Amino Acid Metabolism
Protein metabolism
xiaoli
Reviews:
synthesis
metabolism
NH3
H
catabolism
C COO
R
Major content
 Digestion and absorption of protein
 Normal metabolism of amino acids
 Special products of amino acids
Nutritional Function of Protein
Proteins play a major role in ensuring your health well being.
There are innumerable functions of proteins in the body.
building and repairing of body tissues.
protein makes up nearly 17 percent of the total body weight. For
example: muscle contains about 1/3 protein, bone about 1/5 part and skin
consists of 1/10 portion. The rest part of proteins is in the other body
tissues and fluids.
Take part in some kinds of important physiological
activities
regulation of body processes and formation of enzymes and
hormones, antibody. There are distinctive kinds of proteins, each
performing a unique function in the body.
Oxidation and supply energy
How to assess the condition of protein
metabolism?
1. Nitrogen balance
the balance between the amount of nitrogen
taken in (foods or the body) and the amount given
off (lost or excreted)
Significance:
Measuring the amount of intake and losses of total
nitrogen can help us to know the general situation of
protein metabolism.
nitrogen balance
★ positive:
synthesis > degradation
(e.g., growth, body building)
★ negative:
synthesis < degradation
(e.g., starvation, trauma, cancer cachexia)
★ Equilibrium:
synthesis = degradation
(healthy adults eating a balanced diet)
2. Physical requirements of proteins
Lowest requirement:
30~50g/day
 Recommend requirement:
80g/day (65kg man)

Amino acids are not
stored by the body,
must be obtained from
the diet, synthesized
de novo.
Some sources of dietary protein include:
Meat, poultry and fish
Eggs, Dairy products
Seeds and nuts
Beans and lentils
Soy products
Grains, especially wheat and rice,
barley and corn.
3. Nutrition value of proteins
(1) Essential amino acids :
some Amino acids that cannot be
synthesized by the body and must be obtained
from the diet.
Eight amino acids are generally regarded as
essential for humans:
phenylalanine, valine, threonine, tryptophan,
isoleucine, methionine, leucine, and lysine
(2) Non- essential amino acids
other 12 kinds of AAs, the non-essential or
dispensable amino acids can be synthesized in
the body either other roadways.
Note:
a Arg is synthesized in the urea cycle, but the rate is too slow
to meet the needs of growth in children
b Met is required to produce cysteine if the latter is not
supplied adequately by the diet.
c Phe is needed in larger amounts to form tyr if the latter is
not supplied by the diet.
His and Arg are essential AAs for infants and children.
(4) nutrition value
A protein’s nutritional value is judged by how
many of the essential amino acids it provides and
in what quantity.
Different foods contain different numbers and
amounts of the essential amino acids.
lysine
tryptophan
(5) Complementary effect of dietary proteins

Two or more plant proteins are consumed
together which complement each other in
essential amino acid content.
Digestion Absorption
Putrefaction of protein
2.1 Digestion
hydrolysis
Amino
acids
absorb
Dietary protein
Significance:
◆ Large
small
Help to absorb
◆ eliminate the species specificity and
antigenicity, avoid allergy , toxic reaction.
site:
stomach,
small intestine
Pepsin
Chymotrypsin,
trypsin,
and exopeptidases
Proteolytic enzymes
of pancreatic juice
Amino acids
Initiated in stomach
 enzymes: pepsin
HCl
Pepsinogen
Pepsin
HCl from parietal cells
 Stomach pH 1.6 to 3.2
 Pepsinogen from chief cells
 The substrate mainly are
phenylalanine,tyrosine,tryptophan
Aromatic amino acids
 Products:
insoluble protein, soluble protein,
polypeptides and amino acids
Protein Digestion – Small Intestine
Pancreatic
Zymogens
enzymes secreted
Trypsinogen
Chymotrypsinogen
procarboxypeptidase
Proelastase
trypsin
Chymotrypsin
Carboxypeptidase
elastase
Zymogens
A zymogen is the inactive precursor of an enzyme.
Activation of zymogen
A inactive zymogen become active enzyme.
In a zymogen, a peptide blocks the active site of the
enzyme. Cleaving off this peptide activates the enzyme.
Significance:
1. avoids self-digestion:
This is necessary to prevent the digestive enzymes
from autodigesting the cells that produce them.
2. stored and transported safely :
The body typically secretes zymogens rather than
active enzymes because they can be stored and
transported safely without harm to surrounding
tissues, and released when conditions are favorable
for optimal activity.
In a zymogen, a peptide blocks the active
site of the enzyme. Cleaving off this peptide
activates the enzyme.
The molecule is composed
of amino acids strung together
into a peptide. When the
zymogen is in the presence of
protease, some of the amino
acids are removed.
This cleavage renders the
zymogen a functional enzyme
by changing the shape of the
peptide and forming the active
site where enzymatic action
will occur.
protease
active site
enterokinase
trypsinogen
trypsin
chymotrypsinogen
proelastase
procarboxypeptidase
chymotrypsin
elastase
carboxypeptidase
cascade reaction
Amplification effect
Protein Digestion – Small Intestine
Proteolytic enzymes of pancreatic juice
trypsin: Arg, Lys (C)
endopeptidases
chymotrypsin: Tyr, Trp,
Phe, Met, Leu (C)
elastase: Ala, Gly, Ser (C)
exopeptidases
carboxypeptidase
aminopeptidase
amino peptidase endopeptidase
carboxy peptidase
O
O
H2N-CH-C-NH-CH--- NH-CH-C-NH-C--- NH-CH-C-NH-CH-COOH
Rn
R1
Rn-1
R
R2
O
polypeptide
dipeptidase
O
amino acid + H2N-CH-C-NH-CH-COOH
R
R
amino acid
dipeptide
Protein Digestion

