This document provides information about protein metabolism. It discusses that proteins undergo constant breakdown and resynthesis through protein turnover. The amino acids released are utilized for synthesis of new proteins, nucleic acids, and other biomolecules. Excess amino acids are converted to urea which is excreted in urine. The urea cycle occurring in the liver is the major route for ammonia detoxification. Deficiencies of urea cycle enzymes can cause hyperammonemia.
3. Introduction
Are most abundantly distributed organic compounds.
70 kg man= protein weight constitute 12 kg
Skeleton and connective tissue contains half
Body protein and other half is intracellular.
4. Protein Turnover:
The total amount of protein in the body remains
constant (i.e Rate of protein synthesis is constnt)
Is equal to protein degradation.
This process is called as protein turnover.
300 to 400 Gm/day.
5. Rate turn over
Half-lives Proteins
Hours/Days Digestiive Enzymes &
Plasma proteins.
Months/years Collagen.(Structural Proteins)
Proteins rich in Proline, Glutamate, Serine and
threonine are rapidly degraded and short half-lives
6. AminoAcid pool
Amino acids released by dietary & tissue Protein
Mix with free amino acids of body = Constitutes=100
gm.
Glutamate,Glutamine - 50 %
Essential amino acids - 10%.
Remaining Non-Essential Amino Acids.
7. Proteins rich in Proline,Glutamate,Serine and
Threonine are rapidly degraded and have short half-
lives.
AMINO ACID POOL: -Amino acids released by
1.Dietary and 2.Tissue protein.
8. There is no storage form of amino acids like
Glycogen and Triglycerides.
Excess intake of proteins(Amino acids) are
metabolised then oxidised to provide energy or
converted to glucose or fat.
Amino groups lost as Urea→Excreted.
9. Body Dietary Synthesis
Protein Protein Non-Essential AA
Body Protein Porphyrins
Purines & Pyrimidins
Creatine
Neurotransmitters
UREA
Glucose CO₂ Fattyacids
Glycogen Ketone Bodies
Steroids
AMINO ACID POOL
100 G
10. Digestion of Dietary Proteins
Proteins are too large to be absorbed by
intestine and must be hydrolysed to yield
amino acids,which can beabsorbed.
Proteolytic enzymes responsible for degrading
proteins are produced by 3 different organs:
Stomach,Pancreas and Small intestine.
11.
12.
13. PROTEIN DIGESTION:- Dietary protein-50-100
gm/day.
30-100gm/Day- Endogenous protein from digestive
enzymes.
Dietary proteins are denatured on cooking.
14. Proteins are degraded by hydrolases which
cleave peptide bonds known as peptidases.
Exopeptidases and endopeptidases.
EXOPEPTIDASES ENDO PEPTIDASES
1.Carboxy peptidases. Aspartate Proteinase
2.Amino peptidases. Eg:- Trypsin
3.Tripeptidyl peptidases. Serine Proteinases
4.Dipeptidyl peptidases. Eg:-Trypsin
5.Dipeptidase Cysteine Proteinases
Eg:-Papain
Metallo Proteinases
Eg:-Metal-ion
15. DIGESTION @ Stomach
HCl , pH=2, Due to HCl, secreted by parietal cells.
Denature Protein
Destroys microorganisms.
Pepsin = Pepsinogen HCl Pepsin.
16. ABSORPTION :- Occurs in small intestine of infants
immediately after birth. This process is known as
PINOCYTOSIS.
Direct transfer is useful for taking up of maternal
γ Globulins.
17. ADULTS:-Direct transfer of intact protein (or) poly
peptide in body elicits Antibody formation(Food
allergy).
NONTROPICAL SPURE:-Tripeptde digestionof wheat
Glutemate stimulates antibody production.
CELIAC DISEASE in children same phenomena has
been obsreved.
18. Abnormality of protein digestion:-HARTNUP’S
disease is due inability of intestinal absorption of
neutral amino acids.
PROTEIN TURNOVER:-Continuous degradation and
resynthesis occurs in all cellular proteins.
Adults degrade 1-2% of their body protein
daily(muscle protein).
75-80% are utilized for protein synthesis.
20-25% for urea.
19.
20. Proteins are degraded at varying rates.
1.High mean rates of protein degradation occurs in
uterine tissue during pregnacy.
2.During strvation ,skeletal muscle protein
degradation is ↑.
21.
22.
23. TRANSMINATION is defined as a process in
which amino group is transferred from an Aminoacid
to Ketoacid to form an corresponding Aminoacid that
itself is forming Ketoacid with out liberation of
ammonia.
The enzymes catalyzing the reaction as a group are
known as AMINO TRANSFERASES.
All amino Transferases require coenzyme –
Pyridoxal phosphate-B6.
25. All amino acids ,except LYSINE,THREONINE
participate in Transmination.
The reaction is Cytoplasmic and takes place in
liver.
Transminases are induced by Glucocorticoids
which promotes Gluconeogenesis.
26. Clinical significance:- ↑Levels in plasma indicates
damage to cells rich in these enzymes.
SGPT↑ :- Toxic Hepatisis.
Viral Hepatisis
Cirrhosis.
SGOT:- Myocardial infarction,Pulmonary disorders.
Function:- Transmination is useful synthesis of
Non- Essential Aminoacids.
Major oxidative deamination is catalysed.
Glutamate DeHydrogenase (GDH)
It is a mitochondrial enzyme in Liver.
30. All amino acids, amino groups are funnelled into
glutamate.
High Protein Diet = High Ammonia formation.
