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Protein & Amino Acid Protein & Amino Acid MetabolismMetabolism
ANDAND
Protein & Amino Acid Protein & Amino Acid MetabolismMetabolism
ANDANDMetabolismMetabolism
ANDANDThe Urea CycleThe Urea Cycle
MetabolismMetabolismANDAND
The Urea CycleThe Urea Cycle
Dr Piyush B.TailorDr Piyush B.TailorDepartment of BiochemistryDepartment of Biochemistry
Govt.Medical CollegeGovt.Medical CollegeSuratSurat
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Three sources of amino acids
• Synthesis of Non-essential amino acid from metabolic intermediate.
• Breakdown of proteins.• Breakdown of proteins.
• Amino acids derived from dietary protein.
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Amino acid is depleted by three routes
• Synthesis of body protein
• Amino acids consumed as precursors of essential nitrogen-containing small essential nitrogen-containing small molecules
• Conversion of amino acids to glucose, glycogen, fatty acids or CO2
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Amino Acid Degradation must account for an amino group
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Protein Degradation
1.Ubiquitin – Proteasome Proteolytic enzyme
2.Chemical Signal for Protein Degradation
2.Chemical Signal for Protein Degradation
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Ubiquitin – Proteasome Proteolytic enzyme
• first covalently attached to ubiquitin, a small, globular protein.
• Through linkage of the Glycine of ubiquitin to a Lysine on protein substrate
• Proteins tagged with ubiquitin are targated by proteasome, which functions like a garbage proteasome, which functions like a garbage disposal.
• The proteasome cuts the target protein into fragments that are then further degraded to amino acids, which enter the amino acid pool.
• The ubiquitins are recycled.
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Chemical Signal for Protein Degradation
• Because proteins have different half-lives, it is clear that protein degradation cannot be random.
• But rather is influenced by some structural aspect of the protein. aspect of the protein.
• For example, some proteins that have been chemically altered by oxidation or tagged with ubiquitin are preferentially degraded.
• The half-life of a protein is influenced by the nature of the N-terminal residue.
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The different forms of excreted nitrogen
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Protein DigestionProtein DigestionProtein DigestionProtein DigestionProtein DigestionProtein DigestionProtein DigestionProtein Digestion
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Monogastric Protein Digestion
• Whole proteins are not absorbed– Too large to pass through cell
membranes intactH N+ C
HC
O
• Digestive enzymes– Break peptide bonds
• Secreted as inactive pre-enzymes– Prevents self-digestion
H3N+ C C
RNH
CH
C
O
RNH
CH
C
R
O
O–
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Monogastric Protein Digestion
• Initiated in stomach–HCl from parietal cells
• Stomach pH 1.6 to 3.2
• Denatures 40, 30, and 20 structures• Denatures 4 , 3 , and 2 structures
–Pepsinogen from chief cells
• Cleaves at phenylalanine, tyrosine, tryptophan
• Protein leaves stomach as mix of insoluble protein, soluble protein, peptides and amino acids
Aromatic amino acids
PepsinogenHCl
Pepsin
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Protein Digestion – Small Intestine
• Pancreatic enzymes secreted– Trypsinogen
– Chymotrypsinogen
– Procarboxypeptidase– Procarboxypeptidase
– Proelastase
– Collagenase
Zymogens
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Digestion – Small Intestine
• Zymogens must be converted to active form– Trypsinogen Trypsin
• Endopeptidase– Cleaves on carbonyl side of Lys & Arg
Enteropeptidase/Trypsin
– Cleaves on carbonyl side of Lys & Arg
– Chymotrypsinogen Chymotrypsin• Endopeptidase
– Cleaves carboxy terminal Phe, Tyr and Trp
– Procarboxypeptidase Carboxypeptidase• Exopeptidase
– Removes carboxy terminal residues
Trypsin
Trypsin
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Protein Digestion• Small intestine (brush border)
– Aminopeptidases
• Cleave at N-terminal AA
– Dipeptidases
• Cleave dipeptides
– Tripeptidase
• Cleave tripeptides
– ( Enterokinase or Enteropeptidase )
• Trypsinogen → trypsin
• Trypsin then activates all the other enzymes
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Protein Digestion• Proteins are broken down to
– Tripeptides
– Dipeptides– Dipeptides
– Free amino acids
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Free Amino Acid Absorption• Free amino acids
– Carrier systems
• Neutral AA
• Basic AA
• Acidic AA Na+ Na+• Acidic AA
• Imino acids
– Entrance of some AA is via active transport
• Requires energy
Na+ Na+
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Amino Acid Transporters –Brush Border Membrane
Transport
system
Energy required Substrates carried
L
B
IMINO
y+
Bo,+
bo,+
No
Yes
Yes
No
Yes
No
Leu, other neutral
Phe, Tyr, Trp, Ile, Leu, Val
Pro, Gly
Basic amino acids
Most neutral and basic
Most neutral and basic
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Peptide Absorption• Form in which the
majority of protein is absorbed
• More rapid than absorption of free amino acids
• Active transport• Active transport– Energy required
• Metabolized into free amino acids in enterocyte
• Only free amino acids absorbed into blood
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Basolateral Membrane
Groff & Gropper, 2000
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Absorption of Intact Proteins• In Newborns
– First 24 hours after birth– Immunoglobulins get absorbed
• Passive immunity
• In Adults– By Paracellular routes– By Paracellular routes
• Tight junctions between cells
– By Intracellular routes• Endocytosis• Pinocytosis
It has little nutritional significance...– Affects health (allergies and passive immunity)
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Protein Transport in the Blood
• Amino acids diffuse across the basolateral membrane – Enterocytes → portal blood → liver →
tissues– Enterocytes → portal blood → liver →
tissues– Transported mostly as free amino acids
• Liver– Breakdown of amino acids– Synthesis of non-essential amino acids
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Catabolism
of of
Amino acids
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• Breakdown of Amino acid.
