Title: What is Phenylketonuria
1What 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.
2Phenylketonuria
- By Ilyssa Ramos
- Biochemistry II
3Autosomal Recessive Disorders
http//upload.wikimedia.org/wikipedia/commons/thum
b/3/3e/Autorecessive.svg/250px-Autorecessive.svg.p
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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
5Phenylalanine
- 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.
6http//www.newbornscreening.info/tools/GraphicsLib
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7Normal Metabolism
www.uic.edu/.../PKU20biochem20intro.htm
8Degradation Pathway
- Enzymes Used
- Phenylalanine Hydroxylase
- Aminotransferase
- p-hydroxyphenylpyruvate
- Homogenistate dioxygenase
- Maleylacetoacetate isomerase
- Fumarylacetoacetase
9Final 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.
10The Initial Step of Degradation
- Rate limiting step in Phe catabolism.
- PKU is caused from problems with
- Phenylalanine hydroxylase.
- Dihydrobiopterin reductase.
- Tetrahydrobiopterin (BH4)
11Phenylalanine 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.
12http//www.med.ufl.edu/biochem/plaipis/html/Teachi
ng/VEM5131-Pku.pdf
13Abnormal Phenylalanine Metabolism
www.uic.edu/.../PKU20biochem20intro.htm
14Phenylalanine 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
15Phenylalanine 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.
16N-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.
17C-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
18Phenylalanine 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
19Phenylalanine Hydroxylase
www.pahdb.mcgill.ca/?TopicAboutSectionCura
20Phenylalanine 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
21Other 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.
22Mechanism
23Dihydropteridine 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.
24Tetrahydrobiopterin (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.
25How 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.
26Summary
- Phenylketonuria.
- Symptoms.
- Phenylalanine.
- Degradation Pathway of Phenylalanine.
- Initial step of phenylalanine degradation.
- Phenylalanine Hydroxylase.
- Other causes of PKU.
- DHPR.
- BH4.