Amino acid metabolism.pptx

By Meskelu S. (Bpharm, MSc in MBC)
Amino acids and its Metabolism
1
8/31/2023 By Meskelu S.

Protein Digestion and Absorption
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Introduction
Digestion is the disintegration of complex nutrients
into simple, soluble and assimilable form.
Most of the nitrogen in the diet is consumed in the
form of proteins.
Proteins are too large to be absorbed.
hydrolyzed to amino acids by proteolytic enzymes,
which can be easily absorbed.
Proteolytic enzymes responsible for degrading
proteins are produced by three different organs;
The stomach
The pancreas and
the small intestine

Introduction cont..
 Begins in the stomach and is completed in the intestine.
• The enzymes for proteins digestion are produced as
• Inactive precursors (zymogens).
• The inactive zymogens cleaved in order to activate
their proteolytic activity.
 Each of these active enzymes has a different specificity.
• In digesting dietary proteins to amino acids and
• Small peptides, which are cleaved by peptidases
associated with intestinal epithelial cells.

5
Digestion of Protein
• Proteins are broken down by hydrolyases (peptidases or
proteases):
• Endopeptidases attack internal bonds and liberate large peptide
fragments (pepsin, trypsin, Chymotrypsin & Elastase).
• Endopeptidases are important for initial breakdown of long
polypeptides into smaller ones which then attacked by
exopeptidases.
• Exopeptidases ( aminopeptidase & carboxypeptidase) remove
one amino acid at a time from COOH or NH2 terminus.
• Digestion of protein can be divided into: a Gastric,
Pancreatic and intestinal phases.

6
I. Gastric Phase of Protein Digestion ( 15%)
1.Pepsin: in adult stomach , secreted as pepsinogen.
 It is specific for peptide bond formed by aromatic or acidic amino
acids.
2. Hydrochloric acid
The acid functions instead to kill some bacteria and to denature
proteins, thus making them more susceptible to subsequent
hydrolysis by proteases.
Pepsinogen
HCL
Pepsin
Protein
oligopeptides & polypeptides + amino acid
3.Rennin: in infants for digestion of milk protein (casein).

Digestion in the Stomach cont..
Gastrin
 Stimulates secretion of gastric acid (HCl) by the parietal cells of
the stomach and
 Aids in gastric motility
The role of hydrochloric acid during protein digestion.
•Stomach pH 1.6 to 3.2
•Denatures 40, 30, and 20 structures the dietary protein.
•Stimulates the activity of pepsin.
•Hydrochloric acid has bactericidal properties.
•Stimulates the peristalsis.
•Regulate the enzymatic function of pancreas.

Rennin
• also possesses a proteolytic activity and
• causes a rapid coagulation of ingested casein.
• But this enzyme plays important role only in children because
the optimal pH for it is 5-6.
Digestion in the Stomach cont…

• Proteases pepsins are endopeptidases.
• Liberate large fragments of peptides.
• Cleaves at phenylalanine, tyrosine, tryptophan
• Protein leaves stomach as mix of:
 insoluble protein
 soluble protein
 peptides and
amino acids
Aromatic amino acids
Digestion in the Stomach cont..

B. Digestion of Proteins by Pancreatic Enzymes(60%)
On entering the small intestine,
large polypeptides produced in the stomach by the action of pepsin
are further cleaved to:
Oligopeptides and amino acids by a group of pancreatic
Proteases.
10