• Prodcuce CO2 and NH3
• NH3 need to be detoxify– Peripheral detoxification
– Peripheral to liver transport
– In Liver detoxification– In Liver detoxification
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• First step is the removal of the α-amino group – by enzymes - Amino-transferases or Transaminases.
Peripheral detoxification
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Transamination Reaction
• The amino group is transferred to α-ketoglutarate to make glutamate.
• Formation of Non-essential amino acid
• Formation substrate of Gluconeogenesis • Formation substrate of Gluconeogenesis
• Detoxification of amide group
•
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Glutamine transports NH3 in the bloodstream
• Glutamate accepts the NH3 by the action of Glutamine Synthetase.
• Glutamine transport to ammonia from • Glutamine transport to ammonia from periphery to liver
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Urea• If Ammonia is not used for production of
new amino acids or other nitrogenous compounds, amino groups are transferred to the liver and converted to urea.
• Urea is produced in the cytosol via the urea cycle.cycle.
• Almost all urea is produced in the liver.
• Than Urea excreted in the urine.
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The Urea Cycle
• The first two steps = mitochondrion.
• Remaining three = cytosol.
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What can be use of this product?
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The enzymes catalyzingthe urea cycle reactions
1. Ornithine transcarbamoylase
2. Argininosuccinate synthetase
3. Argininosuccinase3. Argininosuccinase
4. Arginase
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The Urea Cycle and TCA Cycle are interconnected
• Cytosolic Isozymes of– Fumarase
– Malate dehydrogenase.
• Malate enter in Mitochondria• Malate enter in Mitochondria
• Than enter into the TCA cycle.
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Regulation of the Urea Cycle
• Within an individual the movement of nitrogen through the cycle depends on diet.
• Changes in diet will only affect urea cycle • Changes in diet will only affect urea cycle activity over the long term.
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Regulation of the Urea Cycle
• Short term– Carbamoyl Phosphate Synthetase.– Allosteric regulation– N-acetylglutamate activates CPS-1– Arginine activates N-acetylglutamate synthase, – Arginine activates N-acetylglutamate synthase,
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Energetic cost of The Urea Cycle
• 2NH4+ + HCO3
- + 3ATP + H2O →
urea + 2ADP + 4Pi + AMP + 2H+
• However, through linkage of the pathways • However, through linkage of the pathways the toll is not so bad. Some NADH is produced which regains about 2.5 ATP form respiration.
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Hereditary deficiency of any of the Urea Cycle enzymes leads to hyperammonemia - elevated [ammonia] in blood.
Total lack of any Urea Cycle enzyme is lethal.
Elevated ammonia is toxic, especially to Elevated ammonia is toxic, especially to the brain.
If not treated immediately after birth, severe mental retardation results.
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Mechanisms for toxicity of high Ammonia
1. High [NH3] would drive Glutamine Synthase:
glutamate + ATP + NH3 ���� glutamine + ADP + Pi
This would deplete glutamate – a neurotransmitter &
precursor for synthesis of the neurotransmitter GABA.
2. Depletion of glutamate & high ammonia level would
drive Glutamate Dehydrogenase reaction to reverse: drive Glutamate Dehydrogenase reaction to reverse:
glutamate + NAD(P)+ αααα-ketoglutarate +
NAD(P)H + NH4+
The resulting depletion of α-ketoglutarate, an essential
Krebs Cycle intermediate, could impair energy
metabolism in the brain.
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Mechanisms for toxicity of high Ammonia
3. Due to high ammonia, conc. of Glutamine remains
high in brain cell.
Glutamine is co-transported outside from brain cell with
tryptophan influx.
So, More Tryptophan get accumulated in brain cell if
more glutamine goes out.more glutamine goes out.
From accumulated Tryptophan, Serotonine
synthesis & that have depressive effect on neurons.
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Treatment of deficiency of Urea Cycle enzymes (depends on which enzyme is deficient):
� limiting protein intake to the amount barely adequate to supply amino acids for growth, while adding to the diet the α-keto acid analogs of essential amino acids.
� Liver transplantation has also been used, since liver is the organ that carries out Urea Cycle.
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One-carbon Transfer Reactions
• Cofactors for one-carbon transfer reactions in amino acid degradation.
• Tetrahydrofolate (H4 folate) – Transfers carbon in intermediate oxidation states, carbon in intermediate oxidation states, sometimes methyl.
• S-adenosylmethione (SAM or adoMet) –Transfers carbon as methyl groups.
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