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

Metabolic energy و من أحياها

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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.

Protein Metabolism - كلية الطب · The mechanism of amino acid metabolism is to get rid of...

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