Digestion by Enzymes From the Pancreas
As the gastric contents enter into the intestine.
• they encounter the pancreatic secretions from the exocrine
Pancreas.
Pancreatic secretions contain:
1.Bicarbonate
 Neutralizing the stomach acid
 Raises the pH for the pancreatic proteases.
2.Pancreatic proteases
 As secreted, these pancreatic proteases are in the form
zymogens.
 Because the active forms of these enzymes can digest
each other.
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Pancreatic zymogens
• Pancreatic enzymes secreted
• Trypsinogen
• Chymotrypsinogen
• Procarboxypeptidase
• Proelastase
• Collagenase Zymogens
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Activation of the pancreatic zymogens
The trypsinogen is cleaved to form trypsin by
Enteropeptidase secreted by the brush border cells.
The active trypsin cleaves the other pancreatic zymogens.
Zymogens must be converted to active form
Trypsinogen Trypsin
• Endopeptidase
• Cleaves on carbonyl side of Lys & Arg.
Chymotrypsinogen Chymotrypsin
• Endopeptidase
• Cleaves carboxy terminal Phe, Tyr and Trp.
Procarboxypeptidase Carboxypeptidase
• Exopeptidase
• Removes carboxy terminal residues.
Enteropeptidase/Trypsin
Trypsin
Trypsin
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Cleavage of dietary protein by proteases from the pancreas
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III. Intestinal Phase of Protein digestion(25%)
 Intestinal enzymes are:
• aminopeptidases (attack peptide bond next to amino
terminal of polypeptide) &
• dipeptidases : the end product is free amino acids
: dipeptides & tripeptides.
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Digestion of Protein in Small Intestine
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 the
gastric HCl,
abruptly increasing the pH to about 7
Arrival of amino acids in the upper part of the
intestine (duodenum) causes release into the blood of
the hormone cholecystokinin.
which stimulates secretion of several pancreatic
enzyme with activity Optimal pH 7 to 8.
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Protein Digestion cont.…
Small intestine (brush border)
• Enterokinase (or enteropeptidase)
• Trypsinogen  trypsin
• Trypsin then activates all the other zymogens.
• Aminopeptidases
• Cleave at N-terminal AA
• Dipeptidases
• Cleave dipeptides.
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Protein Digestion cont..
In lumen, Proteins are broken down to
Tripeptides
• Dipeptides
• Free amino acids
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Absorption
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Trans epithelial amino acid transport
Secondary active Na+-dependent
transport systems.
Transport both Na+ and an amino
acid into the intestinal epithelial
cell.
Na+ is pumped out on the serosal
side (across the basolateral
membrane) in exchange for K+ by
 the Na+, K+- ATPase.
 On the serosal side, the amino
acid is carried by a facilitated
transporter into the blood.
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Free Amino Acid Absorption
• Free amino acids
• Carrier systems
• Neutral AA
• Basic AA
• Acidic AA
• Imino acids
• Entrance of some AA is
via active transport.
• Requires energy
Na+ Na+
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Peptide Absorption
• Form in which the
majority of protein is
absorbed.
• More rapid than
absorption of free amino
acids.
• Metabolized into free
amino acids in enterocyte.
• Only free amino acids
absorbed into blood.
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Clinical Significance
 Cystinuria
Common transporter for
cystine, ornithine,
arginine and lysine
(COAL) is present in
gut and renal tubules.
Deficiency of
transporter results in loss
of these amino acids in
the feces and urine.
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Hartnup’s Disease
 There is deficiency of transporter for tryptophan and neutral
amino acid.
 No absorption of tryptophan takes place.
 The deficiency produce neurological and skin manifestation
(pellagra-like rashes).
Clinical Significance
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Intra cellular Protein Degradation
( Endogenous source)
Body proteins:
Continuously renewed /replaced with new ones.
The intracellular degradation of body proteins takes
place by 2 different mechanisms.
1.ATP-independent degradative enzyme system of the
lysosome.
Lysosome dependent (within the lysosome).
Lysosomal enzymes (acid hydrolases) degrade primarily
extracellular proteins, such as plasma proteins.
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Intracellular Protein Degradation
(Endogenous source)
 Non- functional and old proteins are taken in to the
lysosome and
 digested by intracellular proteases called cathepsins –
present in the lysosome.
 There are 18 different types of cathepsins in our body,
Cathepsin (A to T).
 These enzymes are active only at the acidic PH inside
the lysosome.
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2. The ATP-dependent ubiquitin-proteasome system of
the cytosol (Lysosomal independent ).
Takes place with the help of a protein called ubiquitin.
Protein complex, taken in to an assembly of proteases
called proteasome.
 Proteasome complex formed.
large number of proteases with ubiquitin are
arranged in the form of a cylinder/barrel.
Inside the proteasome the target protein is digested into
amino acids by the surrounding proteases.
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Proteasomes degrade mainly endogenous proteins.
Ubiquitin-proteasome proteolytic pathway
• Ubiquitination occurs.
• Through linkage of the α-carboxyl group of the C-
terminal glycine of ubiquitin to the £-amino group of a
lysine on the protein by:
• a three-step, enzyme-catalyzed
• ATP-dependent process.
• The consecutive addition of ubiquitin moieties generates a
Polyubiquitin chain.
Proteins tagged with ubiquitin recognized Proteasomes which
functions like a garbage disposal.
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Fasting and protein degradation
• Intracellular protein degradation is accelerated
during fasting to supply amino acids for the
following essential processes.
1. For gluconeogenesis and
2. For energy production –amino acid catabolism.
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The replacement of body protein by new and fresh
protein is called protein turn over.
 This is a normal process taking place in a
healthy individual.
In children the rate of protein synthesis will exceed
that of protein degradation that is why
the body is growing (increase in weight).
In adults the rate of protein degradation almost balances
with that of protein synthesis.
 In an old individual the rate of protein degradation
exceeds the rate of protein synthesis, i e. the renewal
efficiency is less in an old individual compared
youngsters.
Protein turn over
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Amino acids pool
Amino acids pool
the amount of amino acids available in free form
Sources and Uses of Amino Acids
Sources
1.Proteins in the diet.
2.Turnover of endogenous proteins
3.De novo biosynthesis(non-essential amino acids)
Uses
1.Protein synthesis
2.Energy
2.Nitrogen and carbon source of general and special
product biosynthesis.
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Amino acids pool
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Nitrogen balance or equilibrium:
N balance = Nin - Nout
 The quantitative difference between nitrogen intake into
(i.e., gain) and output from (i.e., loss) the body.
 The balance between protein anabolism and
catabolism.
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Positive Nitrogen Balance
Positive nitrogen balance:
 When intake exceeds the output, it means that the body is
in a state of protein anabolism
It occurs in:
 During growth (growing children).
 During pregnancy.
 During convalescence from states of negative nitrogen
balance, e.g., surgery.
 During administration of anabolic hormones such as
androgens, insulin and growth hormone.
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Positive Nitrogen Balance
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 It means that the output exceeds the intake and
 Indicates excessive breakdown of protein
(catabolism) and tissues and muscles wasting.
 It occurs in:
1.Increased protein catabolism: in chronic diseases
 Diabetes Mellitus.
 Cushing's syndrome.
 Hyperthyroidism.
 Chronic illnesses,
 Wasting diseases such as AIDS, cancer
and tuberculosis.
Negative Nitrogen Balance
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2.Inadequate dietary intake of proteins:
 Starvation and deficiency of one or more of the
essential amino acid.
 Malnutrition, e.g., protein and energy deficiency
syndromes such as kwashiorkor and marasmus.
 Gastrointestinal diseases.
3.Loss of proteins
 Chronic hemorrhage.
 Extensive burns and trauma.
 Albuminuria or proteinuria.
 Lactation with inadequate diet.
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1. Stress
2. Decreased Intake
3. Lack of an essential AA
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Amino Acid & Protein Metabolism
◊ Unlike Carbohydrates, amino acids are not stored by the body, that
is, no protein exists whose sole function is to maintain a supply of
amino acids for future use.
◊ Therefore, amino acids must be obtained from the diet, synthesized
de novo, or produced from normal protein degradation.
◊ Any amino acids in excess of the biosynthetic needs of the cell are
rapidly degraded.
◊ The first phase of catabolism involves the removal of the α-amino
groups (usually by transamination and subsequent oxidative
deamination), forming ammonia and the corresponding α-ketoacid
the “carbon skeletons” of amino acids.
◊ A portion of the Free ammonia is excreted in the urine, but most is
used in the synthesis of urea , which is quantitatively the most
important route for disposing of nitrogen from the body.
40

