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A Molecular View of Phenylketonuria

A Molecular View of Phenylketonuria. By: Sindhu Kilakkathi. What is Phenylketonuria (PKU)?. Autosomal recessive genetic disorder (Incidence: 1/10,000 newborns) Mutation of Phenylalanine hydroxylase (PAH) gene on chromosome 12 1 Lack of PAH, defective PAH, insufficient BH 4. PAH.

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A Molecular View of Phenylketonuria

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  1. A Molecular View of Phenylketonuria By: Sindhu Kilakkathi

  2. What is Phenylketonuria (PKU)? • Autosomal recessive genetic disorder (Incidence: 1/10,000 newborns) • Mutation of Phenylalanine hydroxylase (PAH) gene on chromosome 121 • Lack of PAH, defective PAH, insufficient BH4 PAH Phenylalanine Tyrosine BH4 Phe Normal PAH Tyrosine

  3. What is Phenylketonuria (PKU)? • Autosomal recessive genetic disorder (Incidence: 1/10,000 newborns) • Mutation of Phenylalanine hydroxylase (PAH) gene on chromosome 121 • Lack of PAH, defective PAH, insufficient BH4 PAH Phenylalanine Tyrosine BH4 Phe Mutated PAH Phe Metabolites Phe Metabolites Phe Metabolites Phe Metabolites Phe Metabolites

  4. Effects of PAH Enzymopathy • Accumulation of Phe elevated blood and urine Phe levels • Decreased levels of Tyr  lack of catecholamines (necessary for development) and melanin Melanin PAH TH Phenylalanine Tyrosine DOPA BH4 BH4 Catecholamines

  5. Symptoms of PKU • Severe mental retardation, brain damage, seizures, mousy odor in skin and hair, lack of pigmentation, eczema, IQ of <50, aggressive behavior, negative mood • Reduced dopamine levels • hypomyelination5 • Variability in expressivity • More prevalent in certain ethnic populations (e.g. Turkish- 1/2600)1 http://www.dshs.state.tx.us/newborn/over_pku.shtm

  6. Diagnosis • PKU first detected with FeCl3 test (phenylpyruvate + FeCl3 green urine)2 • Now Guthrie test is used (4 mg/dL) • Prenatal testing (DNA probes)1 http://www.flickr.com/photos/ozewiezewozewiezewallakristallix/2632833781/

  7. Implications for Carriers of PKU • 1.5% population are heterozygotes • Appear phenotypically normal, but have lower levels of PAH and higher blood levels of Phe • Definitive test: measure kinetics of disappearance of injected Phe2 ?

  8. Treatment • Low Phe diet started soon after birth (restricted protein and dairy consumption)3 • Supplements- BH4 (Kuvan and Phenoptin) • Phenylalanine ammonia lyase (enzyme substitution) • Gene therapy (viral vectors to introduce functional PAH gene into liver cells)1

  9. Understanding the Biochemistry of PKU • Root of the Problem: • Mutations in PAH [PDB ID: 2PAH] • Cause of the Symptoms: • Interaction of Phe with Large Neutral Amino Acids (LNAAs) at the Blood Brain Barrier (BBB) [PDB ID: 2DH2] • Treatment: • How PAL can treat PKU [PDB ID: 1Y2M]

  10. A Closer Look at PAH Tetramer Monomer Regulatory Domain 2 identical alpha subunits – cyan 2 identical beta subunits – red

  11. Mutations of PAH • 400+ mutations of PAH gene that cause PKU • Most frequent mutation- R408W • Tryptophan substituted for arginine

  12. An Examination of LNAAs • LNAA carriers transport LNAAs across BBB • LAT1 transporter encoded for by SLC3A2 and SLC3A5 genes in 4F2hc • 4F2hc (CD98hc)- multifunction type II membrane glycoprotein • Phe blocks transport of Tyr and Trp Acetone

  13. Treatment with PAL • Another enzyme that can catabolizePhe PAL Trans-cinnamic acid NH3 Phenylalanine

  14. PAL Structure Homotetrameric Overlap of the 4 subunits 4 identical monomers

  15. Issues with PAL in Treatment • Accessible PAL trypin and chymotrypsin cleavage sites- Arg123 and Tyr 110 • Conjugate with Polyethylene gycol (PEG) to increase efficacy • So far there have not been major side effects

  16. References • 1. Williams RA, Mamotte CD, Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. ClinBiochem Rev. 2008; 29(1):31-41. • 2. Berg, Jeremy Mark., John L. Tymoczko, and LubertStryer. Biochemistry. 6th ed. New York: W.H. Freeman, 2007. 673-74. Print. • 3. Michals-Matalon K. Developments in phenylketonuria. Topics ClinNutr. 2001;16:41–50. • 4. Dyer CA. Pathophysiology of phenylketonuria. Ment Retard Dev Disab Res Rev. 1999;5:104–12. • 5. Erlandsen H, Stevens RC. 1999. The structural basis of phenylketonuria. Mol Genet Metab 68: 103-125.

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