Metabolism of Proteins

Metabolism of Protein
Objectives
Explain the metabolism of Proteins
After the completion of this unit students will be
able to:
1. Review the digestion and absorption of protein.
2. Explain the significance of nitrogen balance
3. Describe the synthesis of protein
4. Discuss the transamination, deamination and
decarboxylation.
5. Discuss the formation of urea and ammonia
disposal
Protein Digestion &
Absorption
• The digestion and absorption of protein is
extremely efficient:
• only 1-2 g of nitrogen=equivalent to 6-12
of protein is lost into the feces daily.
• Proteins are hydrolyzed by peptidases
• Endopeptidases (cleave internal peptide bonds)
• Exopeptidases
• Carboxypeptidases
• Aminopeptidases
• Endopeptidases break down large
polypeptides to smaller oligopeptides
which can be acted upon by
exopeptidases to produce amino acids
and di- and tripeptides which are absorbed
by enterocytes (intestinal absorptive cells,
are simple epithelial cells found in the
small intestine).
• Depending on the source of peptidases,
the protein digestive process can be
divided into 3 phases:
1-Gastric
2-Pancreatic
3-Intestinal
• Protein digestion begins in the stomach.
• Entry of dietary protein into the stomach
stimulates the gastric mucosa to secrete
gastrin.
• HCI secreted reduces the pH of stomach to 1-
2
• The acidic gastric juice is both an antiseptic
agent, killing most bacteria and other foreign
cells, and a denaturating agent, unfolding
globular proteins.
• Denaturation unfolds polypeptide
chains, making proteins more accesible
to protease activity.
• Pepsins are secreted by the chief cells
of the gastric mucosa, as inactive
precursors, pepsinogen I and II, and are
activated either by autoactivation at
ph<5 or by autocatalysis.
(a cleavage mediated by pepsinogen
itself)
• At ph>2.0, the liberated peptide remains
bound to pepsin and acts as an inhibitor of
pepsin activity.
• This inhibition is removed either by a drop in
pH below 2.0 or by further pepsin action.
• Pepsin hydrolyzes ingested proteins at
peptide bonds on the amino-terminal side of
aromatic amino acid residues-Phe, Trp and
Tyr
• The end product of protein digestion in
the stomach is peptide.
• As the acidic stomach contents pass
into the small intestine, the low pH
triggers secretion of the hormone
secretin into the blood.
• Secretin stimulates the pancreas to
secrete bicarbonate into the small
intestine to neutralize gastric HCI,
abruptly increasing pH to about 7.
• Gastric protein digests stimulate
cholecytokinin release in the duodenum,
triggering the release of main digestive
enzymes by the pancreas.
• Proteolytic enzymes ,released from the
pancreas,are inactive zymogens.
• Duodenal enteropeptidase converts
trypsinogen to active trypsin.
• This enzyme is capable of autoactivation and
activation of all other pancreatic zymogens -
chymo-trypsinogen, proelastase, procarboxy-
peptidases (A and B)
• Because of this prime role of trypsin in
activating other pancreatic enzymes, its
activity is controlled within the pancreas
and pancreatic ducts by a small
molecular weight inhibitory
peptide.(pancreatic trypsin inhibitor)
• Synthesis of enzymes as inactive
precursors protects the exocrine cells
from destructive proteolytic attack.
• Pancreatic proteases have different
substrate specificity with respect to
peptide bond cleavage.
• Trypsin arginine and Iysine
residues
• Chymotrypsin aromatic amino
acids
• Elastase hydrophobic amino
acids
• Carboxypeptidases are zinc containing
enzymes that remove successive
carboxyl-terminal residues from
peptides.
• The combined effect of these pancreatic
enzymes produces free amino acids
and peptides of 2-8 residues.
• .Sodium bicarbonate, produced by the
pancreas, neutralizes the acid contents
of the stomach as they pass into
duodenum, thus promoting pancreatic
protease activity.
• The final digestion of di- and
oligopeptides is carried by small
intestinal membrane-bound
endopeptidases, dipeptidases and
aminopeptidases.
• The end products of this surface enzyme
activity are free amino acids, and di-and
tripeptides which are absorbed across the
enterocyte membrane by specific carrier-
mediated transport.
• Di-and tri-peptides are further hydrolyzed to
their constituent amino acids within the
enterocyte.
• Final step is the transfer of amino acids out of
the enterocyte into blood.
• In humans, most globular proteins from
animal sources are almost completely
hydrolyzed to amino acids in the GI
tract, some fibrous proteins, such as
keratin, are only partly digested.
• Acute pancreatitis is a disease caused
by obstruction of the normal pathway by
which pancreatic enzymes enter the
intestine.
• The zymogens of the proteolytic
enzymes are converted to their
catalytically active forms,prematurely,
inside the pancreatic cells and attact the
pancreatic tissue itself.
Protein Digestion:
Summary
1. Stomach: Protein breakdown begins in the stomach.

