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Urea Cycle and Inborn Errors of metabolism
M.F.Ullah, Ph.D
COURSE TITLE: BIOCHEMISTRY 2
COURSE CODE: BCHT 202
PLACEMENT/YEAR/LEVEL: 2nd Year/Level 4, 2nd Semester
Learning objectives
1. Amino acid breakdown leads to the generation of keto-acid products which can
be utilized for the synthesis of glucose by gluconoegensis (glucogenic amino acid)
or ketone bodies (ketogenic amino acid).
2. The final outcome of amino acid catabolism (breakdown) is the removal
of amino group from the amino acid in the form of ammonium ions (NH4+)
by transamination and oxidative deaminaton reactions.
3. Excess of ammonium is toxic and so it is converted to urea (less toxic) by urea cycle
and is excreted from the body in urine.
4. Inborn errors of amino acid metabolism are inherited disorders due to defect in genes
synthesizing the metabolic enzymes of certain amino acids such as phenylalanine
and tyrosine
Recapitulation of the previous lecture on amino acid breakdown
Transamination:
The α-amino group of an amino acid is transferred to an α-keto acid (such as αketoglutarate) to form glutamate.
The enzymes that catalyze these reactions are called transaminases or
aminotransferases.
There are many transaminases tabulated below and the reactions catalyzed
Oxidative deamination:
Removes α-amino group from Glutamate (amino-acid) which is released as
inorganic ammonium ion (+NH4 is toxic- excreted through urea cycle)
 Provides α-ketoglutarate for transamination
 Catalysed by Glutamate Dehydrogenase
Ammonia / Uric acid / Urea – An Introduction
NH3
Ammonia
+NH
4
Step wise reactions in Liver
Urea Cycle
Ammonium ion
(ionized form in living system)
(derived from catabolism of surplus amino-acids)
(Excessive is toxic)
Urea
(Less Toxic)
Uric Acid
In most terrestrial vertebrates/mammals excess +NH4 is converted to urea and then excreted- Ureotelic
 In birds and terrestrial reptiles +NH4 is converted to uric acid and then excreted- Uricotelic
In aquatic animals +NH4 is excreted as such in original form- ammonotelic
Urea Cycle
Urea cycle operates in Liver
Important points and reactions in urea cycle
 Urea contains two amino groups: one is from inorganic ammonium (NH4+) and the
other is derived from the side chain amine group of amino acid aspartate as shown
in the color above.
 Formation of carbamoyl phosphate:
CO2 + +NH4 + 2 ATP + H2O
Catalyzed by carbamoyl phosphate synthetase
+ 2 ADP + Pi
Inborn Errors of Metabolism or Congenital Metabolic Diseases or
Inherited Metabolic Diseases
 comprise a group of disorders in which a single gene defect causes a clinically
significant block in a metabolic pathway resulting either in accumulation of substrate
behind the block or deficiency of the product.
 All IEMs are all genetically transmitted typically in an autosomal recessive fashion.
Inborn Errors of Metabolism
 Defect in one or more genes; Inherited
 Results in absence/ deficiency of an enzyme
Disturbed metabolism
A
Substarte Excess
B
C
D
Product defciency
Toxic metabolite
Genetic defects in phenylalanine and tyrosine catabolism cause
several disorders
O2 + NADH
H2O + NAD+
phenylalanine
tyrosine
phenylalanine hydroxylase
phenylketonuria
CO2
homogentisic acid
O2
2
Glu
tyrosinemia II
O2
p-hydroxyphenylpyruvate
p-hydroxyphenylpyruvate dioxygenase
3
homogentisate 1,2-dioxygenase
H+
a-kG
1
tyrosine
aminotransferase
alkaptonuria
tyrosinemia III
4
5
maleylacetoacetate isomerase
maleylacetoacetate
fumarylacetoacetate
6
Alkaptonuria was the first
inherited disease that was
linked to a single enzyme
(Garrod, 1900).
fumarylacetoacetase
fumarate
acetoacetate
tyrosinemia I
4
Individuals with phenylketonuria convert phenylalanine to products
other than tyrosine
NH3+
Phe
H2O + NAD+
O2 + NADH
- CH2-CH-CO2-
HO-
pyruvate
blocked
in PKU
Ala
phenylpyruvate
O
- CH2-C-CO2NADH
H2O
NAD+
CO2
OH
- CH2-CO2-
phenylacetate
- CH2-CH-CO2-
phenyllactate
NH3+
Tyr
- CH2-CH-CO2-
Phenylketonuria, which has an
incidence of about 8 per 100,000
births, causes severe intellectual
/brain disability. If the disorder is
diagnosed shortly after birth, the
damage can be prevented by
restricting the amount of
phenylalanine in the diet.
If the enzyme which converts
phenylalanine
into
tyrosine
(Phenylalanine hydroxylase) is
missing,
then
phenylalanine
undergoes
a
transamination
reaction to make phenylpyruvic
acid instead.
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Phenylketonuria (PKU): More details
Phenylketonuria (PKU) is a rare condition in which a baby is born without the
ability to properly break down an amino acid called phenylalanine.
 Absence or defiiciency of Phenylalanine hydroxylase
BLOCK
SYMPTOMS:
Phenylalanine plays a role in the body's production of melanin, the pigment
responsible for skin and hair color. Therefore, infants ( not treated) with the condition
Often have lighter skin, hair, and eyes than brothers or sisters without the disease.
 Other symptoms are
Delayed mental and social skills/ Head size significantly below normal/ Hyperactivity/
Jerking movements of the arms or legs/ Mental retardation/ Seizures/ Skin rashes
Tremors/ Unusual positioning of hands.
Untreated: half are dead by age 20 Years.
Treatment: PKU is a treatable disease. Treatment involves a diet that is extremely
low in phenylalanine, particularly when the child is growing. A special infant formula
called Lofenalac is made for infants with PKU (life long replacement for proteins)
Alkaptonuria
Alkaptonuria is a rare condition in which a person's urine turns a dark brownish-black
color when exposed to air.
 A defect in the HGD (homogentisate 1,2-dioxygenase ) gene causes Alkaptonuria.

The gene defect makes the body unable to properly break down certain amino acid
(tyrosine and phenylalanine). As a result, a substance called homogentisic acid
builds up in the skin and other body tissues. The acid leaves the body through the
urine. The urine turns brownish-black when it mixes with air.
 Alkaptonuria is inherited, which means it is passed down from parents to their
children. To get this disease, each of your parents must pass you a copy of the faulty
HGD gene.
Urine in an infant's diaper may darken and can turn almost black after several hours.
However, many persons with this condition may not know they have it until midadulthood (around age 40), when joint and other problems occur.
Other symptoms: Arthritis that worsens over time, Darkening of ear, Dark spots on
white of eye (Sclera) and cornea
Goitrous cretinism
Defective tyrosine metabolism
 Hypothyroidism results from the defect in the peroxidase enzyme system that
incorporate iodine into tyrosine in the first step in the synthesis of thyroxine and
triiodothyronine (growth hormones)
 The result is stunted growth, lethargy, course hair, poor muscle tone
and other facial defects

Inherited disorder
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Albinism- Inherited Disorder
Defective Tyrosine metabolism
Another defect of tyrosine metabolism is albinism
Which appears due to the absence of the
enzyme tyrosinase, which prevents the synthesis
of melanin pigment from tyrosine by
pigment-forming cells.
These individuals have white skin, fine white hair,
pink or light blue irises of the eyes, and
a variety of other eye defects