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PRINCIPLES OF BIOCHEMISTRY
Carnitine Deficiencies
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LEARNING DICUSSION
Case
Carnitine deficiency
A teenage boy was brought to a hospital as he complaints
that he always get too tired when asked to participate in
the any school activities. The doctor found muscle
weakness in the boys arms and legs. From the muscle
biopsy, the lab pathologist found greatly elevated amount
of triglycerides esterified with primary long chain fatty
acid. They also found significant presence of lipid
vacuoles in the muscle biopsy. What cause these
symptoms?
What is Carnitine?
Role of Carnitine?
Carnitine -helps the body turn fat into
energy. Our body makes it in the liver
and kidneys and stores it in the skeletal
muscles, heart, brain, and sperm.
The compound plays role in energy
production, as it is responsible for
transporting fatty acids to the
mitochondria. arnitine transports longchain fatty acids into mitochondria
where they are burned (oxidized) to
produce energy.
Carnitine-transports waste and toxic
compounds out of the mitochondria,
preventing their buildup.
Carnitine Deficiency
Carnitine deficiency is one of a
group of metabolic muscle
diseases that interferes with the
processing of food (in this case,
fats) for energy production.
Inborn error of fatty acid transport
caused by a defect in the
transporter responsible for moving
carnitine across the plasma
membrane
When carnitine cannot be
transported into tissues, fatty acid
oxidation is impaired, leading to a
variety of symptoms
a)
b)
c)
d)
e)
f)
g)
h)
In more severe cases, where other tissues are affected, symptoms can include :
low blood sugar
fatigue
vomiting
abdominal pain
growth retardation
low weight
enlarged liver
brain function abnormalities.
The metabolic diseases of muscle are caused by genetic defects that interfere with chemical
reactions involved in drawing energy from food.
The fuel molecules derived from food must be further broken down inside each cell before
they can be used by the cells mitochondria (or "engines") to make energy.
Metabolic muscle diseases are caused by problems in the way certain fuel molecules are
processed before they enter the mitochondria, or by the inability to get fuel molecules into
mitochondria.
When one of the enzymes in the line is defective, the process goes more slowly or shuts
down entirely.
Our bodies use carbohydrates (starches and sugars), fats and protein for fuel.
Defects in the cells carbohydrate- and fat-processing pathways usually lead to weakness in
the voluntary muscles, but also may affect the heart, kidneys or liver
a)
b)
c)
d)
Fatty acid are activated on the outer mitochondrian membrane, whereas they
are oxidized in the mitochodrial matrix
A special transport mechanism is needed to carry the long chain acyl CoA
molecules across the inner mitochondrial membrane.
Activited long chain fatty acid are transported across the membrane by
conjugating them to carnitine, zwitterionic alcohol.
The acyl group is transfer from the sulfur atom of CoA to the hydroxyl group
of carnitine to form acyl carnitine.
This reaction is catalyzed by carnitine acyl transferase I ( also called carnitine
palmitoly transferase I) which is bound to the outer mitochodrial membrane .
Acyl carnitine is then shuttled across the inner mitochodrial membrane.
The acyl group is transferred back to CoA on the matrix side of the membrane.
The reaction, which is catayzed by carnitine acyl is transferase II (Carnitine
palmitoly transferase II) is simply the reverse of the reaction that takes place in
the cytosol
Finally, the translocase returns carnitine to the cytosodic side in exchange for
an incoming actyl carnitine
The process of mitochondrial fatty acid oxidation is termed -oxidation since it occurs
through the sequential removal of 2-carbon units by oxidation at the -carbon position of the
fatty acyl-CoA molecule.
The oxidation of fatty acids and lipids in the peroxisomes (see below) also occurs via a
process of -oxidation.
Each round of -oxidation involves four steps that, in order, are oxidation, hydration,
oxidation, and cleavage.
The first oxidation step in mitochondrial -oxidation involves a family of FAD-dependent
acyl-CoA dehydrogenases. Each of these dehydrogenases has a range of substrate
specificity determined by the length of the fatty acid. Short-chain acyl-CoA dehydrogenase
(SCAD, also called butyryl-CoA dehydrogenase) prefers fats of 46 carbons in length;
medium-chain acyl-CoA dehydrogenase (MCAD) prefers fats of 416 carbons in length with
maximal activity for C10 acyl-CoAs; long-chain acyl-CoA dehydrogenase (LCAD) prefers fats
of 616 carbons in length with maximal activity for C12 acyl-CoAs.
The next three steps in mitochondrial -oxidation involve a hydration step, another
oxidation step, and finally a hydrolytic reaction that requires CoA and releases acetylCoA and an acy-CoA two carbon atoms shorter than the initial substrate.
The water addition is catalyzed by an enoyl-CoA hydratase activity, the second oxidation
step is catalyzed by an NAD-dependent long-chain hydroxacyl-CoA dehydrogenase activity
(3-hydroxyacyl-CoA dehydrogenase activity), and finally the cleavage into an acyl-CoA and
an acetyl-CoA is catalyzed by a thiolase activity.
These three activities are encoded in a multifunctional enzyme called the mitochondrial
trifunctional protein, MTP.
MTP is composed of eight protein subunits, four -subunits encoded by the HADHA gene
and four -subunits encoded by the HADHB gene.
The -subunits contain the enoyl-CoA hydratase and long-chain hydroxyacyl-CoA
dehydrogenase activities, while the -subunits possess the 3-ketoacyl-CoA thiolase (ketothiolase or just thiolase) activity.
The mammalian genome actually encodes five distinct enzymes with thiolase activity.
Synthesis of Triglycerides
Fatty acids are stored for future use as triacylglycerols (TAGs) in all cells,
but primarily in adipocytes of adipose tissue.
TAGs constitute molecules of glycerol to which three fatty acids have been
esterified.
The fatty acids present in TAGs are predominantly saturated.
The major building block for the synthesis of TAGs, in tissues other than
adipose tissue, is glycerol.
Adipocytes lack glycerol kinase, therefore, dihydroxyacetone phosphate
(DHAP), produced during glycolysis, is the precursor for TAG synthesis in
adipose tissue.
This means that adipocytes must have glucose to oxidize in order to store
fatty acids in the form of TAGs. DHAP can also serve as a backbone
precursor for TAG synthesis in tissues other than adipose, but does so to a
much lesser extent than glycerol.
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