Protein Metabolism - كلية الطب · The mechanism of amino acid metabolism is to get rid of...
Transcript of Protein Metabolism - كلية الطب · The mechanism of amino acid metabolism is to get rid of...
Protein Metabolism الفريق الطبي األكاديمي
لكــية الطب البرشي
البلقاء التطبيقية / املركز
6102/6166أ حياها و من
Done By :- Rasha Rakan & Shady Soghayr
Corrected By :- Yousef Marwan
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Previous lecture:
LDL has 3 mechanisms in peripheral tissue:
1.Decrease synthesis
2.Increse storage
3.Decrease synthesis of receptors
Hyperlipidemias:
1. Primary (Familial & genetic):
a. Heterozygous low number of receptors possible to treat by
increase the number of the receptors
b. Homozygous Complete absence of receptors impossible to treat
2. Secondary:
other causes like DM, Obesity.
LDL Oxidation and Atherosclerosis: (it loses its elasticity, with age, causes
spasm in muscles because of the slowing down of the circulation)
Injury in the endothelial cells that line the blood vessel Infection
Modification of LDL (oxidation) oxidized LDL enters macrophages
macrophages become foam cells it collects more modified LDL
accumulation of platelets Thrombus formation (decreased blood
supply)
Things that oxidize (modify) LDL:
superoxide, nitric oxide, hydrogen peroxide
Things that antioxidize LDL:
Vitamin E, ascorbic acid, β-Carotene, antioxidants
Downregulation: when the cells take their needs, they inhibit the
receptors and synthesis
no more entry of LDL
cells have receptors for LDL
but foam cells don’t have receptors for modified LDL no inhibition
continues entry of modified LDL
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accumulation in the endothelial layers accumulation of Platelets
thrombus and clotting brain (stroke) , heart (Myocardial
infarction), legs (peripheral vascular occlusion)
Protein Metabolism
citric acid cycle has 2 functions:
1. Energy catabolic road
2. Anabolic road intermedius amino acids
CAC takes (consumes) amino acids , and gives them to different
metabolic pathways
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• The continuous degradation and synthesis of cellular proteins occur in all forms of life. Each day humans turn over 1–2% of their total body protein, principally muscle protein. Skin, nails, hair, intestinal mucosal cells (their life span is 3-5 days) Approximately 75% are reutilized. Because body needs the proteins, so there shouldn’t be loss of proteins The excess nitrogen forms urea.
• Proteins represent 10-15 % of total energy supply. The higest consumption is the carbohydrate 60% of energy supply.
Amino Acid Metabolism
Digestion and Absorption of Proteins.
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Protein is degraded in the stomach by the pepsin, then pancreatic enzymes: trypsin, chymotrypsin and elastase continue the degradation. The protein then reaches the intestine in the form of free amino acids, dipeptides or tripeptides. In the intestine we have dipeptidases and tripeptidases to degrade di and tripeptides. Only free amino acids will be absorbed. Why doesn’t absorption happen to polypeptides and large molecules ? to prevent antigen-antibody reaction, because the body does antigen-antibody reaction on every large molecule An exception: Polio Vaccine in children, because their intestine is not well developed yet.
In general the problem in amino acids is the nitrogen. Nitrogen (in other words ammonia) is toxic, and thus should be removed.
The α-amino group of many amino acids is transferred to α-ketoglutarate to form glutamate,
which is then oxidatively deaminated to yield ammonium ion (NH4+).
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The mechanism of amino acid metabolism is to get rid of ammonia. The ammonia is transferred from one amino acid to the other to be removed. The process is called deamination. Amino acids give their ammonia to α-ketoglutarate. α-ketoglutarate uses NADPH and becomes glutamate, and the reaction is reversible. Glutamate becomes Glutamine by the enzyme glutamate dehydrogenase that requires ATP. Glutamate is ammonia carrier in peripheral tissue, it collects ammonia and gives it to the liver. It has the same principle of HDL that collects cholesterol and transferred it to the liver. s NH3
+ ammonia
NH4+ ammonium
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There is 3 Buffer systems in the kidney:
1.Carbonate and Bicarbonate (in the lung and the kidney)
HCO3- + H+ <===> H2CO3 <===> CO2 + H2O )لالستزادة(
2.Ammonia and Ammonium (الذي ذكر فوق) 3.Phosphate H2PO4
- <===> H+ + HPO4 )لالستزادة( 2-
Their aim is : if there’s Acidosis, they change pH and it removes
H+, and if there’s Alkalosis they change the pH to keep the H+
Reactions of amino acids are called general metabolic reactions
of amino acids, one of them is Transamination.
