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What is Phenylketonuria

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Title: What is Phenylketonuria


1
What is Phenylketonuria?
  • Autosomal Recessive Disorder.
  • Inherited error of metabolism caused by
    deficiency in the enzyme phenylalanine
    hydroxylase (PAH).
  • Mutation in both alleles of the gene for the
    enzyme.
  • Chromosome 12.
  • Recessive allele carried by 1 out of every 60
    individuals.

2
Phenylketonuria
  • By Ilyssa Ramos
  • Biochemistry II

3
Autosomal Recessive Disorders
http//upload.wikimedia.org/wikipedia/commons/thum
b/3/3e/Autorecessive.svg/250px-Autorecessive.svg.p
ng
4
  • Symptoms Appear within the 1st year
  • Vomiting/Convulsions
  • Mental Retardation
  • Albinism
  • Light skin and hair color
  • Two forms
  • Common - defect in Phenylalanine Hydroxylase
  • Rarer - defect in tetrahydrobiopterin synthesis
  • Proposed Treatment
  • Low intake of phenylalanine (synthetic diet)
  • must contain Tyrosine
  • Adult phenylketonurics can go off diet with only
    minor symptoms.
  • But mothers-to-be should be on synthetic diet at
    least 3 months prior to conception

www.uhmc.sunysb.edu/som/courses/mgac/ANLect8AACa
tabC.ppt
5
Phenylalanine
  • L-phenylalanine-natural form found in proteins
    throughout the body.
  • 1of 20 amino acids.
  • Not manufactured in vivo.
  • Obtained through consumption of foods that
    contain the amino acid.
  • A vital component of proteins
  • Chief precursor for numerous aromatic compounds
    needed for bodily function.

6
http//www.newbornscreening.info/tools/GraphicsLib
/phenylketonuria.jpg
7
Normal Metabolism
www.uic.edu/.../PKU20biochem20intro.htm
8
Degradation Pathway
  • Enzymes Used
  • Phenylalanine Hydroxylase
  • Aminotransferase
  • p-hydroxyphenylpyruvate
  • Homogenistate dioxygenase
  • Maleylacetoacetate isomerase
  • Fumarylacetoacetase

9
Final Products of the Pathway
  • Breakdown of glucose is considered
  • Glucogenic-converted to glucose by
    gluconeogenesis.
  • Ketogenic-converted to a ketone body.
  • Final products of 6-step degradation pathway
    include
  • Fumarate-Citric Acid Cycle intermediate.
  • Convert to oxaloacetate stimulating
    gluconeogenesis.
  • Glucose exported into the blood.
  • Acetoacetate-Ketone body.
  • Used by neurons, and muscle tissue in oxidative
    degradation.

10
The Initial Step of Degradation
  • Rate limiting step in Phe catabolism.
  • PKU is caused from problems with
  • Phenylalanine hydroxylase.
  • Dihydrobiopterin reductase.
  • Tetrahydrobiopterin (BH4)

11
Phenylalanine Degradation
  • Phenylalanine is converted to tyrosine via PAH
    during the 1st degradation step.
  • After initial step of phenylalanine catabolism
    the degradation pathway is the same as that of
    tyrosine.
  • Tyrosine is a direct product of the breakdown of
    phenylalanine.

12
http//www.med.ufl.edu/biochem/plaipis/html/Teachi
ng/VEM5131-Pku.pdf
13
Abnormal Phenylalanine Metabolism
www.uic.edu/.../PKU20biochem20intro.htm
14
Phenylalanine Hydroxylase
  • Liver specific enzyme.
  • Member of the monoxygenase group.
  • Can be allosterically inhibited by its substrate,
    phenylalanine.
  • Main function is to maintain a low yet steady
    amount of phenylalanine circulating in the blood.
  • Catalyzes the formation of L-tyrosine from
    L-phenylalanine using
  • (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)
  • Molecular Oxygen

15
Phenylalanine Hydroxylase
  • In its native environment PAH exists as
    homotetramers and homodimers
  • Enzyme is composed of 3 domains
  • N-terminal-regulatory domain (1-142)
  • Catalytic domain (143-410)
  • C-terminal-tetramerization domain (411-452)
  • Note The C-terminal is said to contain the
    catalytic domain.