When energy levels are low amino acid degradation
by GDH is High,Provides α-KG for TCA cycle.
Allosteric regulators=
ATP,GTP=Inhibitors
ADP,GDP=Activators
31. NON-OXIDATIVE DEAMINATION
1.Enzymes that acts as dehydratases forms
corresponding keto acid and ammonia.
Threonine Deaminase Keto Butyrate +NH₃
2.Transulfuration:
Cysteine Pyruvate+NH₃ + H₂S
3.Histidine undergoes non-oxidative deamination
by histidase.
4.Glutamine Glutaminase* Glutamate + NH₃
Aspargine Asparginase* Aspartate + NH₃.
These enzymes have been utilized as Anti-Tumor
Agents.
*Acts as anti tumor agents
32. Metabolism of Ammmonia:-
SOURCES OF AMMONIA :-
Amino acids Synthesises Protein,
Protein degraded to Amino acids.
From Liver : a) Transamination
b) Oxidative deamination
From Kidney : Glutaminase reaction
From Intestine : By Bacterial action
From Diet : Amines
From Catabolism : Purines (Adenine)
Pyrimidines (Cytosine)
From Non–oxidative: Deamination : Aminoacids
33. UTILIZATION OF AMMONIA:-
Glutamate+ Ammonia Glutamine.
Glutamine synthetase- Liver, Brain and Kidney.
Brain :- Major mechanism for removal of
Ammonia is Glutamate formation.
αKG+NH3+NADPH+H⁺ Glutamate+NADP⁺
Glutamate may be considered as a major transport
form of NH₃ from tissue to liver.Concentration of
Glutamate in blood is 10 times more than other
amino acids.
34. 3 Important disposal route of ammonia is formation
of Urea.
End product Amino Nitrogen
In mammals is Urea - Ureotelic.
Fishes is Ammonia - Ammonotelic.
Birds & Reptiles is Uric acid - Uricotelic
35. TRANSPORT OF AMMONIA:-
Ammonia is constantly produed in tissues.
Plasma ammonia - 10-20 μg /dl.
Elevated levels cause symptoms of ammonia
intoxication.
SYMPTOMS:-Tremor, Slurring of speech, Blurring of
vision→Coma and death.
37. HEREDITARY HYPER AMMONEMIA:-
All inherited deficiencies of UREA CYCLE ENZYMES
result in HYPER AMMONEMIA.
Prevalence is 1 in 30000 individuals.
38.
39. UREA CYCLE
1.Enzymes of Urea cycle
2.Regulation of Urea cycle
3.Energetics of Urea cycle
4.Clinical significance of blood Urea
5.Disorders of Urea cycle
40. Urea cycle is also called as Krebs-Henseleit or
Ornithine cycle.
Site: Liver
Urea synthesized in Liver, released into Blood, cleared
by Kidneys.
Urea cycle is devided into Five steps.
41.
42. Two nitrogen atoms of urea are derived from
ammonia and alpha amino group of aspartic
acid.
One mol of urea synthesis requires 4 mol of ATP.
Step 1 in Mitochondria:-
CO₂ + Ammonia + 2 ATP Carbamoyl
Phosphate+2ADP+PPi
Carbamoyl phosphate synthase 1(CPS-1)
It is a Mitochondrial enzyme,
Allosteric activator is N-Acetyl Glutamate.
43. Step 2. Formation of Citrulline
Carbamoyal phosphate +Ornithine
Ornithine Transcarbamoylase
Citrulline + Pi
Ornithine trans carbmoylase is also a Mitochondrial
enzyme
44. This step onwards the reactions occurred in
CYTOPLASM
Step3- Formation of Argininosuccinate.
Citrulline + Aspartate + ATP
Argininosuccinate synthase
Argininosuccinate + AMP + PPi
46. 2.Regulation of Urea Cycle :
a) Carbamoyl Phosphate Synthase-1:
Allosteric activator –N-acetylglutamate.
More glutamate, more N-acetylglutamate,
more CPS-1 activity, leads more Urea synthesis.
b) During starvation, Urea cycle enzyme activities are
increased to meet the demands of increased rate of
protein catabolism.
47. 3 Energetics of Urea cycle:
ATP UTILIZED
Carbamoyal phosphate synthase -2ATP
Argininosuccinate synthase -2ATP
ATP GENERATED
Fumarate- Malate- MDH +3ATP
Net Energy expenditure -1ATP
48. Clinical significance of Blood Urea:
Normal Blood Urea = 15 - 40 mgs %
Normal Urine Urea = 15 - 30 grams/day
Increased Blood Urea levels:
Prerenal causes
a) High protein diet
b) Increased protein catabolism –starvation
c) Gastro-intestinal haemorrhage.
49. Renal causes
a) Chronic renal failure
B) Acute glomerulonephritis
c) Nephroscelerosis.
Postrenal causes
a) Renal stone
B) Prostate enlargement
c) Malignant stricture
50. Decreased Blood Urea Levels:
a) Low protein diet.
b) Liver diseases
c) Water retention.
51. DISORDERS OF UREA CYCLE:
a) Hyperammonemia - Type I
-Enzyme Defeciency - CPS 1
-Symptoms - Increased blood ammonia (↑ NH₄)
Mental retardation
Autosomal recessive .
52. HYPER AMMONEMIA Type II
Enzyme deficiency –Ornithine transcarbamoylase
↑ NH₃ in Blood; Glutamine ↑ in C.S.F, urine, blood.
X-Linked inheritance.
Orotic aciduria, Mental retardation.