Amino acid metabolism is the main part
of the overall process of nitrogen
metabolism.
Nitrogen enters the body primarily from
the diet amino acids from dietary
protein.
Nitrogen exits the body as urea,
ammonia, and other products.
The role of body proteins in amino acid
metabolism involves two important
concepts: the amino acid pool and
protein turnover.
The amino acid pool includes amino acids
released by hydrolysis of dietary protein,
those synthesized de novo, and free amino
acids distributed throughout the body.
Protein turnover is a process in which the
rate of protein synthesis is just sufficient to
replace the protein that is degraded.
41

Catabolism of Amino Acids
It involves;
I. Removal of the amino acid nitrogen (α-amino group) by;
A. Transamination or
B. Oxidative deamination.
These two reactions finally produce ammonia and
aspartate that are the sources of urea nitrogen.
II. Metabolism of the carbon skeleton of the amino acid
which includes either;
A. Conversion into glucose, fatty acid or ketone bodies or
B. Oxidation to CO2 and energy.
42

Removal of Nitrogen from amino acids
Complete breakdown of proteins and amino acids give rise to
Urea, CO2, H2O and Energy.
Removing the α-amino group is essential for producing energy
from any amino acid.
The liver is the major site of removal of amino group.
The two key mechanisms in removal of amino group are
transamination and oxidative deamination.
Both reactions yield ammonia and aspartate; these products are
sources of urea nitrogen.
43

