PRINCIPLES IN

BIOCHEMISTRY
SBK3013
2015/2016

GROUP MEMBERS :

Aisyah Sahira bt Abdul Rahim

D20141066916
Nur Syaliyana bt Abu Samah
D20141066904
Nor Athirah bt Zalbador
D20141066901
Ainul Izzatti bt Zulkifli
D20141066907
Nur Insyirah bt Tokijoh
D20141066923
Nurul Akma bt Yaziz
D20141066900
Nurul Jannah bt Md Yassin
D20141066913
Nurul Natasha binti Mohd Sham
D20141066903

TEAM RESPONSIBILITY
NAME

RESPONSIBILITY

AISYAH SAHIRA BINTI ABDUL RAHIM

HOW PRIMARY CARNITINE OCCUR,

SYMPTOMS

NUR SYALIYANA BINTI ABU SAMAH

CAUSES

NOR ATHIRAH BINTI ZALBADOR

HOW PEOPLE WITH DISORDER

METABOLIZE GLYCOGEN
AEROBICALLY

AINUL IZZATTI BINTI ZULKIFLI

FUNCTION CARNITINE

NUR INSYIRAH BINTI TOKIJOH

PRIMARY & SECONDARY CARNITINE

NURUL AKMA BINTI YAZIZ

DEFINITION

NURUL JANNAH BINTI MD YASSIN

RISKS OF TOO MUCH CARNITINE

NURUL NATASHA BINTI MOHD SHAM

TREATMENT, CONCLUSION

CARNITINE
DEFICIENCY

CASE:
A teenage boy was brought to a hospital as he complaints
that he always get too tired when asked to participate in
the any of school activities. The doctor found muscle
weakness in the boys arms and legs. From the muscle
biopsy, the lab pathologist found that greatly elevated
amount of triglycerides esterified with primary long
fatty acid chain. They also found significant presence of
lipid vacuoles in the muscle biopsy. What causes this
symptoms?

Focus of this case

1.What is the effect of low carnitine?
2.How people with the disorder metabolize
muscle glycogen aerobically?

What is Carnitine ?
Carnitine is the quaternary ammonium compound biosynthesized from the
amino acids lysine and methionine.
Carnitine play an important role in the production of energy by
transporting the fatty acids into the mitochondria.
Carnitine can form into three types :
1. L Carnitine
2. Acetyl-L-carnitine
3. Propionyl-L-carnitine

Function of Carnitine
The amino acid carnitine is required for the transport of long-chain fatty
acyl coenzyme A (CoA) esters from the intermembraneous space in the
mitochondria into mitochondrial matrix , where they are oxidized for
produce energy by breaking down the lipids.
Transports toxic or waste compounds out of cellular organelle to prevent
accumulation.
Convert fat into energy - by transports of fatty acids into the
mitochondria

Website http://www.asbmb.org/asbmbtoday/asbmbtoday_article.aspx?id=8742

Carnitine produced by ?
Carnitine produced at liver and kidneys, but mostly located in the voluntary
muscle and cardiac muscles.
The skeletal and cardiac muscle used fatty acids as a dietary fuel because
they need high concentration of carnitine.
Only L-carnitine that is active in the body.

How to get carnitine ?

Red meat has higher content of carnitine.
Diary products contain carnitine primarily in the way fraction and there are
several foods which also contain carnitine.
There are also supplement that contain carnitine.

Table 1 : Selected food sources

of carnitine

Source: National Institutes of Health, Office of Dietary Supplements. Website https://ods.od.nih.gov/factsheets/CarnitineHealthProfessional/

Absorption and Metabolism of

Carnitine:
For adults, normally they can obtain about 60-180 milligrams of carnitine
per day.

For vegetarian adults, they obtain less because they do not eat meat.
About 54-86% of the dietary carnitine are observed in the small intestine
and enter to the bloodstream to provide energy.
Kidney also help in excreted the excess carnitine that not being
metabolized in form od urine so that it can maintaining the stable blood
concentration

L-carnitine vs. Acetyl-Lcarnitine:

The research studies show that acetyl-L-carnitine is better absorbed by the
small intestine and more efficient to crosses the brain barrier compared to
the L-carnitine.