Transamination: transferring amino groups from one amino
acid to the other to produce new amino acid and keto acids.
Transamination
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We have 10 essential amino acids (they are 12 in children) and
10 nonessential. Essential must be taken from food.
Nonessential amino acids are important and synthesized using
essential amino acids via transamination. Their deficiency
doesn’t produce disease.
• All the protein amino acids except lysine, threonine, proline, and hydroxyproline participate in transamination.
• Transamination is readily reversible, and aminotransferases also function in amino acid biosynthesis. Transaminase enzyme.
• The coenzyme pyridoxal phosphate (PLP) is present at the catalytic site of aminotransferases. Vitamin B6 produces it.
Thiamine Pyrophosphate (TPP) vitamin B1 Pantothenic acid vitamin B5 Folic acid vitamin B12
Aspartate aminotransferase(AST), one of the most important of
these enzymes, catalyzes the transfer of the amino group of
aspartate to α-ketoglutarate
It was called SGOT: serum glutamate-oxaloacetate
transaminase.
Aminotransferases
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AST mainly present in the liver, heart, kidney, lung and so on,
but increases in myocardial infarction.
AST Cardiac enzyme function (cardiac function tests)
Alanine aminotransferase(ALT) catalyzes the transfer of the amino group of alanine to α -ketoglutarate.
it was called SPGT: serum glutamic-pyruvic transaminase
or SGPT: serum glutamate-pyruvate transaminase.
Present in heart, muscle, liver and kidney, but increases in liver
disease.
ALT Liver enzyme function (liver function tests)
AST & ALT increase in both the cardiac and liver diseases, but
ALT increases significantly (more than AST) in the liver diseases,
and AST increase significantly (more than ALT) in myocardial
infarction.
Their natural amount is 30-40 unites. If they rise up to 42-45 is
not a problem because it may be caused of natural things like
stress. The problem is when the enzymes amount becomes 5 to
10 times their natural amount (above 100 unite).
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Alanine serves as a carrier of ammonia and of the carbon skeleton of pyruvate from skeletal muscle to liver. The ammonia is excreted and the pyruvate is used to produce glucose, which is returned to the muscle. Alanine can be converted to glucose in the liver.
Glucose - Alanine Cycle
Blood Alanine
UREA
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Oxidative deamination
This reaction is catalyzed by glutamate dehydrogenase. This enzyme is unusual in being able to utilize either NAD+ or NADP+. *α-ketoglutarate comes from glutamate by glutamate dehydrogenase enzyme and it loses ammonia group and utilize either NAD+ or NADP+.
Peripheral Tissues Transport Nitrogen to the Liver
Nitrogen can also be transported as glutamine. Glutamine synthetase catalyzes the synthesis of glutamine from glutamate and NH4 + in an ATP-dependent reaction:
The nitrogen of glutamine can be converted into urea in the
liver.
*glutamine is a nontoxic carrier for ammonia from the
peripheral tissue to the liver
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Fates of the Carbon Skeletons of Amino Acid
Glucogenic amino acids are shaded red, and ketogenic amino
acids are shaded yellow. Most amino acids are both glucogenic
and ketogenic.
*amino acids give either glucose or ketone bodies
*how the glucogenic amino acids will give glucose?
By entering the citric acid cycle as intermediates and in the end
producing oxaloacetate phosphoenol pyruvateglucose
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*leucine and lysine will produce acetyl CoA
Proteins and nucleic acids give carbohydrates ATTENTION!!!!*
(by entering citric acid cycle) but lipids doesn't.
Ammonia
Ammonia (NH3) is a relatively strong base, and at physiological
pH values it is mainly present in the form of the ammonium ion
NH4+.
*the idea of protein metabolism and catabolism is to get rid of
ammonia
NH3 and NH4+ are toxic, and at higher concentrations cause
brain damage in particular. Ammonia therefore has to be
effectively inactivated and excreted. This can be carried out in
various ways.
, hepatitisor cirrhosisIf liver function is compromised, as in
elevated blood ammonia levels generate clinical signs and
(causes .“hepatic coma”may lead to coma symptoms which
brain damage)
Rare metabolic disorders involve each of the five urea cycle
enzymes.
