Urea Cycle and Inborn Errors of metabolism

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Urea Cycle and Inborn Errors of metabolism
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Learning objectives

• 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.
• 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.
• 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

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Recapitulation of the previous lecture on amino
acid breakdown
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• Transamination
• The a-amino group of an amino acid is transferred
  to an a-keto acid (such as a-ketoglutarate) 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 a-amino group from Glutamate (amino-acid)
  which is released as inorganic ammonium ion (NH4
  is toxic- excreted through urea cycle)
• Provides a-ketoglutarate for transamination
• Catalysed by Glutamate Dehydrogenase

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Ammonia / Uric acid / Urea An Introduction
NH3
Step wise reactions in Liver
NH4
Urea Cycle
Ammonia
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

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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
  2 ADP Pi
  
• Catalyzed by
  carbamoyl phosphate synthetase

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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.

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Inborn Errors of Metabolism

• Defect in one or more genes Inherited
• Results in absence/ deficiency of an enzyme
• Disturbed metabolism

C
A
B
Product defciency
D
Substarte Excess
Toxic metabolite
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Genetic defects in phenylalanine and tyrosine
catabolism cause several disorders
O2 NADH H2O NAD
phenylalanine
tyrosine
tyrosine amino-transferase
phenylalanine hydroxylase
a-kG
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phenylketonuria
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Glu
tyrosinemia II
CO2 O2
homogentisic acid
p-hydroxyphenylpyruvate
p-hydroxyphenylpyruvate dioxygenase
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tyrosinemia III
homogentisate 1,2-dioxygenase
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alkaptonuria
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maleylacetoacetate isomerase
fumarylacetoacetate
maleylacetoacetate
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Alkaptonuria was the first inherited disease that
was linked to a single enzyme (Garrod, 1900).
fumarylacetoacetase
tyrosinemia I
fumarate
acetoacetate
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Individuals with phenylketonuria convert
phenylalanine to products other than tyrosine
O2 NADH H2O NAD
Tyr
Phe
blocked in PKU
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.
phenylpyruvate
If the enzyme which converts phenylalanine into
tyrosine (Phenylalanine hydroxylase) is missing,
then phenylalanine undergoes a transamination
reaction to make phenylpyruvic acid instead.
phenylacetate
phenyllactate
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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)

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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 mid-adulthood (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

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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