Athletic Performance: Carnitine supplement can improve exercise or

physical performance. It increase the amount of carnitine in the muscle but
not to increase the bodys use of oxygen or improve metabolic during
exercise.

L-carnitine vs. Acetyl-L Aging : Acetyl-L-carnitine can decline the function of

carnitine:

mitochondria to

contribute in the aging process.

Research in aged rat : supplementation with high doses of acetyl-L-carnitine

and alpha-lipoic acid (an antioxidant) to reduce mitochondrial decay.
Mental function can be improved and the deterioration in older adults with
mild cognitive impairment and Alzheimer's disease can decrease.

Carnitine deficiency?
Do you know what is carnitine deficiency?
A metabolic state in which carnitine concentrations in plasma and tissues
are less than the levels required for normal function of the organism.
This is a metabolic muscle disease that interferes with the processing of
food such as fats for energy production.
Carnitine deficiency results from inadequate intake of or inability to
metabolize the long chain of amino acids.

Types of carnitine deficiency ?

Primary carnitine deficiency : Genetic disorder of the cellular carnitine
where the transport system that usually manifests itself by five years of
age with symptoms of cardiomyopathy, skeletal muscle weakness and
hypoglycemia.
Secondary carnitine deficiency : Shows in the certain disorder such as
chronic renal failure or under certain condition which using certain
antibiotic. It can reduce the carnitine absorption and increase its
excretion.

Primary Carnitine Deficiency:

Prevent the body from using certain fats for energy .
Appear during infancy or early childhood:
- Brain disfunction
- Weak and enlarged heart (cardiomyopathy)
- Muscle weakness
- Low blood sugar (hypoglycemia)
Some people are asymptomatic : does not show any signs or signals.

How Primary Carnitine Occur ?

Low level of carnitine level in blood
Gene mutation
The gene provide information for making protein that transports
carnitine into cells.
This mutation can affect carnitine transport by impairing maturation of
transporters to the plasma membrane.

 Result of mutation causes an absent/dysfunctional of the protein

Shortage (deficiency) of carnitine within cells
Without carnitine, fatty acids cannot enter mitochondria and be used to
make energy
Reduced energy production lead to muscle weakness and
hypoglycemia(low blood sugar)

Gene Mutation ?
Mutation :
- SLC22A5 gene : give instruction to make OCTN2 protein to transport
the carnitine.
- Result of the mutation : an absent or dysfunction of OCTN2 proteins
- Create a premature stop signal in the instructions for making the
OCTN2 protein, resulting in an abnormally short, nonfunctional
protein. Other mutations change single protein building blocks
(amino acids) in the OCTN2 protein.

Website http://ghr.nlm.nih.gov/gene/SLC22A5

Secondary Carnitine Deficiency:

May present with crises consisting of hypoglycemia, ketoacidosis, and

hyperammonemia.

Also may present with abnormal fatigability and lactic acidosis associated with
exertion. These children also may present with encephalopathy and/or lipid
storage myopathy and carnitine depletion.

Carnitine deficiency has been observed in children with urea cycle defects, and it
may exacerbate episodes of hyperammonemia.

* excess of a particular protein building block (amino acid), called methionine,

in the blood

Primary Carnitine vs Secondary

PRIMARY CARNITINE
SECONDARY CARNITINE
Carnitine
Rare congenital deficiency

Decreased carnitine synthesis due to

liver disease

Carnitine palmitoly transferase system

- Prevents renal absorption of
carnitine
- Faulty transporter prevents
carnitine uptake

Severely restricted vegetarian diet

Has very low levels of carnitine in the

blood due to a faulty carnitine
transporter

During high metabolic requirement

- Pregnancy
- Severe infections
- Trauma
Patient undergoing hemodialysis

Carnitine Transport Pathway:

