β-OXIDATION OF FATTY ACIDS.
TRANSPORT OF FATTY ACIDS IN TO THE MITOCHONDRIA.
FATE OF ACYL-CARNITINE IN MITOCHONDRIA
INHIBITOR OF THE CARNITINE SHUTTLE
METABOLIC DISORDERS ASSOCIATED WITH CARNITINE
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CARNITINE Is a specialized carrier protein (Low
molecular weight compound), which transports the
long chain fatty acyl groups from the cytosol in to the
SOURCES OF CARNITINE IN THE BODY
From the diet, primarily in Meat products.
Synthesis from amino acids, LYSINE and
METHIONINE by the enzymatic pathway found in
the liver and kidney.
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4. β-OXIDATION OF FATTY ACIDS
This is a mitochondrial pathway; a major
pathway of the Catabolism of fatty acids in which
two-carbon fragments are successively removed
from the carboxyl group or end of the fatty Acyl
CoA, producing Acety CoA, NADH and FADH2.
Example of fatty acyl CoA is shown below,
The energy yield from the β-oxidation
pathway is high.
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5. TRANSPORT OF FATTY ACIDS IN TO THE
Because β-oxidation occurs in the mitochondrial
matrics, the fatty acid must be transported across
the inner mitochondrial membrane that is
impermeable to Coenzme A (CoA).
After a long chain fatty acids enters a cell, they
are converted in the cytosol to its CoA
derivative by long-chain fatty acyl CoA
synthetase (thiokinase), an enzyme of the outer
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6. TRANSPORT OF FATTY ACIDS IN TO THE
Fatty acids shorter than 12 Carbons gets activated
to their CoA derivatives inside the mitochondria
by matrix enzymes, and are oxidized.
The entry of short and medium chain fatty acids
in to the mitochondria do not require the help of
Those fatty acids with 14-Carbon or more can not
pass directly through the mitochondria
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7. TRANSPORT OF FATTY ACIDS IN TO THE
The transport of long chain fatty acids (LCFA)
in to the mitochondria requires a specialized
carriers. These carriers are called CARNITINE.
This rate limiting transport process is called
Carnitine deficiency leads to the occurance of
among of the LIPID METABOLISM DISORDERS.
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8. CARNITINE SHUTTLE
Three enzymatic reactions are involved.
1st Reaction; The acyl group is transferred
from CoA to carnitine by Carnitine
acyltransferase-I (CAT-I). This reaction forms
acylcarnitine and regenerate free CoA.
2nd Reaction; The Acylcarnitine is transported
in to the mitochondrial matrix in exchange for
free carnitine by carnitine-acylcarnitine
translocase (Facilitated diffusion).
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9. CARNITINE SHUTTLE
3rd Reaction; Carnitine acyltransferase-II an
enzyme of the inner mitochondrial membrane
catalyses the transfer of the acyl group from
carnitine to CoA in to the mitochondrial
matrix in which free Carnitine is regenerated.
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11. FATE OF ACYL-CARNITINE IN
Once in the mitochondrial matrix,acyl-
carnitine is converted to the acyl-CoA and
The enzyme involved is carnitine
Then carnitine move from matrix to the
cytosol for transporting another LCFA.
The acyl-CoA enter the β-Oxidation.
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12. INHIBITOR OF THE CARNITINE
Malonyl CoA inhibits Carnitine
acyltransferase-I (CAT-I) thus preventing the
entry of Long chain acyl groups in to the
Example; Newly made palmitate in the cytosol
can not be transferred in to the mitochondria
and dagraded in the presence of Malonyl CoA.
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14. CARNITINE DEFICIENCIES
These can be broadly classified in to two
Primary carnitine deficiencies and
Secondary carnitine deficienices.
These deficiencies result in a decreased
ability of the tissues to use long-chain fatty
acids (LCFA) as a metabolic fuel.