Transamination
Involves the transfer of the -
amino moiety of amino acids to -
keto acids.
The products are an -ketoacid
(from the parent amino acid) and
glutamate.
Facilitated by aminotransferases
(found in the cytosol of cells).
 Pyridoxal phosphate (Vitamin
B6) is required as a coenzyme.
All the amino acids participate in
the reaction of transamination
except threonine and lysine. 44

Lysine and threonine do not
participate in transamination;
instead, they lose their α-amino
groups via deamination
The two most important
aminotransferase reactions are
catalyzed by
Alanine aminotransferase
(ALT) and
Aspartate aminotransferase
(AST),
see figure
45

Biological Importance of Transamination
I. Synthesis of new non-essential amino acids.
II. Degradation of most amino acids except lysine and
threonine.
III. Formation of components of citric acid cycle (filling up
reaction of citric acid cycle).
IV. Transaminase enzymes are used in diagnosis and prognosis
of the diseases.
E.g.
In cardiac infarction, SGOT is increased
In hepatic infection, SGPT is increased above the normal levels.
46

Oxidative Deamination
It is catalyzed by amino acid
oxidases.
It includes removal of hydrogen
(oxidation) and removal of NH3
(deamination).
Occur mainly in liver and kidney.
Oxidative deamination by
glutamate dehydrogenase results
in the liberation of the amino
group as free ammonia.
Coenzyme can be either NAD+ or
NADP+.
The products are -ketoacids and
ammonia (Source of Nitrogen in
urea synthesis).
47

Metabolism of Ammonia
Sources of ammonia
1.From amino acids – via the
aminotransferase and glutamate
dehydrogenase reactions.
2.From bacterial action in the intestine –
bacterial urease acts on urea to produce free
ammonia and CO2.
3.From amines – amines obtained from the
diet and monoamines can also lead to
ammonia formation via the action of amine
oxidase.
4.From purines and pyrimidines –
catabolism of these compounds results in the
release of NH3. 48

Transport of Ammonia to the Liver
Two mechanisms are available in
humans for the transport of ammonia
from the peripheral tissues to the liver for
its ultimate conversion to urea.
1.The first, found in most tissues,
uses glutamine synthetase to
combine ammonia with glutamate
to form glutamine a non-toxic
transport form of ammonia.
2.The second transport mechanism,
used primarily by Muscle, involves
transamination of pyruvate (the
end product of aerobic glycolysis)
to form alanine. 49
By Meskelu S.
8/31/2023

NH3
Oxidative Deamination Non Oxidative Deamination Transdeamination
Glutamine Purine and pyrimidine
Urea
New aminoacid
Traces in the blood
up to 100 ug / dl
Sources and Fates of Ammonia
90 %
4 %
1 %
50

Urea Cycle (Krebs-Henseleit cycle)
It is the conversion of ammonia to urea.
Occurred at mitochondria and cytosol of liver cells only.
Urea is the major disposal form of amino groups derived
from amino acids, and accounts for about 90% of the
Nitrogen-containing components of urine.
Five reactions each of them utilizes specific enzyme in
urea cycle.
The first 2 reactions of urea cycle are mitochondrial and
the rest 3 reactions are cytoplasmic.
51

Steps in Urea Cycle
52

The carbon and oxygen of
urea are derived from CO2 via
kreb cycle.
One nitrogen of the urea
molecule is provided by free
NH3, and the other nitrogen by
aspartate.
Both nitrogen atoms of urea
come from glutamate, which,
in turn, obtains nitrogen from
other amino acids (see figure).
Sources of the Atoms of Urea
53

Overall reaction of the urea cycle
Aspartate + NH3 + CO2 + 3ATP  Urea + Fumarate +
2ADP + AMP + 2Pi + PPi + 3H2O
Urea, once synthesized in the liver, diffuses from its site
and is transported in the blood to the kidneys.
In the kidneys, urea is filtered and excreted in the urine.
In patients with kidney failure, plasma urea levels are
high, which induces a greater transfer of urea from blood
into the intestine – hyperammonemia.
Some of the urea diffuses from the blood into the intestine,
and is degraded to CO2 and NH3 by bacterial urease.
54

Regulation of the Urea Cycle
N-Acetyl Glutamate is a key activator
for Carbamoyl Phosphate Synthetase I
(the rate-limiting enzyme in the urea
cycle).
N-acetyl Glutamate is derived from
Acetyl CoA and glutamate (see figure).
Arginine is the activator of N-
acetylglutamate reaction, thus increases
urea formation.
Excess ammonia stimulates urea
formation.
High urea level inhibits
carbamoylphosphate synthase (reaction
1) Ornithine transcarbamoylase (reaction
2) and arginase enzymes (reaction 5). 55