Only traces of ammonia (10–20μg/dL) normally are present in
peripheral blood.
*if sedosis or hepatitis or any inflammation in the in the
liver happened because of alcohol or viral hepatitis,
infection the ammonia will aggregate in the blood
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(doesn't become urea), so ammonia will stay in the
circulation and reach the brain causing hepatic coma
Formation & Secretion of Ammonia
Maintains Acid-Base Balance
Excretion into urine of ammonia produced by renal tubular cells
facilitates cation conservation and regulation of acid-base
balance. Ammonia production from intracellular renal amino
acids, especially glutamine, increases in metabolic acidosis and
decreases in metabolic alkalosis.
*ammonia from urine is in the form of ammonium ions
NH4+
(NH3 in the blood and with amino acids)
Aquatic animals can excrete NH4+ directly.
For example, fish excrete NH4+ via the gills (ammonotelic
animals).(need water)
Terrestrial vertebrates, including humans, hardly excrete any
NH3, and instead, most ammonia is converted into urea before
excretion (ureotelic animals).(need water)
Birds and reptiles, form uric acid, which is mainly excreted as a
solid in order to save water (uricotelic animals).(doesn't need
water)
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Urea Cycle
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*urea cycle is the way the body gets rid of ammonia
*takes place in the liver only (between the cytosol
and the mitochondria)
*the first two steps occur in the mitochondria and
the rest in the cytosol
[1]In the first step, carbamoyl phosphate is formed in the
mitochondria from hydrogen carbonate (HCO3–) and NH4+,
with two ATP molecules being consumed. In this compound,
the carbamoyl residue (–O–CO–NH2) is at a high chemical
potential. In hepatic mitochondria, enzyme [1] makes up about
20% of the matrix proteins.
limiting enzyme of -, the ratesynthase ICarbamoyl phosphate
allosteric the urea cycle, is active only in the presence of its
activator
N-acetylglutamate, which enhances the affinity of the
synthase for ATP.
Major changes in diet can increase the concentrations of
individual urea cycle enzymes 10-fold to 20-fold.
, for example, elevates enzyme levels to cope with Starvation
the increased production of ammonia that accompanies
enhanced protein degradation.
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[2] In the next step, the carbamoyl residue
is transferred to the non-proteinogenic amino acid ornithine,
converting it into citrulline, which is also non-proteinogenic. This is passed into the cytoplasm via a transporter.
*ornithine and citrulline are non-protein amino acids
(found in cycles)
[3] The second NH2 group of the later urea molecule is
provided by aspartate, which condenses with citrulline into
argininosuccinate.
ATP is cleaved into AMP and diphosphate
(PPi) for this endergonic reaction. To shift the equilibrium of the
reaction to the side of the product, diphosphate is removed
from the equilibrium by hydrolysis.
[4] Cleavage of fumarate from argininosuccinate leads to the
proteinogenic amino acid arginine,which is synthesized in this
way in animal metabolism.
[5] In the final step, urea is released from the guanidinium
group of the arginine by hydrolysis , and is immediately
rearranged into urea. In addition, ornithine is regenerated and
returns via the ornithine transporter into the mitochondria,
where it becomes available for the cycle once again.
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*arginase enzyme is present only in the liver (the last enzyme of urea cycle)
The rate of urea formation is mainly controlled by reaction [1].
N-acetyl glutamate, as an allosteric effector, activates
Carbamoylphosphate synthase. In turn, the concentration of
acetyl glutamate depends on arginine and ATP levels, as well as
other factors.
Krebs Bi-cycles
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*the links between urea cycle and krebs cycle are :
CO2 leaves the krebs cycle and enters the urea cycle
Aspartate fumarate
Inherited Defects of the Urea Cycle Cause
Hyperammonemia and Can Lead to
Brain Damage
Brain Damage
All defects in the urea cycle lead to an elevated level of NH4+ in
the blood (hyperammonemia). Some of these genetic defects
become evident a day or two after birth, when the affected
infant becomes lethargic and vomits periodically.
Coma and irreversible brain damage may soon follow.
Symptoms of Ammonia Intoxication
This include tremor, slurred speech, blurred vision,
coma, and ultimately death.
Ammonia may be toxic to the brain in part because it reacts
with α-ketoglutarate to form glutamate. The resulting depleted
levels of α-ketoglutarate then impair function of the
tricarboxylic acid (TCA) cycle in neurons.