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15. PRIMARY CARNITINE DEFICIENCY
Congenital deficiencies in one of the
Carnitine-acyltransferase (CAT) system which is also
known as Carnitine palmitoyltransferase (CPT)
system or Mutations in the SLC22A5 gene (making
of OCTN2 protein-transport Carnitine in to cells)
Genetic Carnitine palmitoyl transferase I (or CAT-
1) deficiency which affects the liver. This result in
a decreased or inability of the liver to synthesize
glucose during a fast.
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16. PRIMARY CARNITINE DEFICIENCY
This can lead to;
i. Severe hypoglycemia
ii. Coma and
Genetic Carnitine palmitoyltransferase-II (or
CAT-II) deficiency which occur primarly in
Cardiac and Skeletal muscles.
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17. PRIMARY CARNITINE DEFICIENCY
There are three main forms of CAT-II based on tissue-
specific symptomology and age of onset.
Most common form of the disorder.
Mild to severe adult form with the following
Rhabdomyolysis (release of myoglobin due to
breakdown of muscle fibers).
Myalgia (muscle pain) and weakness.
Myoglobinuria (myoglobin in urine).
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18. PRIMARY CARNITINE DEFICIENCY
It is severe infantile form.
Involves multiple organ systems
Symptoms occur between 6 and 24 months of
Characterized by the following symptoms.
Acute liver failure.
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19. PRIMARY CARNITINE DEFICIENCY
It is a lethal form in neonatal.
It is the least common clinical presentation of
Symptoms occur just hours after birth to
within 4 days of life
Symptoms are; Encephalopathy, confusion,
Hypoglycemia, liver failure, Cardiomyopathy
and muscle weakness.
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20. SECONDARY CARNITINE DEFICIENCY
This may occur in many situations, such as;
A patient with liver disease causing decreased
synthesis of Carnitine.
Individual suffering from malnutrition and those
on strictly vegetarian diets.
Those with an increased requirements for
carnitine as a result of, for instance, Pregnancy,
severe infection, burns or trauma
Those undergoing Haemodialysis, which removes
carnitine from the blood.
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Primary systemic carnitine deficiency was
estimated in Japan to occur in 1 per 40,000
In Australia, the incidence has been estimated to
be between 1:37,000 to 1:100,000 newborns
The frequent of this condition is not known
However, in UK the previous report identified 4
affected mothers in 62,004 infants screened, with
a frequency of 1 per 15,500 (1:15,500).
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In neonates, carnitine palmitoyltransferase
deficiency (CPT) is diagnosed using mass
spectrometry to screen blood.
Prenatal diagnosis may be possible using
amniotic villous cells.
In adults, the definitive diagnosis is based on
acylcarnitine levels in serum, urine, and
tissues(muscle and liver for systemic deficiency;
muscle only for myopathic deficiency).
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Avoid prolonged fast
Adopting a diet high in carbohydrate
Adopting a diet low in Long-chain fatty acids
Supplements with medium chain fatty acids
and Carnitine. This is because their oxidation
is not dependent on CPT-I hence it is not
subject to inhibition by malonyl CoA.
Treated by giving L-carnitine 25mg/kg per 6
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Infantile metabolic and childhood myopathic
forms of the conditions can be FATAL if
Long-term prognosis is exellent with oral
If the disorder is not recognised for a long
time, death can occur due to Cardiac failure,
hypoglycemia and arrhythmias or sudden
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Carnitine is thus considered as a
“conditionally essential nutrient” since
individuals requirements might exceed dietary
intake during specific disease states.
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• Richard H & Denise F. (2011).Lippincott’s Illustrated
Reviews: Biochemistry, 5th ed.
• Ayman W El-Hattab. Systemic primary carnitine
deficiency. GeneReviews .November 3,2016;
• Carnitine transporter defficiency. Screening,
Technology and Research in Genetics
• Agnetti A, Bitton L, Techana B, Raymond A and
Caranon. Primary carnitine deficiency dilated
cardiomyopathy:28 years follow-up. Jun 2 2012;
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