Hyperammonemia
The capacity of the hepatic urea cycle exceeds the normal rates of
ammonia generation, and the levels of serum ammonia are normally
low (5–35 μmol/L).
However, when liver function is compromised, due either to genetic
defects of the urea cycle or liver disease, blood levels can rise above
1,000 μmol/L.
Such Hyperammonemia is a medical emergency, because ammonia
has a direct neurotoxic effect on the CNS.
For example, elevated concentrations of ammonia in the blood cause
the symptoms of ammonia intoxication, which include tremors,
slurring of speech, somnolence, vomiting, cerebral edema, and
blurring of vision.
56

Hyperammonemia
At high concentrations, ammonia can cause coma and
death.
Liver disease is a common cause of hyperammonemia in
adults, and may be due, for example, to viral hepatitis or to
hepatotoxins such as alcohol.
Cirrhosis of the liver may result in formation of collateral
circulation around the liver.
As a result, portal blood is shunted directly into the
systemic circulation and does not have access to the liver.
The conversion of ammonia to urea is, therefore, severely
impaired, leading to elevated levels of ammonia.
57

Kidney Disease and BUN (Blood Urea Nitrogen)
Urea is waste product of protein metabolism, it synthesized in liver
via urea cycle from ammonia which is produced from amino acids
by deamination.
Then it transported by blood to kidney to be excreted in urine.
BUN= 50% urea
High blood urea can indicates:
Renal insufficiency due to obstruction or cancer.
Blockage of the urinary tract (by a kidney stone or tumor).
Low blood flow to the kidneys caused by dehydration or heart
failure.
Some medicines.
High-protein diet.
58

Low blood urea may be due to:
Very low protein diet as in malnutrition.
Severe liver damage inhibits urea cycle, decrease urea
formation and increase free ammonia leads to hepatic comma.
59

Blood Urea Nitrogen
Normal range: 7-18 mg/Dl.
Elevated in increased amino acid catabolism.
Increased Glutamate leads to increased N-acetylglutamate.
which leads to increased CPS-1 activation.
Elevated in renal insufficiency Decreased in hepatic failure
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 the brain.
 If not treated immediately after birth, severe mental retardation
results.
60

Ammonia Intoxication (Ammoniacal encephalopathy)
It is defined as toxicity of the brain due to increase in NH3 level.
This increased ammonia will be fixed to α- ketoglutaric acid to
form glutamic acid then glutamine leading to interference with
citric acid cycle so decrease ATP production in the brain cells.
Causes:
I. Congenital:
The 5 types of hyperammonaemia due to enzymes deficiencies in
urea cycle.
II. Acquired:
Liver disease as cirrhosis due to failure of urea formation and
glutamine synthesis.
Gastrointestinal bleeding by action of bacterial flora on the
blood urea and thus NH3 is released in large amounts.
61

Manifestations of ammonia intoxication
Tremors
Blurred vision
Slurred speech
Vomiting
Confusion followed by coma and death.
Treatment:
1.Injection of Glutamic acid and -ketoglutaric acid
2.Restrict protein diet.
3.Sodium benzoate and phenylacetate are given to conjugate
with glycine and glutamine and rapidly the conjugates are
excreted in urine.
4.Frequent small meals to avoid sudden increase in blood
ammonia levels.
5.Removal of excess NH3 by dialysis in acute cases.
62

Links between Urea cycle and Citric acid cycle
63

Links between Urea cycle and Citric acid cycle
The interconnected cycles have been called the “Krebs.
bicycle” and also called aspartate-argininosuccinate shunt;
These effectively link the fates of the amino groups and the
carbon skeletons of amino acids.
Some citric acid cycle enzymes, such as fumarase and malate
dehydrogenase, have both cytosolic and mitochondrial
isozymes.
Fumarate, produced in the cytosol by the urea cycle, can be
converted to cytosolic malate, which is used in the cytosol or
transported into mitochondria (via the malate-aspartate
shuttle) to enter the citric acid cycle.
64

Fates of carbon skeletons of Amino Acid
 After removing of amino group, the carbon skeletons of amino
acids are transformed into metabolic intermediates that can be
converted into Glucose, Fatty acids, Ketone bodies or oxidized
by the citric acid cycle.
 The carbon skeletons of 20 fundamental amino acids are
funneled into seven molecules:
 pyruvate,
acetyl CoA,
acetoacetyl CoA,
-ketoglutarate,
succinyl CoA,
fumarate,
oxaloacetate.
65