16
N-terminal Regulatory Domain
  • Used for auto-regulation.
  • Extends over active site located within the
    catalytic domain.
  • Regulatory domain of PAH consists of
  • An a-ß sandwich
  • A ßaß motif.
  • The crystal structure of PAH tetramer showed that
    the enzyme contains
  • 2 ß strands which form a ß ribbon.
  • 40 Å long a-helix.
  • Four a helices pack into tight antiparallel
    coiled coil located centrally in the tetramer
    structure.

17
C-terminal/Catalytic Domain
  • Basket like arrangement.
  • Active site located in catalytic domain.
  • 13-Å-deep and 10-Å-wide pocket.
  • Amino acids lining active site mostly
    hydrophobic.
  • Exception being 3 glutamates, 2 histidine, and
    1 tyrosine.
  • Entrance covered by a short loop composed of
    residues 378-381.
  • Composed of
  • 13 a-helices
  • 8 ß-strands

18
Phenylalanine Hydroxylase
Monomer of PAH Red C-terminus/Catalytic
domain Cyan N-terminal/autoregulatory
domain. Green Hinge (111-117)
www.bio.davidson.edu/.../Castle/assign1home.html
19
Phenylalanine Hydroxylase
www.pahdb.mcgill.ca/?TopicAboutSectionCura
20
Phenylalanine Hydroxylase
  • Phenylalanine Hydroxylase
  • Non-heme iron at its active site.
  • Ligands to the iron atom His nitrogen Glu
    oxygen Water oxygen atoms

www.rpi.edu/.../MBWeb/mb2/part1/aacarbon.htm
21
Other Sources of the Disease
  • Small percent of cases of PKU have risen from
    defects in
  • Dihydropteridine reductase
  • Biosynthetic route to tetrahydrobiopterin (BH4)
  • Dihydropteridine reductase (DHPR) catalyzes the
    reduction of the quinoid dihydrobiopterin (q-BH2)
    into tetrahydrobiopterin.
  • Tetrahydrobiopterin is a natural cofactor for the
    initial step in phenylalanine degradation.
  • Facilitates monoxygenase activity
  • Tetrahydrobiopterin is maintained in its reduced
    state by DHPR.

22
Mechanism
23
Dihydropteridine Reductase
  • Dimeric protein
  • Composed of two identical peptides.
  • Molecular weights between 21-27 kDa.
  • The enzyme is an aß protein.
  • The ß sheet is composed of 7 parallel and 1
    antiparallel strand at the C-terminus.
  • Motif referred to as dinucleotide or Rossman
    Fold.

24
Tetrahydrobiopterin (BH4)
  • co-factor that carries electrons for reduction
    reactions.
  • Produced from dihydrobiopterin from dihydrofolate
    reductase.
  • Cases of PKU stemming from BH4 deficiency termed
    malignant.
  • Patients experience progressive deterioration of
    neurological function.

25
How does this cause PKU?
  • Lack of functional DHPR will result in the
    failure to convert BH4 to q-BH2
  • This inhibits the recycling of BH4 because q-BH2
    is a substrate for DHPR.
  • Results in a buildup of phenylalanine because
    this is the initial conversion from phenylalanine
    to tyrosine.

26
Summary
  • Phenylketonuria.
  • Symptoms.
  • Phenylalanine.
  • Degradation Pathway of Phenylalanine.
  • Initial step of phenylalanine degradation.
  • Phenylalanine Hydroxylase.
  • Other causes of PKU.
  • DHPR.
  • BH4.
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