Once the fatty acids accumulate in the blood, coenzymeA (CoA) attaches and
activates the fatty acids, bringing them into the cells cytosol.
A carnitine molecule then attaches, which allows the transporting receptor, carnitinepalmitoyl-transferase 1 (CPT1), to recognize and transport the fatty acid across the
outer mitochondrial membrane into the intermembrane space.
Then, a carnitine-specific transfer enzyme in the inner mitochondrial membrane
brings the fatty acid into the mitochondrion for breakdown by carnitine-palmitoyltransferase 2 (CPT2), and the carnitine molecule is transferred back to the
cytosol to shuttle more fatty acids.

Carnitine Transport Pathway :

Greatly Elevated Amount Of

Triglycerides:
Lab pathology found the great elevated amount of triglycerides because
the muscle biopsy reveals that there are triglyceride storage which been
seen with the oil red O stain in frozen sections.

This condition transmitted as an autosomal recessive traits because it was

though that the primary biochemical defect involved the active transport of
carnitine from blood into muscle but there is no such defect been
documented.
Therefore, the muscle carnitine deficiency is secondary to a primary
enzyme defect.

Greatly Elevated Amount Of

Triglycerides:
The inherited as an autosomal recessive trait is due to the defect of the

specific high-affinity, low concentration, carrier-mediated carnitine-uptake

mechanism.

Documented in cultured fibroblasts and muscle cultures but the same

uptake system is shared by heart and kidney, thus explaining the
cardiomyopathy and excessive leakage of the carnitine into the urine.
The boy has a decrease in tissue and plasma concentration of carnitine and
an excessive urinary excretion of carnitine

Presence Of Lipid Vacuole In

Happen due to defects
of the carnitine transport system leading to
Muscle
Biopsy:
accumulation of fat.
This carnitine deficiency occur in the systemic form or myopathic form and
presents with the slow progressive muscle weakness.
The CPK level are elevated cause the muscle biopsy shows the vacuoles
filled with lipid within the muscle fibers.
The carnitine levels in muscle tissue is low, but the serum carnitine level is
normal.
Treatment is with L-carnitine.

Oxidation of Fatty Acid:

1. Activation of fatty acids take place at the outer mitochondrial
membrane.
2. Transport fatty acyl CoA into the mitochondria.
3. Degradation of acetyl CoA in the mitochondrial matrix through Oxidation

1. Activation of Fatty Acids

1. Fatty acids are converted to CoA thioesters by acyl-CoA synthetase.
2. The PPi released is hydrolysed by a pyrophosphatase to 2 Pi
3. Two phosphoanhydride bonds are consumed to activate one of the fatty
acid to thioester.

2. Transport of Fatty Acyl CoA

into
mitochondria:
The carnitine
shuttle system.
Fatty acyl CoA is converted to acylcarnitine by carnitine acyltransferase 1
(CPT1)
Acylcarnitine enters into mitochondrial by translocase.
The acyl group then transferred back to CoA by carnitine acyltransferase 2
(CPT2)

Fatty Acid
Transport:

3. Reactions through Oxidation

-Oxidation is the catabolic process by which the fatty acids molecule are
broken down in the mitochondria to produce acetyl-CoA.

Enzyme that involved are acyl-CoA dehydrogenase, enoyl-CoA hydratase,

hydroxyacyl-CoA dehydrogenase and ketoacyl-CoA thiolase.
During -Oxidation NADH are produced during catalysed by hydroxacylCoA dehydrogenase and FADH2 are produced during the catalysed by acylCoA dehydrogenase.
NADH and FADH2 are used by the electron transport chain to form ATP.

Fatty Acid
-Oxidation:

What would happen for the

Fatty Acid that cannot enter the
mitochondrion ?

What is the causes ?

Inadequate intake of nutrition due to fad diet or long term TPN

*TPN is stand for Total Parental Nutrition which is a method of feeding that bypasses the
gastrointestinal tract. It is used when a person cannot receive food or drink through his/her mouth.