Proteins are broken down to
 Tripeptides
 Dipeptides
 Free
amino acids
2.2 absorption
Free
amino acids Absorption
★ Carrier
systems
cycle/ γ-glutamyl cycle
transport amino acids
★ Meister
Free Amino Acid Absorption

Lumen
(small intestine)
Carrier systems
Neutral AA
 Basic AA
 Acidic AA
 Amino acids

Amino
acids
Amino
acids
Na+
Na+ pump
Na+
Entrance of some AA is
via active transport
Requires energy
carrier
protein
ATP
Brush broad membrance
Amino
acids
Na+
Meister cycle/ γ-glutamyl cycle
transport amino acids
γ-glutamyl cycle include two steps：
• GSH(glutathione) transport amino acids
• GSH synthesis
extracellular
COOH
Cell
membrance
intracellular
γ-glutamyl amino acid
COOH
CH2
COOH
CH2
C
COOH
Cys-Gly
R
AA
NH
O
H2NCH
CH
γglutamyl
cyclotra
nsferase
H2NCH
R
R
peptase
γ-glutamyl
transferase
5-pidolic
acid
ATP
5-oxoproline
glycine
cysteine
GSH
ADP+Pi
ATP
AA
CHNH2
ADP+Pi
glutamic
γ-glutamylcysteine
synthetase(γ-GCS)
glutathione
synthetase
γ-glutamylcysteine
γ-glutamyl cycle / Meister cycle
ATP
ADP+Pi
目录
Peptide Absorption

Form in which the majority of
protein is absorbed

More rapid than absorption of
free amino acids

Active transport
 Energy
required

Metabolized into free amino
acids in enterocyte

Only free amino acids
absorbed into blood
§2.3 Putrefaction of proteins
Putrefaction of proteins:
Some undigested proteins and no absorbed
products are anaerobic decomposed by the
bacteria in intestine.
The products are toxic to body except
few vitamin and fatty acid.
1. Production of amines
CO2
R CH COOH
R CH2 NH2
bacteria
NH2
amino acid
amine
histidine
histamine
tryptophan
tryptamine
tyrosine
phenylalanine
tyromin
e
β-hydroxytyramine
liver
CO2+H2O
phenolethanolamine
phenylethylamine
liver
CO2+H2O
CH2NH2
CH2NH2
H
CH2
C
OH
CH2NH2
CH2NH2
H
CH2
C
OH
hydroxylase
hydroxylase
phenylethylamine
phenolethanolamine
noradrenalin
OH
tyramine
OH
β-hydroxytyramine
dopamine
•false neurotransmitter
is a chemical compound which closely imitates the
action of a neurotransmitter in the nervous system,but
that has no or little effect on postsynaptic receptors.
CH2NH2
H
noradrenalin
C
OH
phenolethanolamine
CH2NH2
H
dopamine
C
OH
OH
β-hydroxytyramine
2. Production of ammonia (NH3)

Two sources:
(1) Metabolism on unabsorbed amino acids
(2) Urea hydrolyzed by urease
3. Some other toxic materials
→ phenol
 Trp → indole
 Cys → hydrogen sulfide (H2S)
 Tyr
General Metabolism of
Amino Acid
§ 3.1 Protein turnover
the balance between protein synthesis and protein
degradation .
In healthy adults, the total amount of protein in the
body remains constant, because the rate of protein
synthesis is just sufficient to replace the protein that is
degraded. this process is called protein turnover.
Rapid protein turnover ensures that some regulatory
proteins are degraded so that the cell can respond to
constantly changing conditions.
half-life
Half-life is the period of time it takes
for a substance undergoing decay
to decrease by half.
Examples of protein turnover in the body
§ 3.2 Degradation of protein
in cells
1. Lysosomal pathway

