Transcript 107105_pku

Phenylketonurics:Contains phenylalanine
H 3N
CH
O
H
N H
C
O O
O
CH3
O
H3N
=
O
O
O
O
+
H 3N
O
HO
Aspartame
Aspartate
Phenylalanine
protein
X
X
phenylalanine
hydroxylase
X
CO2
NH3
O2
HO
CO2
NH3
phenylalanine
tyrosine
CO2
O
phenylpyruvate
CO2 + H2O + energy
Phenylketonuria (PKU)
First desc ribed in 1934 by Fљlling.
Diagnost ic symptom is high leve l of pheny lalanine in blood.
Autoso mal recess ive d isease.
Occurs in 1 out of 10,000 b irths in European and O rienta l popu lations (1% must
be carriers.)
Due to lack of suff icient pheny lalanine hydroxy lase.
Diagnosed sho rtly afte r birth when a c ouple of d rops of b lood d rawn from a hee l
prick revea l a high leve l of pheny lalanine in the b lood.
Effects of untreated PKU
Progressive, severe mental r etardation
Seizures, tremors or jerking movements in the a rms and legs
Behavioral or social problems
Rocking
Hyperactivity
Stunte d growth
Skin ra shes (eczema)
Small head size (microcephaly)
Vomiting
A musty odor in the child's breath, skin or urine, caused by too much phenylalanine in
the body
Fair skin and blue eyes, because phenylalanine canno t transform into melanin С the
pigment responsible for hair and skin ton e
Dietary treatment for PKU
Limited phenylalanine. Meat, fish, eg gs, cheese, milk products, legumes, and
bread, high in phenylalanine are eliminated or greatly r educed. (No Diet Coke.)
Artificial protein substitute s are given which contain amino acids wi thout ph enylalanine.
These come in fo rmulas, such as Phenex-1 and Phenylfree.
Some phenylalanine is necessary i n the diet, taken as a specific amount of b reast milk
or regular infant fo rmula for babies, or food exchang es in older children. For example
1Ъ
4 cup of fresh or cooked carrots is equivalent to one exchange. A new-born baby with
classic P KU may require 20 exchanges a day, a five y ear old requires between 14 and
30 exchang es, and an adult woman requires between 15 and 50 exchanges a day.
This photo was taken at my wedding a few years ago. I have PKU. I was diagnosed on the 3rd day of my life when treatment with
the diet began. I stayed on the diet for 16 years. After I married and when my husband and I decided we would like to have a
child, I went back on the diet before conception and I stayed on it throughout the pregnancy. Our daughter Stephanie was born
without any evidence of maternal PKU effects. She is now in her second year and passing all her developmental milestones in
style. The other woman in the picture is my older sister. She also has PKU but when she was born there was no newborn
screening program for PKU. The diagnosis of her disease was made late in her first year of life when she developed convulsions.
It was too late for treatment and she has never known the benefits of early diagnosis and treatment as I know them. Our picture is
on this web site so that parents of newly-diagnosed infants with PKU will have some evidence of good news. (Irene, May 1998)
Stephanie, age 2 years.
protein
X
X
phenylalanine
hydroxylase
X
CO2
NH3
O2
HO
CO2
NH3
phenylalanine
tyrosine
CO2
O
phenylpyruvate
CO2 + H2O + energy
531 mutations causing PKU known as of 2007:
62% missense (wrong amino acid, seldom in active site)
13% deletion (base pair omitted)
11% splicing (exons joined incorrectly
6% silent (no change in amino acids)
5% nonsense (protein ends too soon)
2% insertion (extra base pair)
14% are in introns and donХt affect amino acid sequence
Structure of the human phenylalanine hydroxylase gene
~125,000 base pairs codes for a protein of 454 amino acids
only 1362 base pairs code for amino ac ids
13 exons conta ining 41-184 base pairs coding for protein
12 introns from 1, 200 to 23,500 base pairs in length
Mutations in phenylalanine hydroxylase have a variety of effects
Inactive enzyme
unstable protein
partially active protein
Enzyme kinetics
descr ibes how fast an enzym e makes a reaction go
descr ibes how much su bstrate is needed for the reaction
A substrate is the molecule which binds in the active site of an enzyme
and reacts
Vmax is the fastest rate for the enzyme
Km is the concentration of the substrate at which the rate is one-half as large as Vmax
A mutation which decreases Vmax will result in a less active protein
A mutation which increases Km will result in less active protein.
Phenylalanine hydroxylase contains iron
Example of a cofactor
Required part of a protein which is not an amino acid
metals
small molecules derived from vitamins such as riboflavin
Structure of the human phenylalanine hydroxylase gene
Pterin-dependent enzymes
H H
N
H
H H
H3 C C C
N
OH OH H H
NH2
N
H
R
NH
O
H H
N
NH 2
N
N
H H O
O
H
N
tetrahydrobiopterin
phenylalanine
hydroxylase
HO
CO2
CO2
NH3
NH3
phenylalanine
tyrosine
HO
tyrosine
hydroxylase
HO
HO
CO2
CO2
NH3
NH 3
DOPA
tyrosine
CO2
N
H
NH3
tryptophan
Removes excess phenylalanine in dietmutations cause phenylketonuria
tryptophan
hydroxylase
Catalyzes first step information of
dopamine, epinephrine, and
norepinephrinemutations are lethal or cause
dystonia
HO
CO2
N
H
NH3
5-hydroxytryptophan
Catalyzes first step in formation
of serotoninmutations cause depression
Domain
structurally independent portion of a longer protein
typically ~100-200 amino acids long
Phenylalanine hydroxylase
Tryptophan hydroxylase
Tyrosine hydroxylase