Excess loss of carnitine due to diarrhea, diuresis and hemodialysis.

Decrease muscle carnitine level due to mitochondrial impairment (due to
the use of zidovudine).
Inability to metabolize carnitine due to enzyme deficiency.(carnitine
palmitoyltransferase disease)
Use of valproate

Symptom of Carnitine
Severe brain dysfunction (encephalopathy)
Deficiency:

Fatigue

Lipid storage myopathy

Hyperammonia (metabolic disturbance by excess of ammonia in blood)

Hypoglycemia (low blood sugar)

Symptom of Carnitine
Vomitting
Deficiency:

Fatty liver

Muscle weakness

Myoglobinuria (presence of myoglobin in urine)

Cardiomyopathy (weakened and enlarged heart)

Treatment
Better diagnosis to allow for earlier identification of at-risk individuals
and earlier treatment
Continued examination of the role of exercise and diet in metabolic
diseases
Development of enzyme replacement therapies
Development of gene therapies.
Avoidance of fasting and strenuous exercise
Dietary interventions, based on cause

1. L-carnitine
The main treatment for CTD is lifelong use of L-carnitine. This is a safe
and natural substance that helps body cells make energy. It also helps
the body get rid of harmful wastes. L-carnitine can reverse the heart
problems and muscle weakness that happen in children with CTD.
Your doctor will decide whether or not your child needs L-carnitine.
Unless you are advised otherwise, use only L-carnitine prescribed by your
doctor. Do not use L-carnitine without checking with your doctor.

2. Avoid going a long time without food

Infants and young children with CTD need to eat frequently to prevent a
metabolic crisis. Your metabolic doctor will tell you how often your child
needs to be fed. In general, it is often suggested that infants be fed every
four to six hours. Some babies need to eat even more frequently than
this. It is important that infants be fed during the night. They may need to
be woken up to eat if they do not wake up on their own.

 Your metabolic doctor and dietician will give you an appropriate feeding
plan for your infant. Your doctor will also give you a sick day plan
tailored to your childs needs for you to follow during illnesses or other
times when your child will not eat.
Your metabolic doctor will continue to advise you on how often your
child should eat as he or she gets older. When they are well, many teens
and adults with CTD can go without food for up to 12 hours without
problems. The other treatments usually need to be continued
throughout life.

3. Diet
Sometimes, in addition to L-carnitine treatment, a low-fat, high carbohydrate food plan is
recommended. Any diet changes should be made under the guidance of a dietitian familiar with
CTD. Ask your doctor whether your child needs to have any changes in his or her diet.

4. If your baby has CTD, call your doctor at the start of any illness
Always call your healthcare provider when your baby has any of the following:

poor appetite

low energy or excessive sleepiness

vomiting

diarrhea

an infection

a fever

persistent muscle pain or weakness

Are there health risks from too

much
carnitine?
1. Supposedly
3g/day
2. Carnitine supplement can cause nausea, vomiting, abdominal cramps,
diarrhea
3. Rarer side effects include muscle weakness in uremic patients and
seizures in those with seizure disorders
4. May increase the risk of cardiovascular disease
5. More pronounced effect to those people who likes meats than
vegetarians

How people with the disorder

metabolize muscle glycogen
aerobically?
Small energy demands do not initiate glycogenolysis
Lightly loaded muscles manage to cover their energy needs
through oxidation of circulating glucose and fatty acids.
However, increasing work loads demands more powerful
contractions and ATP utilization. This increases the rate of
glycogen breakdown to cover these needs.

CONCLUSION FOR THE CASE

For our patient, we are sure that he suffered Primary Carnitine Deficiency.
From the muscle biopsy, the lab pathologist found that greatly elevated
amount of triglycerides esterified with primary long fatty acid chain.
A person with primary carnitine deficiency has very low levels of carnitine in
the blood due to a faulty carnitine transporter which prevents carnitine from
getting into the cells where it is needed. Thats why, a boy felt tiredness during
activities.