No protein hydrolyzing enzymes are found in saliva.
Hydrolysis (10% of peptide bonds) & denaturization by
pepsin enzyme & HCl produce short chain
polypeptides in the stomach.
2. Pancreas: Trypsin, chymotrypsin, &
carboxypeptidase from Pancreatic juices, and
Aminopeptidase from cells in the small
intestine create “free” amino acids.
 Free amino acids are absorbed through intestinal
wall via active transport.
 Enter bloodstream and are brought to cells.
 The total supply of free amino acids available is called:
the Amino Acid Pool.
Three sources of “free” amino acids:

1. Dietary protein breakdown
2. Biosynthesis of amino acids in the Liver
3. Protein turnover (I prefer apple turnovers)
Protein turnover is the breakdown & re-synthesis
of body protein:
• Old tissues
• Damage
• Recycling enzymes & hormones
Amino Acid Pool
• Input=output—Amount of amino acid contained in the

pool is contant (Steady State)
• Individual--- In Nitrogen balanced
• Protein Degradation:
1. ATP dependent Ubiquitin-Proteosome System
2. ATP independent degradation enzyme System of the
lysozymes
Summary of protein digestion in
the human body.(Possible fates for amino acid
degradation products).
Amino Acid
Catabolism
Transamination and Oxidative Deamination:
Two steps in degrading amino acids

1) remove -amino group
2) breakdown & process carbon skeleton
Release of an amino group is also two steps:

1) Transamination
2) Oxidative deamination
• Transamination: The
First step in the
catabolism of most
amino acids is the
transfer of alpha amino
group to alpha
ketoglutarate…. Thereby
becoming glutamate.
• This glutamate produced
can be oxidatively
deaminated or used
as amino group donar in
the synthesis of non
essential amino acids.
• Aminotransferases carries out
Transamination reactions.
• These have substrate specificity.
• E.g: Alanine Aminotransferase
• Aspartate Aminotransferase
Central role of glutamate:
Amino acids:
Glutamate, aspartate, alanine & glutamine
present in higher concentrations in mammalian cells.
Have metabolic functions as well as roles in proteins.
Glutamate is the most important, metabolically.
Some transaminases are used for diagnosing disorders:
enzyme alanine aminotransferase
Escapes in large amounts from dead or dying liver tissue.
Measured in blood samples for diagnostic purposes.
Transaminase enzyme aspartate aminotransferase
very active enzyme inside heart cells.
Also escapes in large amounts from dead or dying
heart tissues & enters bloodstream.
Measured in blood for diagnosing myocardial infarction.
Deamination
Most transaminases share a common substrate
and product (oxoglutarate and glutamate) with the
enzyme glutamate dehydrogenase.
This permits a combined N excretion pathway for

individual amino acids: "trans-deamination.”
Glutamate has a central role in the overall control
of nitrogen metabolism.
a.k.a.-ketoglutarate
Oxidative Deamination
The glutamate produced from the transamination
step is then deaminated by oxidative deamination
using the enzyme glutamate dehydrogenase:
Recycles back to a ketodiacid & releases ammonia