Extracellular proteins, membraneassociated proteins and long-lived proteins

ATP-independent process

Enzyme: Cathepsins
2. Cytosol pathway

Abnormal proteins, damaged proteins
and short-lived proteins
ATP
ubiquitin
enzyme
ubiquitination
ubiquitin-proteins
Proteasome
7~9 residues peptides
ubiquitin
ubiquitious
Ubiquitin (Ub) is a small protein that is composed of 76
amino acids; exists in all eukaryotic cells, only in
eukaryotic organisms.
Among eukaryotes, ubiquitin is highly conserved, meaning
that the amino acid sequence does not differ much when
very different organisms are compared. For example, there
are only 3 differences in the sequence when Ub from yeast
is compared to human Ub.
Ubiquitin performs its myriad functions through
conjugation to a large range of target proteins.
ubiquitination
ATP
AMP+Pi
ubiquitin + E1
ubiquit -E1
Activate ubiquitin
1. E1 enzymes known as Ub-activating enzymes. These
enzymes modify Ub so that it is in a reactive state (making it
likely that the C-terminal glycine on Ub will react with the lysine
side-chains on the substrate protein).
E2
ubiquitin -E1
E1
ubiquitin -E2
Ub-conjugating
enzymes
2. E2 enzymes known as Ub-conjugating enzymes. These
enzymes actually catalyze the attachment of Ub to the
substrate protein
pro
ubiquitin -E2
E3
E2
Ub-ligases
Ubiquitin-pro
3. E3 enzymes known as Ub-ligases. E3's usually
function in concert with E2 enzymes, but they are thought
to play a role in recognizing the subtrate protein.
proteasome
Ubiquitin-pro
Degratation(7~9 residues
peptides)
The general reaction pathway is shown in the figure below. First, Ub
is activated by E1 in an ATP-dependent fashion.
E2 and E3 then work together to recognize the substrate protein and
conjugate Ub to it. Ub can be attached as a monomer or as a
previously synthesized chain (as shown).
From this point, the ubiquinated protein is shuttled to the proteasome
for degradation
Degradation of protein in cells
Amino acid pool:
amino acids in intracellular and
extracellular fluids.
muscle
liver
kidney
Amino acids%
50%
10%
4%
blood
1~6%
§ 3.1 The sources and fates of AAs
Sources of amino acids
Fates of amino acids
NH3
Dietary
proteins
Ketone bodies
Tissue degradation
Amino acid
proteins synthesis metabolic pool
Amino acids
synthesized
Urea
α-Keto acid
Oxidation
Glucose
conversion
Non- protein nitrogen
compounds
CO2
Amine
Synthesis of proteins
§ 3.3 The catabolism of AAs
1. Deamination of AAs
Four types:
transamination
oxidative deamination
non-oxidative deamination
union deamination
(1) Transamination
aminotransferase
Transamination is the process by which an
amino group, usually from glutamate, is
transferred to an α-keto acid, with formation of
the corresponding amino acid plus αketoglutarate.
Key points:
① reversible:Transaminases (aminotransferases)
catalyze the reversible reaction at right.
② Lys and Pro cannot be transaminated.
③ Aminotransferases utilize a coenzyme
- pyridoxal phosphate - which is derived
from vitamin B6.
H
O
O
P
O
O
C
H2
C
OH
O

N
H
CH3
pyridoxal phosphate (PLP)
The prosthetic group of Transaminase is
pyridoxal phosphate (PLP), a derivative
of vitamin B6.
Amino acid
α-keto
acid
pyridoxal
phosphate
pyridoxamine
phosphate
Schiff base
Isomer of Schiff base
O
EnzLysNH2
What was an
amino acid
leaves as an
a-keto acid.
CH2
O
O
H2
C
P
O
NH2
R
C
COO
a-keto acid
OH
O

N
CH3
H
Pyridoxamine phosphate (PMP)
The amino group remains on what is now
pyridoxamine phosphate (PMP).
A different a-keto acid reacts with PMP and the
process reverses, to complete the reaction.
Transaminases equilibrate amino groups
among available a-keto acids.
This permits synthesis of non-essential amino
acids, using amino groups from other amino
acids & carbon skeletons synthesized in a cell.
Thus a balance of different amino acids is
maintained, as proteins of varied amino acid
contents are synthesized.
Although the amino N of one amino acid can be
used to synthesize another amino acid, N must
be obtained in the diet as amino acids
(proteins).
In addition to equilibrating amino groups among
available a-keto acids, transaminases funnel
amino groups from excess dietary amino acids to
those amino acids (e.g., glutamate) that can be
deaminated.
Carbon skeletons of deaminated amino acids can
be catabolized for energy, or used to synthesize
glucose or fatty acids for energy storage.
Only a few amino acids are deaminated directly.
Two important transaminases:
1. GPT (serum glutamate pyruvate transaminase)
/ Alanine transaminase (ALT)
GPT(ALT)
2. GOT
(serum
glutamate oxaloacetate transaminase)
/ Aspartate aminotransferase (AST)
GOT(AST)
organ
GOT
GPT
organ
GOT
GPT
heart
156000
7100
pancrease 28000
2000
liver
142000
44000
spleen
14000
1200
skeletal 99000
4800
lung
10000
700
kidney
19000
20
16
91000
serum
ALT is
an enzyme produced in hepatocytes and is highly
concentrated in the liver.
Therefore, when the liver is injured, ALT is
released into the bloodstream.
！！
Elevated levels of ALT may indicate :
 alcoholic liver disease
 cancer of the liver
 cholestasis or congestion of the bile ducts
 cirrhosis or scarring of the liver with loss of function
 death of liver tissue
 Hepatitis or inflammation of the liver
 noncancerous tumor of the liver
 use of medicines or drugs toxic to the liver

