10. general protein metabolism
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Proteins or polypeptides are polymers of
amino acids.
They perform many essential functions in
mammalian body.
These functions are:These functions are:
II -- Dynamic functions:Dynamic functions:
IIII-- Structural functions:Structural functions:
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I - Dynamic functions:
a) Transport functions
Albumin that transports some drugs, calcium, bilepigments and FFA
Hemoglobin that transports oxygen.
Transferrin that transports iron.
* Lipoproteins that transport lipid.
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y b) Metabolic control as theyenters in the formation
ofenzymes and somehormones, e.g. Insulin
and glucagon.
y c) Contraction , e.g. Proteins of muscles
(actin and myosin)
y d) Protection, e.g.Immunoglobulins.
y e) Blood clot e.g.Fibrinogen,thromboplastin,
and prothrombin.
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II- Structural functions:
y a) Essential component of cell membrane
cytoplasm, cell organells and receptors.
y b) Enter in the structure of collagen,
elastin, keratin, and rhodopsin
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ySources of Dietary Proteins:
1- Animal : as milk, fish, meat and eggs.
2- Plant : as cereals and beans.
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Protein Digestion :It is not digested in the mouth dueto absence of proteolytice nzymes.
Proteolytic enzymes
(peptidases or proteases)
They are responsible for degradationof proteins
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Proteolytic enzymes :
They are produced by three different organs:
1.The stomach,
2.The pancreas
3.Tthe intestine.
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A- Gastric proteolytic enzymes
B-Pancreatic proteolytic enzymes
C- intestinal proteolytic enzymes
proteolytic enzymes:
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N.B. :
Protein is an antigen i.e. able to stimulate
the immune system if it reaches blood in theform of large molecules (e.g. If it is taken
intravenously).
The digestion of protein to amino acids
destroys its antigenicity. If protein is not
digested completely and absorbed as
polypeptide, immunologic response willoccur and manifest itself as allergy in the
form of urticaria , bronchial asthma and
hay's fever.
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Absorption:
The end products of protein digestion
are amino acids, di-and tripeptides. These
are absorbed by epithelial cells via amino
acid or peptide transport system. It is an
active process against concentration
gradient it needs Na+ as a co-transport
system. ATP is the source of energy of
this active process.
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Fate of absorbed amino acids:
Anabolic pathway
Catabolic pathway
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A
nabolic pathway:
Amino acids enter in the formation of
proteins for wear and tear, plasma proteins,hemoglobin, enzymes, some hormones
also enter in the formation ofnon protein
nitrogenous compounds (NPN) as purines,pyrimidines, creatine and thyroxine.
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yCatabolic pathway:
a) Urea: formed in the liver, is considered as
the main metabolic endoproduct of protein
catabolism.
b) Supplyingenergy: 1 gram proteinyields
4.1 K cal, onlyif there is shortage incarbohydrate and fats.
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Nitrogen Balance
There is no storage (depot) for protein, there is a certain percentage of protein that
undergoes a constant process of breakdown and
resynthesis i.e. turnover.
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Nitrogen balance:
is a comparison between the intake ofnitrogen (mainly in the form of dietary
protein) and the excretion of nitrogen
(mainly in the form of undigested proteinin stool and urea and ammonia in urine).
Also nitrogen output is through nails,hair and desquamated skin.
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Nitrogen equilibrium:
The normal adult human will be in nitrogen
equilibrium when N2 lost (in urine, feces and sweat)
just balanced by N2 in diet intake.
N2 LOST = N2 INTAKE
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y Positive nitrogen balance:
Acondition in which there is increase in the N2 intakeover the output.
N2 INTAKE > N2 LOST
It mayoccur in growth, pregnancyor convalescencefrom diseases.
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Negative nitrogen balance:
Acondition in which there is either decreased
N2 intake as in :
y starvation, poverty,
y malnutrition,maldigestion, malabsorption,
y severe vomiting, severe diarrhea
Or increased N2 output as iny hemorrhage, burns,
y old age or debilitating disease.
N2 LOST > N2 INTAKE
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N.B.
1- Daily protein needs are
One gram protein per kilogram body weight
(i.e. about70-100 gm protein per day).