Fates Carbon skeleton Amino Acid Catabolism
66

Glucogenic and ketogenic amino acids
A. Glucogenic amino acids
Degraded into pyruvate or one of
the intermediates of the TCA cycle
Precursors for gluconeogenesis
14 amino acids
B. Ketogenic amino acids
 Degraded into acetyl CoA or
acetoacetyl CoA
Can contribute to synthesis of
fatty acids or ketone bodies
Not substrates for
gluconeogenesis
Two amino acids
Some amino acids are both
glucogenic and ketogenic (four
amino acids)
67

Amino acids that form oxaloacetate
Includes asparagine and
aspartic acid
Asparagine is hydrolyzed by
asparaginase to give ammonia
and aspartate (see figure)
Aspartate loses its amino
moiety via transamination to
give oxaloacetate.
68

Amino acids that form -ketoglutarate
Includes Glutamine,Proline, Arginine, Histidine.
Glutamine converted to glutamate and ammonia via the
enzyme glutaminase.
Glutamate converted to -ketoglutarate by transamination, or
through oxidative deamination by glutamate dehydrogenase.
Proline oxidized to Glutamate, which in turn is converted to -
ketoglutarate.
Arginine cleaved by arginase to form ornithine, which is
subsequently converted to -ketoglutarate.
Histidine is oxidatively deaminated by histidase to urocanic
acid and then to glutamate and -ketoglutarate.
69

Amino acids that form pyruvate
Alanine gives pyruvate upon loss of the
amino group via transamination (see
figure)
Serine can be converted to glycine and
N5,N10-methylenetetrahydrofolate.
Serine can also be changed into pyruvate
via serine dehydratase.
Glycine can either be converted to serine
or oxidized to CO2 and NH4
+.
Cystine reduced to cysteine, using NADH
as the reducing agent; cysteine then loses
sulfur groups to give pyruvate.
Threonine converted to pyruvate or to -
ketobutyrate, which forms succinyl CoA.
70

Amino acids that form Fumarate
Phenylalanine and tyrosine:
Hydroxylation of phenylalanine
gives rise to tyrosine by
phenylalanine hydroxylase.
The metabolism of phenylalanine and
tyrosine merge, ultimately forming
fumarate and acetoacetate.
Phenylalanine and tyrosine are both
Glucogenic and ketogenic.
Genetic deficiencies in enzymes of
phenylalanine and tyrosine
metabolism lead to albinism.
71

Amino acids that form succinyl CoA
Include Methionine, Valine, isoleucine and threonine.
Breakdown of methionine,Valine, isoleucine and threonine
produce succinyl CoA.
Methionine is one of four amino acids that form succinyl CoA.
It is converted to S-adenosylmethionine (SAM), the major
methyl-group donor in one-carbon metabolism.
Methionine also the source of homocysteine (which is
associated with atherosclerotic vascular disease).
72

AminoacidsthatformacetylCoAoracetoacetylCoA
Leucine, isoleucine, lysine, and tryptophan form acetyl
CoA or acetoacetyl CoA directly.
Phenylalanine and tyrosine also produce acetoacetate
Therefore, there are a total of six ketogenic amino acids
74

Catabolism of the branched-chain amino acids
These amino acids are isoleucine, leucine, and valine
These amino acids are metabolized mainly by the peripheral
tissues (e.g. muscle).
They undergo transamination, followed by oxidative
decarboxylation, and dehydrogenation.
Isoleucine leads to acetyl CoA and succinyl CoA (both
ketogenic and glucogenic).
Valine yields succinyl CoA (Glucogenic)
Leucine is metabolized to acetoacetate and acetyl CoA
(ketogenic).
75

Biosynthesis of Non-essential amino acids
Non-essential amino acids are
synthesized from intermediates of
metabolic processes (except for
tyrosine and cysteine, which are
produced from essential amino acids)
Alanine, aspartate and glutamate
are produced via transfer of an amino
group to the -ketoacids- pyruvate,
oxaloacetate, and -ketoglutarate,
respectively (see figure).
These transamination reactions are
the most direct of the biosynthetic
pathways.
76

Glutamine and asparagine are synthesized via amidation.
In the case of glutamine, glutamate and ammonia are
combined through an amide linkage in the presence of
glutamine synthetase; this reaction is ATP driven.
This reaction also helps to detoxify ammonia in brain and
liver.
In the case of asparagine, aspartate and ammonia are
combined by an amide linkage via asparagine synthetase;
reaction also requires ATP.
Proline is produced upon cyclization and reduction of
glutamate.
77