AST also reflects damage to the hepatic cells and
is less specific for liver disease. It can also be released
with heart, muscle and brain disorders.
 Therefore,
this test may be ordered to help diagnose
various heart, muscle or brain disorders, such as a
myocardial infarct (heart attack).
Two important transaminases:
ALT: Alanine aminotransferase (in liver)
AST: Aspartate aminotransferase (in heart)
pyruvate
glutamate
ALT
alanine
oxaloacetate
AST
a -ketoglutarate
aspartate
No net removal of N from the amino acid pool.
(2) Oxidative deamination
COOH
CHNH2
(CH2)2
NAD+
NADH+H+ COOH
C NH
(CH2)2
L-Glu
COOH Dehydrogenase COOH
L-Glu
H2O
NH3
COOH
C O
(CH2)2
COOH
¦Á-ketoglutarate
1. Glutamate Dehydrogenase catalyzes a major
reaction that effects net removal of N from the
amino acid pool.
2. It is one of the few enzymes that can use NAD+ or
NADP+ as e- acceptor.
Oxidation at the α-carbon is followed by hydrolysis,
releasing NH4+.
+
H2O NH4
H2O
HO
CH2
H
C
COO
NH3+
serine
H2C
C
COO
O
H3C
C
COO
NH3+
aminoacrylate
pyruvate
Serine Dehydratase
Some other pathways for deamination of amino acids:
1. Serine Dehydratase catalyzes:
serine  pyruvate + NH4+
2. Peroxisomal L- and D-amino acid oxidases catalyze:
amino acid + FAD + H2O 
a-keto acid + NH4+ + FADH2
FADH2 + O2  FAD + H2O2
Catalase catalyzes: 2 H2O2  2 H2O + O2
(3) Union deamination
COOH
R-CH-COOH
NH2
¦Á-amino acid
transaminase
CH2
2
NADH + H+ + NH3
C O
COOH
¦Á-ketoglutarate
L-glutamate dehydrogenase
COOH
R-C-COOH
O
¦Á-keto acid
CH2
2
NAD+ + H2O
CHNH2
COOH
Glu
The α- amino group of most amino acids is transferred to αketoglutarate to form an α- keto acid and glutamate by
transaminase. Glutamate is then oxidatively deaminated to yield
ammonia and α- ketoglutarate by glutamate dehydrogenase.
Alanine + α-ketoglutarate
Glutamate + NAD+ + H2O
Net Reaction:
Alanine + NAD+ + H2O
Pyruvate + glutamate
α-ketoglutarate + NADH
+ NH4+
pyruvate + NADH + NH4+
(4) Purine nucleotide cycle (in muscle)
amino
acid
transaminase
¦Á- keto
acid
O
adenylosuccinate
COOH
N
synthetase
HN
HOOCCH2CHCOOH
(CH2)2
NH3
N
N
NH2
CO
R-5'-P
Asp
HOOCCH2CHCOOH
COOH
IMP
AMP
H2O
NH
¦Á- ketoAST
deaminase
glutarate
N
N
CH2COOH
NH2
COOH
N
N
COCOOH
N
(CH2)2
N
R-5'-P
oxaloacetate
adenylosuccinate
CHNH2
N
N
COOH
'
R-5
-P
CHCOOH
L-Glu
CH2COOH
adenyloAMP
succinase
CHCOOH
CHOHCOOH
fumarate
malate
liver
NH3
H
C
NH3
urine
COO
R
Ketone bodies
Amino acid
oxidation
glucose
Section 4
Metabolism of Ammonia
§ 4.1 Source and outlet of ammonia
(NH3)
1. Sources:
⑴ Endogenous sources:
① Deamination of AAs--main source
② Catabolism of other nitrogen containing
compounds.
RCH2NH2
amine oxidase
RCOH + NH3
③ Kidney secretion (Gln)
COOH
CONH2
(CH2)2
Glutaminase
(CH2)2
CHNH2 + H2O
CHNH2 + NH3
COOH
COOH
Gln
Glu
⑵ Exogenous sources：
① Putrefaction in the intestine.
② Degradation of urea present in fluids
secreted into the GI tract
NH3 is easy to dispersion, NH4+ is not .
pH<7 H+ + NH3
NH4+
urea
expel
Liver desfunction
Reduce the
absorption of
ammonia:
acidifying diuretic
weakly acidic dialysate in colonic
dialysis
alkaline dialysate ,alkaline medician
soapsuds enema
2. Outlets:
(1) Formation of urea
(2) Formation of Gln
(3) Excrete in urine ( NH4+ )
(4) Synthesis of AA
§ 4. 2 Transportation of NH3
1. Alanine-glucose cycle
2. Transportation of ammonia by Gln
1. Alanine-glucose cycle
protein
muscle
liver
blood
amino acid
NH3
Glu
G
G
pyruvate
pyruvate
¦Á-keto
Ala
glutarate
G
Ala
Ala
Glu
NAD+ + H2O
¦Á-keto
+
NADH
+
H
glutarate
+ NH3
urea
2. Transportation of ammonia by Gln
ATP
Gln synthetase
COOH
(CH2)2
CHNH2
ADP + Pi
(CH2)2
+ NH3
CHNH2
COOH
Glu
CONH2
COOH
Glutaminase
H2O
Gln
§ 4. 3 Formation of urea
O
liver
Transportation of NH3
H 2N
C
NH2
urea
Urea is less toxic than ammonia.
The Urea Cycle occurs mainly in liver.
( ornithine cycle / Krebs cycle )
 Most animals convert excess nitrogen
to urea, prior to excreting it.
1. Site: liver (mitochondria and
cytosol)
2. Process --------- Urea Cycle
urea
ornithine
NH3 + CO2
arginase
H2O
H2O
Arg
citrulline
NH2
H2O
NH3
CO2 + 2NH3
C=O+H2O
NH2
① Formation of carbamoyl phosphate
(in mitochondria)
2ATP
NH3 + CO2 + H2O
2ADP+Pi
CPS I
O
H2N-C-O~PO3H2
carbamoyl phosphate
Carbamoyl phosphate synthase Ⅰ
Carbamoyl phosphate
synthase backbone
structure
• Tunnel connecting active sites (blue wire)
Carbamoyl phosphate synthetaseⅠ:
Occurs in mitochondria of liver cells. It is involved
in urea synthesis.
Carbamoyl phosphate synthetaseⅡ:
Present in cytosol of liver cells which is involved
in pyrimidine synthesis.
Carbamoyl phosphate synthetase Ⅰ (CPSⅠ) is an
allosteric enzyme and is absolutely dependent up on Nacetylglutamic acid (AGA) for its activity.
② Formation of citrulline
(in mitochondria)
NH2
NH2
£¨ CH 2£©
3
CHNH2
O
+ H2N-C-O~PO3H2
COOH
ornithine
Pi
OCT
carbamoyl
phosphate
OCT: ornithine carbamoyl transferase
C O
NH
£¨ CH 2£©
3
CHNH2
COOH
citrulline
③ Formation of arginine (in cytosol)
two sub-steps
NH2
C O
NH
+
£¨ CH 2£©
3
CHNH2
COOH
citrulline
NH2
COOH
H2-N-C-H
CH2
COOH
Asp
ATP
AMP+PPi
ASS
COOH
N-C-H
CH2
NH
£¨ CH £©COOH
C
2 3
CHNH2
COOH
arginino succinate
ASS: argininosuccinate synthetase
NH2
COOH
NH2
N-C-H
C
CH2
COOH
£¨ CH £©
3
NH
2
CHNH2
COOH
arginino succinate
ASL
COOH
CH
C NH
NH
+ HC
£¨ CH 2£©
COOH
3
fumarate
CHNH2
COOH
Arg
ASL: argininosuccinate lyase
④ Formation of urea (in cytosol)
NH2
C
NH
NH
£¨ CH2£©
3
CHNH2
COOH
Arg
NH2
H2O
arginase
£¨ CH2£©
3
NH2
+ C O
CHNH2
COOH
ornithine
NH2
urea
Urea cycle
CO2 + NH3 + H2O
2ATP
N-acetylglutamic acid
2ADP+Pi
Carbamoyl phosphate
ornithine
mitochondria
Pi
citrulline
citrulline
ATP
AMP + PPi
ornithine
Asp
α-ketoglutaric
acid
Amino
acids
Arginino succinate
urea
in cytosol
oxaloacetic
acid
Arg
Glutamic α-keto
Acid
acid
fumarate
malic acid
目录
Summary of urea synthesis
Total formula：
2NH3 + CO2 + 3ATP + 2H2O
urea + 2ADP + AMP + 2Pi + PPi