At least part of this protein should be of
high biological value.
A protein of high biological value should
contain all essential amino acids.
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General Metabolism of Proteins :
Complete breakdown of proteins andamino acids give rise to
Urea + Co2 + H2O + Energy.
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y The major pathwayfor amino acids excess after proteinsynthesis is theremoval of the amino group and itsconversion to ammonia (as there is no amino acid storage).
y The liver is the major site of removal of amino group fromamino acids..
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The amino group is removed bydifferent mechanisms:
y 1.Transamination
y 2. Oxidative deamination
y 3. Non-oxidative deamination
y
4.Transdeamination
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I . Transamination :y It transfers the amino group from an amino acid to -
keto acid.
y All the amino acids participate in the reaction oftransamination except threonine and lysine.
y Vitamin B6 is required as a coenzyme.
y Its enzymes are termed transaminases
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a) Aspartate transaminase: (AST) or(GOT)
COOH
CHNH2
CH2
CH2
COOH
COOH
C
CH2
COOH
O
COOH
C
CH2
CH2
COOH
O
COOH
CHNH2
CH2
COOH
B6
+ GOT +
Glutamic acid Oxaloacetic acid -Ketoglutaric acid Aspartic acid
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b) Alanine transaminase: (ALT)or(GPT)
COOH
CHNH2
CH2
CH2
COOH
COOH
C
CH3
O
COOH
C
CH2
CH2
COOH
O
COOH
CHNH2
CH3
+ GPT
B6+
Glutamic acid Pyruvic acid -Ketoglutaric acid Alanine
Transaminases are cytosolic and mitochondrial enzymes. It isTransaminases are cytosolic and mitochondrial enzymes. It is
a freely reversible process.a freely reversible process.
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Biological importance of Transamination
1- Synthesis of new non-essential amino acids.
2- Degradation of most amino acids except lysineand threonine.
3- Formation of components of citric acid cycle(filling up reaction of citric acid cycle).
4-Transaminase enzymes are used in diagnosis andprognosis of the diseases.
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y N.B. Transaminase enzymes are present inside the cellsand small traces are present in the blood (5-40 IU/L).
y The increase in their level denote cell damage with therelease of enzymes from the destructed cells.
y
E.g.in cardiac infarction SGOTis increased
in hepatic infection, SGPTis increasedabove the normallevels.
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II. Oxidative deamination:
y It is catalyzed by: Amino acid oxidases Occur in liver andkidney.
y It includes removal of hydrogen (oxidation) and removal of
NH3 (deamination).y There areD- and L-amino acid oxidases that oxidizes D-
and L-amino acids respectively, to the corresponding -ketoacids and the amino group is released as ammonia (NH3).
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R-CH-COOH R-C-COOHAmino acid oxidase
NH2
NH
Flavin Flavin-H2
H2O
H2O
2O
2
1/2 O2
H2O
CatalaseR-C-COOH
-Ketoacid
Aminoacid Iminoacid
O
NH3
E
Oxidative deaminationOxidative deamination
1
2
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y D-amino acid oxidase uses FAD as coenzymewhich is of
limited natural occurance in mammals and of high activity,
y L-amino acid oxidase uses FMN as coenzymewhich is ofnatural occurrance in mammals, but of low activity.
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COOH
CHNH2
CH2
CH2
COOH
NADPH+H
COOH
C
CH2
CH2
COOH
NH
NH3
COOH
C
CH2
CH2
COOH
O
NADH+H+
Iminoacid
L-glutamic acid
dehydrogenase
NADP
(NAD)
H2O
The reaction is both mitochondrial and cytoplasmic,
occurs mainly in the liver and kidney.
ATP and GTP are allosteric inhibitors while ADP and GDPactivate the enzyme.
It is a reversible reaction.
Glutamic acid -ketoglutaric acid
Oxidative deaminationOxidative deamination
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III - Non-oxidative deamination
(direct deamination):
y The - amino group ofserine and threonine
( amino acids containing hydroxyl group) can be directlyconverted to NH3without removal of hydrogen.
y
This reaction is catalyzed byserine and threoninedehydratasewhich need pyriodoxal phosphate as coenzyme.