Serine stems from 3-phosphoglycerate (intermediate of
glycolysis); also produced from glycine through transfer of a
hydroxymethyl group
Glycine is obtained from serine through removal of a
hydroxymethyl group via serine hydroxymethyl transferase.
Cysteine is synthesized from serine and homocysteine
(homocysteine derived from methionine).
Tyrosine comes from phenylalanine by phenylalanine
hydroxylase.
78

Biosynthesis of Nitrogen-Containing Compounds
Amino acids are also precursors of
various Nitrogen-based
compounds that have important
physiological roles.
These compounds include
porphyrines, hormones,
neurotransmitters, purines, and
pyrimidines
Glycine – Poryphrines, Purine
Tyrosine  Dopamine, EPI,
Norepinephrine, melanin
Glutamate  GABA
Histidine  Histamine
Tryptophan  Serotonin
Arginine – Nitric oxide 79

-Aminobutyric Acid (GABA)
Glutamate  GABA + CO2 by glutamate
decarboxylase.
GABA is the major inhibitory neuro-
transmitter in brain.
• Glutamate is the major excitatory neuro-
transmitter
Stimulation of neurons by GABA
•   permeability to chloride ions
• benzodiazepines (valium) enhance
membrane permeability of Cl ions by
GABA
• GABAPENTIN protects against
glutamate excitotoxicity.
Directly regulates muscle tone.
Involved in mechanism of memory.
Its lack leads to convulsions, epilepsia. 80

Catecholamines
These include dopamine, norepinephrine, and epinephrine
Dopamine and norepinephrine are neurotransmitters in the brain
and autonomic nervous system
Norepinephrine and epinephrine are synthesized in the adrenal
medulla, and also act as regulators of carbohydrate and lipid
metabolism
81

Histamine
Histamine is a chemical
messenger that facilitates various
cellular responses such as
Allergic and inflammatory
reactions,
Gastric acid secretion, and
Possibly neurotransmission in
sections of the brain
Histamine produced by
decarboxylation of histidine
that requires pyridoxal
phosphate (see figure)
Biosynthesis of histamine
82

Serotonin
Also called 5-hydroxytryptamine
Derived from tryptophan
Located at intestinal mucosa,
platelets and CNS
Derived from tryptophan via
hydroxylation and decarboxylation
reactions
Serotonin is physiologically involved
in pain perception, affective
disorders, and in regulation of sleep,
temperature, and blood pressure.
Synthesis of serotonin
83

Melanin
Pigment present in several tissues, but concentrated in the
eye, hair, and skin.
Produced in the epidermis by melanocytes (pigment-forming
cells).
Derived from tyrosine, and forms a Dopa intermediate prior
to its formation.
Protect underlying cells from harmful radiation from the sun.
A defect in melanin production results in albinism, the most
common form being due to defects in copper-containing
tyrosinase.
84

Glutathione & Its Functions
It is a tripeptide consist of three amino acid residues and two
peptide bonds.
It consist of glutamate,Cysteine and glycine.
In glutathione, γ-carboxyl group of glutamate is involved in
peptide linkage with cysteine hence it is named as γ-glutamyl
cysteinyl glycine (Glu-Cys-Gly, G-SH).
85

Functions of Glutathione
1.It act as reducing agent in all cells.
 It assumes dimeric form on oxidation .
 It is responsible for the maintenance of –SH groups of
proteins in reduced form.
2. It participates in the removal of H2O2 in erythrocytes.
3. It is required for removal of toxins from body.
4. It is involved in release of hormones.
5. It protects body proteins from radiation effects.
6. It is involved in cellular resistance to anticancer agents.
7. Glutathione regulates telomerase activity and of the cell cycle.
8. Glutathione is involved in modulation of apoptosis.
86

Creatine
Derived from glycine and arginine
Creatine helps to supply energy to
muscle.
Creatine is reversibly
phosphorylated to creatine
phosphate by creatine kinase
Creatine and creatine phosphate
slowly and spontaneously cyclize to
creatinine, which is excreted in the
urine.
The level of creatinine excretion
(clearance rate) is a measure of renal
function.
The amount of creatinine produced
is related to muscle mass. 87

Creatine and creatinine
Creatine:
Is synthesized primarily in the liver from arginine, glycine, and
methionine and then transported to other tissues, such as muscle, where it
is converted to creatine phosphate, which serves as a high-energy
source.
Creatine and creatinine are not the same substance!
Creatine is an amino acid that does not found in protein and found in the
muscles.
Creatine and creatine phosphate exist in a reversible equilibrium in
skeletal muscle.
In skeletal muscle, approximately one-fourth of creatine exists as free
creatine and three-fourth exists as creatine phosphate.
Creatine is synthesized primarily by the liver, kidneys, and pancreas at a
rate of 1 to 2 g/day.
An additional1 to 2 g/day is obtained in the diet, mainly from fish and
meats.
88