One nitrogen of urea molecule comes from
ammonia, another nitrogen comes from Asp.

HCO3- ion provides the carbon atom of urea.

Found primarily in liver and lesser extent in kidney

Synthesis of a urea will consume 3ATP and 4 ~P.
O
H 2N
C
urea
NH2
CO2 + NH3 + H2O
Regulation factors:
1. Ratio of protein in dietary foods:
2. Carbamoyl phosphate synthetase is allosterically
activated by N-acetylglutamate
(acetyl CoA + glutamate  N-acetylglutamate)
3. Rate limiting enzyme: argininosuccinate
synthetase(ASS)
Clinical significance of urea
A moderately active man consuming about
300gm carbohydrates ,100gm of fats and 100gm
of proteins daily must excrete about 16.5gm of N
daily.
95% is eliminated by the kidneys and the
remaining 5%, for the most part as N, in the faeces.
Normal blood ammonia level:
in man ,normal blood level of NH3 varies from
40 to 70µg/100ml.free NH+4 concentration of
fresh plasma is less than 20µg per 100ml.
HYPERAMMONEMIAS
Hyperammonemia is a metabolic disturbance
characterised by an excess of ammonia in the
blood. It is a dangerous condition that may
lead to encephalopathy and death. It may be
primary or secondary.
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 ,cerebraledema,
and blurring of vision.
The two major types of hyperammonemia:
1. acquired hyperammonemia :
dysfunction of liver is common cause of
hyperammonemia(eg hepatic disease).
porto-systemic encephalopathy: communications
between portal and systemic veins.the portal blood
may bypass the liver.
2. hereditary hyperammonemia:
is caused by several inborn errors of metabolism
that are characterised by reduced activity of any of
the enzymes in the urea cycle.
The major reasons of hyperammonemias:
1. Excessive putrefaction in the intestine,
example:hemorrhage of digestive tract.
2. Kidney secretion : kidney desfunction
Degradation of urea in the intestine
3. Liver desfunction or porto-systemic
encephalopathy,haemorrhage into GI tract.
hepatic encephalopathy
Hepatic encephalopathy is the occurrence of confusion,
altered level of consciousness and coma as a result of
excessive blood ammonia. it is also called hepatic coma or
coma hepaticum. It may ultimately lead to death.
Postulated mechanisms for toxicity of high
[ammonia]:
1. Depletion of glutamate & high ammonia level would drive
Glutamate Dehydrogenase reaction to reverse:
a-ketoglutarate + NAD(P)H + NH4+
glutamate + NAD(P)+
The resulting depletion of a-ketoglutarate, an essential Krebs Cycle
intermediate, could impair energy metabolism in the brain.
2. 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.
3. [glutamine], cells swelling
4. false neurotransmitter:
phenylethylamine
tyramine
phenolethanolamine
β-hydroxytyramine
Treatment of deficiency of Urea Cycle
enzymes (some treatments depend 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 a-keto acid analogs of
essential amino acids.
Liver transplantation has also been used,
since liver is the organ that carries out Urea
Cycle.
2. Metabolism of a-keto acid
Metabolism of a-keto acid
(1) Formation of non- essential AAs
(2) Formation of glucose or lipids
(3) Provide energy
(1) Formation of non- essential AAs
a. Synthesis is from a–keto acids
Alanine
pyruvate
Aspartate
oxaloacetate
Glutamate
a-Ketoglutarate
transamination
reaction
b. Synthesis by amidation
Glutamine
asparagine
Glutamate
aspartate
c. proline: glutamate is converted to proline by cyclization and
reduction reaxtions.
D. serine,glycine,cysteine:
3-phosphoglycerate
3-phosphopyruvate
3-phosphoserine
serine
E. tyrosine:
tyrosine
phenyalanine
(2) Formation of glucose or lipids
Amino acids of converted into ketone bodies or
fatty acids are termed ketogenic amino acids.
Amino acids of converted into glucose are termed
glucogenic amino acids.
Amino acids of converted into both glucose and
ketone bodies are termed glucogenic and
ketogenic amino acids.
Glucogenic amino acids:
Carbon skeletons of glucogenic amino acids are
degraded to:

