Urea Cycle and Inborn Errors of metabolism

COURSE TITLE: BIOCHEMISTRY 2COURSE CODE: BCHT 202

PLACEMENT/YEAR/LEVEL: 2nd Year/Level 4, 2nd Semester

M.F.Ullah, Ph.D

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 α-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 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

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

NH3+NH4

Ammonia Ammonium ion (ionized form in living system)(derived from catabolism of surplus amino-acids) (Excessive is toxic)

Urea (Less Toxic)

Step wise reactions in Liver

Urea Cycle

Uric Acid

Urea Cycle

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 + P i

Catalyzed by carbamoyl phosphate synthetase

Urea cycle operates in Liver

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

A

D

B C

Substarte Excess

Product defciency

Toxic metabolite

Defect in one or more genes; Inherited Results in absence/ deficiency of an enzymeDisturbed metabolism

Genetic defects in phenylalanine and tyrosine catabolism cause several disorders

O2 + NADH H2O + NAD+

homogentisic acid p-hydroxyphenylpyruvateCO2 O2

phenylalanine tyrosine

-kG

Glu

O2

H+

maleylacetoacetate fumarylacetoacetate

fumarate acetoacetate

phenylalanine hydroxylasephenylalanine hydroxylase

p-hydroxyphenylpyruvate dioxygenasep-hydroxyphenylpyruvate dioxygenase

tyrosine amino-transferase

tyrosine amino-transferase

maleylacetoacetate isomerasemaleylacetoacetate isomerase

fumarylacetoacetasefumarylacetoacetase

phenylketonuria

tyrosinemia II

tyrosinemia I

tyrosinemia IIIhomogentisate 1,2-dioxygenasehomogentisate 1,2-dioxygenase

alkaptonuria

Alkaptonuria was the first inherited disease that was linked to a single enzyme (Garrod, 1900).

Alkaptonuria was the first inherited disease that was linked to a single enzyme (Garrod, 1900).

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Individuals with phenylketonuria convert phenylalanine to products other than tyrosine

pyruvate

Ala

- CH2-CH-CO2-

NH3+ NH3

+

- CH2-CH-CO2-HO-

O2 + NADH H2O + NAD+

PhePhe TyrTyr

blocked in PKU

phenylacetatephenylacetate

- CH2-CO2-

OH

- CH2-CH-CO2-

phenyllactatephenyllactate

O- CH2-C-CO2

-

phenylpyruvatephenylpyruvate

H2O

CO2

NADH

NAD+

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.

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.

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If the enzyme which converts phenylalanine into tyrosine (Phenylalanine hydroxylase) is missing, then phenylalanine undergoes a transamination reaction to make phenylpyruvic acid instead.

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

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 areDelayed mental and social skills/ Head size significantly below normal/ Hyperactivity/Jerking movements of the arms or legs/ Mental retardation/ Seizures/ Skin rashesTremors/ 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)

BLOCK

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

Goitrous cretinism

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

Defective tyrosine metabolism

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Albinism- Inherited Disorder

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

Defective Tyrosine metabolism