The Reversible Equilibrium between Creatine and Phosphcreatine
90

Creatinine:
Creatinine is a break-down product (a waste product) of creatine
phosphate and creatine in muscles, and is usually produced at a fairly
constant rate by the body (depending on muscle mass).
Creatine phosphate loses phosphoric acid and creatine loses water to
form the cyclic compound, creatinine, which diffuses into the
plasma and is excreted in the urine.
Creatinine is a nitrogenous organic acid.
The creatinine is a waste product of creatine phosphate and it will be
excreted by the kidney in the urine at a rate of 1 to 2 g/day.
91

Approximately 2% of the body’s creatine is converted to
creatinine every day
Creatinine is transported through the bloodstream to the
kidneys
The kidneys filter out most of the creatinine and excrete it
in the urine
Clinical Application
Measurement of creatinine concentration is used to determine
sufficiency of kidney function and the severity of kidney damage
and to monitor the progression of kidney disease.
Plasma creatinine concentration is a function of relative muscle mass,
the rate of creatine turnover, and renal function.
92

If the kidneys are damaged or impaired and
cannot work normally
The amount of creatinine in urine goes down
while its level in blood goes up.
Creatinine has been found to be a fairly reliable
indicator of kidney function
Serum creatinine level is an important diagnostic
tool to asses renal function.
In muscle disease such as muscular dystrophy, poliomyelitis,
hyperthyroidism, and trauma, both plasma creatine and urinary
creatinine are often elevated. 93

Metabolic defects in amino acids metabolism
Inborn errors of metabolism of amino acids
Commonly caused by mutant genes of abnormal proteins
(enzymes).
Expressed by the loss of enzyme activity or partial
deficiency in catalytic activity.
Result in mental retardation or developmental
abnormalities as a result of harmful accumulation of
metabolites.
Constitute a very significant portion of pediatric genetic
diseases.
Phenylketonuria is the most important disease of amino
acid metabolism.
94

A. Phenylketonuria (PKU)
Most common (prevalence
1:15,000).
Caused by a deficiency of
phenylalanine hydroxylase.
Characterized by accumulation of
phenylalanine (and a deficiency of
tyrosine).
Mental retardation, hyperactivity,
seizures, tremor,
hyperpigmentation
Treatable by dietary means
95

B. Maple syrup urine disease (MSUD)
Rare (1:185,000) autosomal recessive
disorder.
Caused by a partial or complete
deficiency in branched-chain α-keto
acid dehydrogenase (leucine, isoleucine,
and valine).
These amino acids and their
corresponding α-keto acids accumulate in
the blood, causing a toxic effect that
interferes with brain functions.
The disease is characterized by feeding
problems, vomiting, dehydration, severe
metabolic acidosis, and a characteristic
maple syrup odor to the urine.
If untreated, the disease leads to mental
retardation, physical disabilities, and even
death. 96

C. Albinism
Characterized by deficiency in the
production of melanin from
tyrosine.
Caused by deficiency of tyrosinase
enzyme
These defects result in the partial or
full absence of pigment from the
skin, hair, and eyes.
In addition to hypopigmentation,
affected individuals have vision
defects and photophobia(sunlight
hurts their eyes).
They are at increased risk for skin
cancer.
Patient with albinism,
showing white eyebrows
and lashes.
97

D. Homocystinuria
a defects in the metabolism of
homocysteine.
Characterized by high levels of
homocysteine and methionine and low
levels of cysteine.
Caused by cystathionine β-synthase
enzyme defect, which converts
homocysteine to cystathionine.
skeletal abnormalities, premature arterial
disease, osteoporosis and mental
retardation.
Treatment includes restriction of
methionine intake and supplementation
with vitamins B6, B12, and folate.
98

E. Alkaptonuria
Inherited disorder of the tyrosine
metabolism caused by the absence
of homogentisate oxidase.
homogentisic acid is accumulated
and excreted in the urine and turns
a black color upon exposure to air
Unique symptoms: Large joint
arthritis and black ochronotic
pigmentation of cartilage and
collagenous tissue.
Dark staining of the diapers
sometimes can indicate the disease
in infants,
Accumulation of oxidized homogentisic acid
pigment in connective tissue (ochronosis)
Urine turns a black color upon
exposure to air
99

THANK YOU!
8/31/2023 101
By Meskelu S.

Amino acid metabolism.pptx

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