pyruvate, or

a 4-C or 5-C intermediate of Krebs Cycle.
These are precursors for gluconeogenesis.
Glucogenic amino acids are the major carbon source
for gluconeogenesis when glucose levels are low.
They can also be catabolized for energy, or converted
to glycogen or fatty acids for energy storage.
Glucogenic amino acids:
Their carbon skeletons are degraded to pyruvate,
or to one of the 4- or 5-carbon intermediates of TCA
Cycle that are precursors for gluconeogenesis.
Glucogenic amino acids are the major carbon
source for gluconeogenesis when glucose levels are
low. They can also be catabolized for energy or
converted to glycogen or fatty acids for energy
storage.
Ketogenic amino acids:
Their carbon skeletons are degraded to acetylCoA or one of its precursors.
Acetyl CoA, acetoacetyl CoA and its precursor
acetoacetate, cannot yield net production of
oxaloacetate, the precursor for the gluconeogenesis
pathway. Carbon skeletons of ketogenic amino acids
can be catabolized for energy in TCA Cycle, or
converted to ketone bodies or fatty acids. They
cannot be converted to glucose.
Classification
types
Glucogenic AAs
Glucogenic and
ketogenic AAs
Ketogenic AAs
amino acids
others
Ile, Phe, Tyr, Trp,
Thr
Leu, Lys
tryglyceride
glucose或糖原
磷酸丙糖
α-磷酸甘油
lipids
PEP
丙氨酸
半胱氨酸
丝氨酸
苏氨酸
色氨酸
Pyruvate
Acetyl
CoA
异亮氨酸
亮氨酸
色氨酸
Acetoacetyl
CoA
Oxaloacetate
天冬氨酸
天冬酰胺
Citric
acid
TAC
Fumarate
苯丙氨酸
酪氨酸
Ketone
bodies
亮氨酸 赖氨酸
酪氨酸 色氨酸
苯丙氨酸
CO2
a-Ketoglutarate
Succinyl CoA
CO2
异亮氨酸 蛋氨酸
丝氨酸 苏氨酸 缬氨酸
谷氨酸
精氨酸 谷氨酰胺
组氨酸 缬氨酸
目录
Ketogenic amino acids
Glucogenic amino aicds
Section 5 Metabolism of
Specific Amino Acid
 Decarboxylation
of amino acids
 Metabolism
of one carbon unit
 Metabolism
of sulfur-containing AAs
 Metabolism
of aromatic AAs
 Metabolism
of branched-chain AAs
§ 5.1 Decarboxylation of
amino acids
RCHCOOH
NH2
amino
acid
NH3+H2O2
CO2
decarboxylase
(Vit B6)
H2O+O2
RCH2NH2
amine
1/2O2
RCHO
amine oxidase
RCOOH
organic
acid
Decarboxylation is the reaction by which CO2 is
removed from the COOH group of an amino acid as a
result an amine is formed.this is mostly a process confirned
to putrefaction in intestines and produces amines.
1. Glu→γ-aminobutyric acid
(GABA)
COOH
CH2
CH2
CHNH2
CO2
L-glu
decarboxylase
COOH
CH2
CH2
CH2NH2
COOH
L-Glu
GABA
GABA is known to serve as a normal regulator
of neuronal activity being active as an inhibitor
(presynaptic inhibition).
2. Cys→taurine
CH2SH
3[O]
CH2SO3H
CHNH2
CHNH2
COOH
COOH
L-Cys
sulfoalanine
CO2
CH2SO3H
sulfoalanine
decarboxylase
CHNH2
taurine
Taurine , constituent of bile acid taurocholic acid
3. His→histamine
CH2CHCOOH
HN
N
L-His
NH2
CO2
HN
L-His
decarboxylase
CH2CH2NH2
N
histamine
Histamine acts as a neurotransmitter, particularly
in the hypothalamus. It acts as an anaphylactic and
inflammatory agent on being released from mast
cells in response to antigens.
4. Trp→5-hydroxytryptamine (5-HT)
(serotonin)
Tryptophan HO
CH2 CH COOH hydroxylase
N
H
CH2 CH COOH
NH 2
NH 2
N
H
5'-hydroxytryptophan
Trp
decarboxylase
HO
CO2
CH2 CH2 NH 2
N
H
5'-hydroxytryptamine
5. Polyamines
SAM
adenosine
S CH3
COOH
CH NH2
(CH2)3
CO2
NH2
NH2
CO2
adenosine
S CH3
adenosine NH
2
(CH2)3
S CH3
(CH2)3 NH
2
NH
NH2
adenosine(CH )
2 3
S CH3
NH
(CH2)4
(CH2)3
(CH2)4
NH2
NH2
(CH2)4
putrescine
NH2
(CH2)3
spermidine
NH2
spermine
Ornithine
HN
β-amino-propionaldehyde
O2
Spermine
spermidine
Polyamine oxidase
H 2 O2
H2O2
Polyamine oxidase
β-amino-propionaldehyde
CO2+ NH4+
putrescine
Major portions of putrescine and spermidine are excreted
in urine after acetylation as acetylated derivatives.
Functions of polyamines
They have been implicated in diverse physiological
processes and are involved in cell proliferation and growth.
putrescine is best “marker” for cell proliferation.
They are required as growth factors for cultured mammalian
and bacterial cells.
Polyamines also exert diverse effects on protein synthesis.
