10.1038/nature02462.
Pubmed: 15164054
Chavan SS, Tian W, Hsueh K, Jawaheer D, Gregersen PK, Chu CC: Characterization of the human homolog of the IL-4 induced gene-1 (Fig1). Biochim Biophys Acta. 2002 Jun 7;1576(1-2):70-80. doi: 10.1016/s0167-4781(02)00295-6.
Pubmed: 12031486
Wiemann S, Kolb-Kokocinski A, Poustka A: Alternative pre-mRNA processing regulates cell-type specific expression of the IL4l1 and NUP62 genes. BMC Biol. 2005 Jul 19;3:16. doi: 10.1186/1741-7007-3-16.
Pubmed: 16029492
Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome Res. 2003 Oct;13(10):2265-70. doi: 10.1101/gr.1293003. Epub 2003 Sep 15.
Pubmed: 12975309
Rettenmeier R, Natt E, Zentgraf H, Scherer G: Isolation and characterization of the human tyrosine aminotransferase gene. Nucleic Acids Res. 1990 Jul 11;18(13):3853-61. doi: 10.1093/nar/18.13.3853.
Pubmed: 1973834
Zelenin SM, Mertvetsov NP: [Nucleotide sequence of the human tyrosine aminotransferase gene]. Bioorg Khim. 1994 Feb;20(2):196-204.
Pubmed: 7908801
Seralini GE, Luu-The V, Labrie F: Cloning and expression of human tyrosine aminotransferase cDNA. Biochim Biophys Acta. 1995 Jan 2;1260(1):97-101. doi: 10.1016/0167-4781(94)00191-5.
Pubmed: 7999802
Kwok SC, Ledley FD, DiLella AG, Robson KJ, Woo SL: Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry. 1985 Jan 29;24(3):556-61. doi: 10.1021/bi00324a002.
Pubmed: 2986678
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.
Pubmed: 15489334
Cotton RG, McAdam W, Jennings I, Morgan FJ: A monoclonal antibody to aromatic amino acid hydroxylases. Identification of the epitope. Biochem J. 1988 Oct 1;255(1):193-6. doi: 10.1042/bj2550193.
Pubmed: 2461704
Ruetschi U, Cerone R, Perez-Cerda C, Schiaffino MC, Standing S, Ugarte M, Holme E: Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III. Hum Genet. 2000 Jun;106(6):654-62. doi: 10.1007/s004390000307.
Pubmed: 10942115
Awata H, Endo F, Matsuda I: Structure of the human 4-hydroxyphenylpyruvic acid dioxygenase gene (HPD). Genomics. 1994 Oct;23(3):534-9. doi: 10.1006/geno.1994.1540.
Pubmed: 7851880
Stenman G, Roijer E, Ruetschi U, Dellsen A, Rymo L, Lindstedt S: Regional assignment of the human 4-hydroxyphenylpyruvate dioxygenase gene (HPD) to 12q24-->qter by fluorescence in situ hybridization. Cytogenet Cell Genet. 1995;71(4):374-6. doi: 10.1159/000134142.
Pubmed: 8521727
Vilboux T, Kayser M, Introne W, Suwannarat P, Bernardini I, Fischer R, O'Brien K, Kleta R, Huizing M, Gahl WA: Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria. Hum Mutat. 2009 Dec;30(12):1611-9. doi: 10.1002/humu.21120.
Pubmed: 19862842
Zatkova A, Sedlackova T, Radvansky J, Polakova H, Nemethova M, Aquaron R, Dursun I, Usher JL, Kadasi L: Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database. JIMD Rep. 2012;4:55-65. doi: 10.1007/8904_2011_68. Epub 2011 Oct 20.
Pubmed: 23430897
Yang YJ, Guo JH, Chen WJ, Zhao R, Tang JS, Meng XH, Zhao L, Tu M, He XY, Wu LQ, Zhu YM: First report of HGD mutations in a Chinese with alkaptonuria. Gene. 2013 Apr 15;518(2):467-9. doi: 10.1016/j.gene.2013.01.020. Epub 2013 Jan 24.
Pubmed: 23353776
Fernandez-Canon JM, Penalva MA: Characterization of a fungal maleylacetoacetate isomerase gene and identification of its human homologue. J Biol Chem. 1998 Jan 2;273(1):329-37. doi: 10.1074/jbc.273.1.329.
Pubmed: 9417084
Board PG, Baker RT, Chelvanayagam G, Jermiin LS: Zeta, a novel class of glutathione transferases in a range of species from plants to humans. Biochem J. 1997 Dec 15;328 ( Pt 3):929-35. doi: 10.1042/bj3280929.
Pubmed: 9396740
Blackburn AC, Woollatt E, Sutherland GR, Board PG: Characterization and chromosome location of the gene GSTZ1 encoding the human Zeta class glutathione transferase and maleylacetoacetate isomerase. Cytogenet Cell Genet. 1998;83(1-2):109-14. doi: 10.1159/000015145.
Pubmed: 9925947
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings