Transcript Phenylketonuria (PKU)

Phenylketonuria
(PKU)
TAM NGUYEN
CHEM 4700
Introduction

PKU is a common inborn metabolic disorder caused
by a deficiency of the liver enzyme phenylalanine
hydroxylase.

It prevents normal metabolization of phenylalanine
(Phe), one of the essential amino acids that cannot
be manufactured by the body and must therefore
be consumed in protein rich foods.

Untreated individuals may give off a musty odor and
they excrete large amounts of phenylalanine in their
urine.
Cause

The most common cause of PKU is a mutation in the
gene coding for the enzyme phenylalanine hydroxylase
(PAH).

The mutation causes a deficiency in the activity of this
enzyme and leads to aberrant amino acid metabolism.

Localized misfolding occurs, in which the misfolding
spreads until the entire four-subunit enzyme can no
longer function

The buildup of phenylalanine hinders the development
of the brain and causes mental retardation
Symptoms

Severe intellectual and developmental disabilities

Behavioral or social problems

Stunted or slow growth

A musty odor in urine, breath, or skin that is a result
of the extra phenylalanine in the body

Fair skin and blue eyes, due to the body’s failure to
transform phenylalanine into melanin (the pigment
responsible for a person’s coloring).
Structure
The structure of PAH. (A) The modeled structure of full-length tetrameric PAH (composite model
prepared by combining the structures of tetrameric human PAH (residues 118-452; PDB 2PAH)
and dimeric rat PAH (residues 19-427; PDB 2PHM)). (B) Detailed structure of PAH including
thienylalanine and BH4 (PDB 1KW0).
Biochemical Nature

Phenylalanine
hydroxylase in complex
with cofactor
tetrahydrobiopterin
(BH4)

The structure of PAH is
shown along with its
interaction points to the
cofactor bound to the
active site proving an
ideal basis for structurebased drug design.
Phenylalanine to Tyrosine

Enzymes are structures that allow
amino acids to combine by acting
on a substrate and producing a
new product.

Individuals with PKU have a
deficiency in the enzyme
phenylalanine hydroxylase, which
converts phenylalanine to tyrosine.

The enzyme catalyzes the
hydroxylation of phenylalanine on
the phenyl ring at the 4 position, to
make tyrosine.
Metabolic Pathways

Individuals with PKU, phenylalanine could not converted into
tyrosine, phenylalanine accumulates and tyrosine is deficient.

Excessive phenylalanine can be metabolized into
phenylketones through the minor route, a transaminase
pathway with glutamate.

Metabolites include phenylacetate, phenylpyruvate, and
phenethylamine.

Elevated levels of phenylalanine in the blood and detection
of phenylketones in the urine is diagnostic.
Phenylalanine vs. Tyrosine
The coiled-coil motif is visible in the center of each tetramer. The iron bound
in the active sites are shown as red spheres
NMR Structure
http://www.drugbank.ca/spectra/nmr_one_d/1177
Treatment

The only treatment available for PKU is a diet where
phenylalanine levels are strictly limited.

Meat, fish, eggs, cheese, milk products, legumes,
and bread are all foods that have high levels of
phenylalanine.

Artificial protein substitutes are given which contain
amino acids without phenylalanine

Permanent monitoring of blood phenylalanine
levels.
Screening Test

Newborn screening allows early
identification and early
implementation of treatment.

Usually a few drops of blood are
obtained by a small prick on the
heel, placed on a card and then
sent for measurement.

Blood tested for excess
phenylalanine, in which blood was
placed on agar plate with
bacteria that need phenylalanine
to grow.
References

Leandro, João, Nina Simonsen, Jaakko Saraste, Paula Leandro, and Torgeir Flatmark.
"Phenylketonuria as a Protein Misfolding Disease: The Mutation PG46S in Phenylalanine
Hydroxylase Promotes Self-association and Fibril Formation." Biochimica Et Biophysica
Acta (BBA) - Molecular Basis of Disease (2010): 106-20. Print.

Fusetti, F. "Structure of Tetrameric Human Phenylalanine Hydroxylase and Its
Implications for Phenylketonuria." Journal of Biological Chemistry (1998): 16962-6967.
Print.

Underhaug, Jarl, Oscar Aubi, and Aurora Martinez. "Phenylalanine Hydroxylase
Misfolding and Pharmacological Chaperones." Current Topics in Medicinal Chemistry
(2013): 36-42. Print.

“What Are Common Symptoms of Phenylketonuria (PKU)?” Web. 16 Mar. 2015.
<http://www.nichd.nih.gov/health/topics/pku/conditioninfo/Pages/symptoms.aspx>.

"Introduction to Phenyketonuria." Faq. Web. 16 Mar. 2015.
<https://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa metab cases/PKU
Cases/faq.htm>.