They act as inhibitors of enzymes that include protein kinase.
Spermidine has been claimed to be best “marker” of tumor
cell destruction. Increased polyamine excretion has been
claimed to be characteristic of maglignant diseases.
Ranges of normal excretion of polyamines: ( In urine )
putrescine: 2.7 ±0.5mg
spermine: 3.4 ± 0.7mg
spermidine: 3.1±0.6mg
§ 5.2 Metabolism of one carbon
unit
1. One carbon unit
One carbon units (or groups) are one carboncontaining groups produced in catabolism of
some amino acids. They are
CH3
methyl
CH2
methylene
CH
methenyl
CH
CHO
formyl
NH
formimino
Attention: CO2 is not one carbon unit.
2. Tetrahydrofolic acid (FH4)
One carbon units are carried by FH4.
The N5 and N10 of FH4 participate in the
transfer of one carbon units.
H2N
3
2
1
N
N
4
OH
H
8N
5N
H
7
9
6 CH2
10
HN
H
CO NH C CH2 CH2 COOH
COOH
• the formation of FH4 carried one carbon unit
N5—CH3—FH4
N5、N10—CH2—FH4
N5、N10=CH—FH4
N10—CHO—FH4
N5—CH=NH—FH4
3. Formation of one carbon unit
(1) Ser→N5,N10-CH2-FH4
CH2
H2O
CH2NH2
5
10
CHNH2 + FH4
+
N , N -CH2-FH4
Ser
COOH
COOH
hydroxymethyl
Ser
Gly
transferase
(2) Gly→N5,N10-CH2-FH4
NADH+H +
NAD +
CH2NH2
COOH + FH4
Gly lyase
Gly
N5, N10-CH2-FH4 + CO2 + NH3
Ser, Gly
(3) His →N5-CH=NHFH4
NH 3
CH 2CHNH 2COOH
HN
N
CH=CHCOOH
HN
N
His
2H 2O
COOH
CHNH 2
£¨ CH2£©
2
COOH
Glu
N5-CH=NHFH4
FH4
subaminomethyl
transferase
HOOC-CH
HN
CH=CHCOOH
N
subaminomethyl Glu
(4) Trp→N10-CHOFH4
CH2CHNH2COOH
O
O2
CCHNH2COOH
N
H
Trp
NHCHO
N-formyl kynurenine
H2O
ADP+Pi
N10 -CHOFH4
FH2+ATP
N10-CHOFH4
synthetase
HCOOH
O
CCHNH2COOH
NH2
kynurenine
4. One carbon unit exchange
H2O
NH3
N5,N10
N5 CH=NHFH4
CH FH4
NADPH+H+ H2O
NH3
NAPD+
N5,N10
CH2 FH4
NADH+H+
NAD+
N5 CH3 FH4
N10 CHOFH4
5. Significance of one carbon unit
1. Substance for synthesis of nucleic acid.
N10－CHOFH4 and N5,N10－CH2－FH4 can
supply C2 and C8 of purine
2. one carbon unit connect amino acids
metabolism and nucleic acids metabolism
If disorder of one carbon unit
metabolism,induce some diseases.for
example:megaloblasticanaemia
§ 5.3 Metabolism of sulfurcontaining AAs
Methionine
S
CH3
cysteine
CH2SH
CH2
CHNH2
CH2
COOH
CHNH2
COOH
cystine
CH2
S
S CH2
CHNH2
CHNH2
COOH
COOH
1. Metabolism of Met
1. S-adenosyl methionine,SAM
A
+
adenosyl
transferase
PPi+Pi
Methionine
ATP
A
S-adenosyl
methionine,SAM
• SAM is the direct donor of
methyl in body.
RH
adenosyl
RH—CH3
Methyl transferase
A
SAM
A
S—adenosyl
homocystein
homocystein
Transmethylation and Met cycle
PPi+Pi
S CH3
£¨CH2£©
2
Met
CH NH2
COOH
ATP
A S CH3
£¨CH2£©
2
CH NH2
adenosyl
transferase
COOH
RH
methyl transferase
FH4
N5 -CH3FH4
Met synthase
£¨ VB12£©
SH
£¨CH2£©
2
CH NH2
COOH
homocysteine
A
SAM
RCH3
H2O
A
SH
£¨CH2£©
2
CH NH2
COOH
S-adenosyl
homocysteine
Significance
(1) SAM is the direct donor of methyl in body.
Methylation can synthesize many
important materials such as: choline,
creatine, etc.
(2) N5-CH3FH4 is the indirect donor of methyl
in the body.
(3) The free folic acid or VitB12
decrease(lack) will cause the
decrease of DNA, which will lead to
anemia.
megaloblasticanaemia
Formation of creatine
Arg
NH2
HN
C
N
Gly
CH3
CH2
COOH
creatine
SAM
Synthesis of Creatine and Creatinine
 Creatine – nitrogenous organic acid - helps to supply energy to
muscle.
 Creatine by way of conversion to and from phosphocreatine is
present and functions in all vertebrates as energy buffer system.
 Keeps the ATP/ADP ratio high at subcellular places where ATP
is needed.
 The amount of creatinine produced is related to muscle mass.
 The level of creatinine excretion (clearance rate) is a measure of
renal function.
Glycine
2. Metabolism of cysteine and
cystine
SH
CH 2
CH NH 2
COOH
cysteine
+
SH
CH 2
2H
CH NH 2
COOH
cysteine
2H
S
CH 2
S
CH 2
CH NH 2 CH NH 2
COOH COOH
cystine
Formation of PAPS
SH
pyruvate NH3
CH2
CH
H2S
NH2
COOH
Cys
[O]
ATP
SO42-
PPi
ATP
adenosine-5'phosphosulfate
(AMPS)
ADP
3'-phosphoadenosine5'-phosphosulfate
(PAPS)