Glutamate dehydrogenase [GluDH] will reversibly
convert glutamate to -ketoglutarate and -
ketoglutarate to glutamate.
Deamination
reaction reverse reaction
uses NAD+ uses NADPH
Uses both NAD+ and NADPH

Nitrogen balance
Nitrogen balance represents the net result of the

continuous ongoing protein anabolism and
catabolism in the body. The balance is influenced
not only of the protein intake in relation to the
nitrogen losses from the body but also by the
protein quality of the dietary protein and
the energy balance. Thus comparing nitrogen
balance obtained with different diets and protein
sources must also be related to the energy
balance.
Regulation
Nitrogen balance: Healthy adults usually maintain

constant lean body mass and neither accumulate protein nor
lose protein mass. Since their combined nitrogen intake
(mainly as protein) more or less equals their nitrogen losses,
they are said to be in nitrogen balance.
Growing children and adolescents accumulate nitrogen for

their growth and development and are therefore said to be in
positive nitrogen balance. Starving, immobilized, and severely
ill people, in contrast, break down tissue protein and lose
more nitrogen than they take in; they are said to be in
negative nitrogen balance.
Urea cycle:
• Urea is produced by the Liver and then transported
to kidneys to be excreted by urine.
• Ammonium salts (NH4+) are toxic compounds.
• Oxidative deamination converting glutamate to
-ketoglutarate
• Ammonium ions building up favors the synthesis
of excessive amounts of glutamate, decreasing the
Krebs cycle intermediate -ketoglutarate.
This in turn decreases ATP production, and that
affects the nervous system.
The answer is Urea:
One N of Urea is supplied by free ammonia and other by
aspartate.
The inputs to the urea cycle are
NH3, CO2 ,aspartic acid and ATP.
The outputs are urea, ADP and fumaric acid.
The carbonyl group of urea is derived from CO2

Ammonia contributes one of the amine groups on urea
The four-step urea cycle in which
carbamoyl phosphate is converted to urea.
The nitrogen content of the various compounds
that participate in the urea cycle.
Does it remind
you of the
Krebs cycle in
any way?
Fumarate from the urea cycle enters the Krebs
cycle. Aspartate produced from oxaloacetate of
the Krebs cycle enters the urea cycle.
Oxaloacetate has 4 potential fates: transamination;

conversion to glucose; formation of citrate; conversion to pyruvate
Summary:
Transamination takes
off amine groups from
amino acids and forms
glutamate
(ionized glutamic acid)
Amine groups form
ammonia when removed
in deamination
This combines with
CO2 & Aspartate.
Forms urea, Arginine,
& Fumarate
Catabolism of of the Carbon Skeletons of
Amino Acids
a. Aminoacids that for oxaoacetate
• Asparagine
b. Aminoacids that form alpha-glutarate via glutamate

• Glutamine
• Proline
• Arginine
• Histidine
c. Amino acids that form Pyruvate

• Alanine
• Serine
• Glycine
• Cystein
• Threonine

Metabolism of Proteins

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Metabolism of Protein

1. Stomach: Protein breakdown begins in the stomach.

Three sources of “free” amino acids:

Amino Acid Pool

• Input=output—Amount of amino acid contained in the

Two steps in degrading amino acids

Release of an amino group is also two steps:

This permits a combined N excretion pathway for

Recycles back to a ketodiacid & releases ammonia

Uses both NAD+ and NADPH

Nitrogen balance represents the net result of the

Nitrogen balance: Healthy adults usually maintain

Growing children and adolescents accumulate nitrogen for

The carbonyl group of urea is derived from CO2

Oxaloacetate has 4 potential fates: transamination;

b. Aminoacids that form alpha-glutarate via glutamate

c. Amino acids that form Pyruvate

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