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Non-oxidative deamination
(direct deamination)
CH2-CH-COOH
L-serine
OH NH2
CH2=C-COOH
NH2
Serine
dehydratase
CH3-C-COOH
NH
CH3-CO-COOH
NH3
H2O
H2O
pyruvic acid
PLP
NonNon--oxidative deaminationoxidative deamination
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IV .Transdeamination (L-Glutamate dehydrogenase):
Vit B6
NAD
NADP
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Metabolism of ammonia
Sources of blood ammoniaSources of blood ammonia
Fates of ammonia (Removal of ammonia)Fates of ammonia (Removal of ammonia)
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Sources of blood ammonia:
1.From amino acids :
y Transdeaminationy Oxidative deaminationy Non-oxidative deamination .
2.From glutamine :
y Renal glutaminase
y Intestinal glutaminase
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ATP ADP+p
+H2O
Glutamine synthetase
H2O
Glutamine synthesis and ammonia formationGlutamine synthesis and ammonia formation
Glutamic acidGlutamineGlutamine Glutamic acid
glutaminaseglutaminase+
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3.From amines : whether dietary amine or monoaminehormones by amine oxidase.
4. From catabolism of purines and
pyrimidines .
5.From bacterial action in the intestine either fromdietary protein residue or from urea diffuses into theintestine
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Fates of ammonia (Removal of ammonia):
y Amination of -ketoacid to form non-essential aminoacids and other biosynthetic reactions.
y Glutamine synthesis in the brain, liver, muscle and renal
tissues (4%).
y The majority ofNH3 (90%) will produce urea in the liverby urea cycle.
y Excretion in urine upto 1 gm /24 hours urine.
y Traces in blood (up to 100 ug / dl).
Oxidative Deamination N O id ti D i ti T d i ti
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NH3
Oxidative Deamination Non Oxidative Deamination Transdeamination
Glutamine Purine and pyrimidine
UreaNew aminoacid
Traces in the blood
up to 100 ug / dl
Sources and Fates of ammonia
90 %
4 % 1 %
From bacterial action inthe intestine on protein
Excretion in urine upto 1Excretion in urine upto 1
gm /24 hours urinegm /24 hours urine
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y urea is released into the blood with a
level of20 - 40 mg/dL
y It is the major end product of nitrogencatabolism in humans representing 80-
90% of the nitrogen excreted.
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Urea formation
NH2
3 ATPCO2 +2 NH3 CO + H2O
NH2ureaurea
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y Five reactions each of them utilisesspecific enzyme in urea cycle.
y The first 2 reactions of urea cycle aremitochondrial and the rest 3 reactionsare cytoplasmic.
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cytoplasmcytoplasm
mitochondriamitochondria
Fi f l
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Five enzymes of urea cycle:
y Carbamoyl phosphate synthase 1
y Ornithine transcarbamoylase(citrulline synthase)
y Argininosuccinate synthetase.
y Argininosuccinase.
y Arginase.
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UreaCycle
Urea Cycle
mitochondriamitochondria
cytoplasmcytoplasm
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Reactions (steps) of the urea cycle:
Carbamoylphosphate formation:Using activeCO2 , NH3 , 2 ATP and
carabmoylphosphate synthase I, which is amitochondrial enzyme active in presence of
N-acetylglutamic acid.
carabmoylphosphate synthase I
CO2 + NH3 + 2ATP H2N.CO. P + 2 ADP + P
Carbamoyl phosphate
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UREA CYCLE
Carbamoyl phosphate synthase 1Carbamoyl phosphate synthase 1
Ornithine transcarbamoylaseargininosuccinase.argininosuccinase.
arginasearginase
argininosuccinate synthetaseargininosuccinate synthetase
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LINKBETWEENKREBS' UREA CYCLE ANDKREBS'
TRICARBOXYLIC ACID CYCLE:
COCO22 + NH+ NH33
2ATP2ATP
2
1
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LINKBETWEENKREBS' UREA CYCLE ANDKREBS'
TRICARBOXYLIC ACID CYCLE:
Malate
Oxalacetate
Glutamate-ketoglutarate
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1. The fumarate resulting from reaction number 4 (inKrebs urea cycle), under the influence of
argininosuccinase, undergoes conversion to malate byfumarase enzyme.