PAPS is the active sulfate group for
addition to biomolecules.
NH2
N
O
O3S O P O
N
CH2 O
N
N
OH
H2O3PO
OH
3'-phosphoadenosine- 5'-phosphosulfate
(PAPS)
§ 5. 4 Metabolism of
aromatic amino acids
phenylalanine
tyrosine
tryptophan

1. Phe
Tyr
Phe
phenyl pyruvate
phenylketonuria
alkaptonuria
Tyr
albinism
Fumarate
+
acetoacetate
Melanin
Catecholamines

1. Phe
Tyr
NADPH+H+
NADP+
dihydrobiopterin
tetrahydroCH2CHNH2COOH biopterin
+
CH2CHNH2COOH
+
O2
Phe hydroxylase
OH
Tyr
Phe
OH
N
H
N
5
3
H2N
OH
1
N
CH-CH-CH3
6
OH OH
HN
8 7
N
H
Tetrahydrobiopterin
N
N
5
3
1
N
CH-CH-CH3
OH OH
8 7
N
H
6
Dihydrobiopterin
H2O
transaminase
CH2 CH COOH
NH2
¦Á-ketoPhe
glutarate
Glu
CH2 C COOH
O
phenyl pyruvate

Phe hydroxylase ↓→phenyl pyruvate in the
body ↑ → phenylketonuria(PKU) → toxicity of
central nervous system →developmental
block of intelligence of children

Treatment: control the input of Phe
2. Tyr
★Catecholamines: Dopamine,
norepinephrine, epinephrine
★ Melanin
★ Tyrosinase decrease will lead to
albinism.
CH2CHNH 2COOH
CH2CHNH 2COOH
CO2
Tyr
HO
OH
OH
Tyr transaminase
O
CH2CCOOH
OH
hydroxyphenylpyruvate
dopa
CH2CH2NH 2
HO
OH
CH2CHNH 2COOH
dopa
quinone
O
O
dopamine
OH
CH2CH2NH 2
norepinephrine
HO
OH
SAM
OH
NH
CH2COOH
OH homogentisate
O
O
OH
CH2CH2NHCH 3
indole-5,6quinone
HO
fumarate + acetoacetate
melanin
epinephrine
OH
3. Trp
 5-HT

One carbon unit

Nicotinic acid

Pyruvate and Acetoacetyl CoA
§ 5.5 Metabolism of branched-chain AAs


Leu, Ile, Val
They are all essential AAs.
Leu
Val
-NH2
Ile
transamination
formation of ¦Á- keto acid
CO2
decarboxylation
acyl-CoA
oxidation
enoyl-CoA
succinayl CoA
acetyl CoA and
acetoacetyl CoA
succinayl CoA
and acetyl CoA