This malate forms oxaloacetate by malate
dehydrogenase. The oxaloacetate undergoesTransamination by SGOT to form aspartate.
This aspartate is needed in urea cycle atargininosuccinic synthase enzyme.
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2.TheCO2 used in urea cycle comes
mainlyfrom Krebs' tricarboxylic acidcycle.
The first NH2 group comes from
L-glutamic acid byL-glutamate
dehydrogenase.
The second NH2 group comes fromamino group of aspartic acid.
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REGULATION OF UREA CYCLE:y1. Excess ammonia formation stimulates
urea formation.
y2. High arginine level stimulates N-acetyl
glutamate synthaseenzyme, thus
increases urea formation.
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y 3. High urea level inhibits
carbamoylphosphate synthase(reaction 1),
ornithine transcarbamoylase (reaction 2)
and arginaseenzymes (reaction 5).
y 4. Carbamoylphosphate synthase is inactive inthe absence of activator, N-acetylglutamate.
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METABOLIC DISORDERS OF UREA CYCLE:
There are five types of congenital hyperammonaemia.
They affect children and manifested by
1.Vomiting,
2. Irritability,
3. Ataxia,
4. lethargy coma ,
5. Mental retardation,and death
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y 1. Hyperammonaemia type I:
y
It may be due to carbamoylphosphate synthasedeficiency.
y It causes increase in blood ammonia level (normally
plasma ammonia is less than 100 g/dL).
y It is a familial disease.
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2. Hyperammonaemia type II:
y
It is due to ornithine transcarbamoylase deficiency.
y It is X-chromosome linked deficiency.
y There is increased glutamine in blood, CSF and urinedue to increased glutamine synthesis as consequenceof increased tissue levels of ammonia.
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3. Citrullinaemia type III:
y It is due to lack ofargininosuccinic synthase .
y It is recessive inherited disorder.
y
There is an increase in citrulline in plasma, CSF andurine.
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4. Argininosuccinic aciduria type IV:
It is due to argininosuccinase deficiency.
y It is recessive inherited disorder.
y There is increase in argininosuccinic in plasma, CSFand urine.
y It is manifested at age of two years.
y It usually ends in death early in life.
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5. Hyperargininaemia type V:
y It is due to arginase deficiency.
y There is increase in arginine in blood, CSF andurine.
y It affects children ( 1: 30,000 ) leading to mentalretardation ,coma and death.
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Ammonia intoxication
(Ammoniacal encephalopathy)
y It is defined as toxicityof the brain
due to increase in NH3 level in thesystemic blood.
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y This increased ammonia will be
fixed to - ketoglutaric acid toform glutamic acid then glutamine
leading to interference with citricacid cycle so decreaseATPproduction in the brain cells.
C
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yCauses:
I. Congenital:
The 5 types of hyperammonaemiadue to enzymes deficiencies inurea cycle.
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II. Acquired:
1. Liver disease as cirrhosis due tofailure of urea formation and glutamine
synthesis.
2. Portocaval shunt as in bilharziasis.
3. Gastrointestinal bleeding by action of
bacterial flora on the blood urea and
thus NH3 is released in large amounts.
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Manifestations of ammonia intoxication:
y1. Tremors
y2. Blurred vision
y3. Slurred speech
y4. Vomiting
y5. Confusion followed by comaand death.
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Treatment:1. Restrict protein diet.
2. Injection of
Glutamic acid and E-ketoglutaric acid:
They act as a carrier forNH3 and combine
with it to form a nontoxic material called
glutamine. Glutamine passes to the kidney
and by glutaminase yielding glutamic acid
and NH3 excreted in urine as ammonium salt.(NH4cl).
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3. Sodium benzoate and phenylacetate
are given to conjugate with glycine
and glutamine and rapidly theconjugates are excreted in urine.
4. Frequent small meals to avoid sudden
increase in blood ammonia levels.
5. Removal of excess NH3 bydialysis in
acute cases.
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