The Urea Cycle in Biochemistry
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Urea Cycle
Objectives:
Understand the reactions for removal of
α
-amino group of
amino acids and formation of
ammonia
Identify the importance of blood transport of ammonia to the
liver in the form of
glutamine/alanine
Understand the importance of conversion of ammonia
into urea by the liver through
urea cycle
Identify
urea
as the major form for the disposal of amino
groups derived from amino acids
Identify the
causes
(hereditary & acquired),
clinical
manifestations
and
management
of hyperammonemia
Background:
Unlike glucose and fatty acids, amino acids
are not stored by the body.
Amino acids in excess of biosynthetic needs
are degraded.
Degradation of amino acids involves:
Removal of
α
-amino group Ammonia (NH
3
)
Remaining carbon skeleton Energy metabolism
Removal of
α
-amino group, formation of
ammonia and its transport to liver
A: Removal of
α
-amino group of amino acids
and formation of ammonia:
1.
Transamination to glutamate
2.
Oxidative deamination of glutamate
B: Blood transport of ammonia into liver:
1.
in the form of glutamine (most tissue)
2.
in the form of alanine (muscle)
A: Removal of
α
-amino group &
formation of ammonia
Amino groups of amino acids are funneled to
glutamate
(Why?)
by
transamination
reactions
with
α
-ketoglutarate
Glutamate is unique. It is the only amino acid
that undergoes rapid oxidative deamination
Oxidative deamination
of glutamate will
release NH
3
and re-generate
α
-ketoglutarate
Transamination
&
P
L
P
P
L
P
:
P
y
r
i
d
o
x
a
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p
h
o
s
p
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a
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,
a
c
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e
n
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r
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v
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a
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i
n
B
6
Transamination by ALT & AST
A
L
T
&
P
L
P
&
P
L
P
&
P
L
P
Oxidative Deamination
Glutamate
α
-ketoglutarate
Glutamate
Dehydrogenase
N
A
D
N
A
D
H
N
H
3
Summary: Removal of
α
-amino group
of amino acid & formation of ammonia
B: Transport of NH
3
from
peripheral tissues into the liver
Ammonia is produced by all tissues and the
main disposal is via formation of urea in liver
Blood level of NH
3
must be kept very low,
otherwise, hyperammonemia and CNS toxicity
will occur
(NH
3
is toxic to CNS)
To solve this problem, NH
3
is transported from
peripheral tissues to the liver via formation of:
Glutamine (most tissues)
Alanine (muscle)
N
H
3
i
s
t
r
a
n
s
p
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d
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b
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p
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r
a
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t
i
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s
u
e
s
:
Transport of NH
3
from
peripheral tissues into the liver
Cont’D
T
h
e
r
e
f
o
r
e
,
N
H
3
i
s
t
r
a
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p
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a
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F
i
r
s
t
,
N
H
3
w
i
l
l
b
e
t
r
a
n
s
f
e
r
r
e
d
i
n
t
o
α
-
k
e
t
o
g
l
u
t
a
r
a
t
e
t
o
f
o
r
m
g
l
u
t
a
m
a
t
e
T
h
e
n
,
g
l
u
t
a
m
a
t
e
w
i
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l
g
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f
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a
n
i
n
e
b
y
A
L
T
F
r
o
m
t
h
e
m
u
s
c
l
e
:
Transport of NH
3
from
peripheral tissues into the liver
Cont’D
Release of ammonia from glutamine
and alanine in the liver
1
.
G
l
u
t
a
m
i
n
e
i
s
c
o
n
v
e
r
t
e
d
i
n
t
o
g
l
u
t
a
m
a
t
e
b
y
g
l
u
t
a
m
i
n
a
s
e
.
2
.
A
l
a
n
i
n
e
w
i
l
l
g
i
v
e
i
t
s
a
m
i
n
o
g
r
o
u
p
t
o
α
-
k
e
t
o
g
l
u
t
a
r
a
t
e
t
o
f
o
r
m
g
l
u
t
a
m
a
t
e
b
y
A
L
T
.
I
n
t
h
e
L
i
v
e
r
:
1
2
3
3
.
G
l
u
t
a
m
a
t
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i
s
c
o
n
v
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d
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α
-
k
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l
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t
a
r
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e
a
n
d
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a
s
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g
N
H
3
b
y
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u
t
a
m
a
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d
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y
d
r
o
g
e
n
a
s
e
.
Summary
Blood transport of NH
3
from
peripheral tissues
(in the form of glutamine
and alanine)
into the liver
and the release of NH
3
back in the liver to start
the urea cycle
Urea Cycle
Urea is the major form for disposal of
amino groups derived from amino
acids
Urea cycle occurs in the liver
One nitrogen of urea is from NH
3
and the
other nitrogen from aspartate
Urea is transported in the blood to the
kidneys for excretion in urine
Urea Cycle
T
h
e
f
i
v
e
e
n
z
y
m
e
s
o
f
u
r
e
a
c
y
c
l
e
:
C
a
r
b
a
m
o
y
l
p
h
o
s
p
h
a
t
e
s
y
n
t
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t
a
s
e
I
O
r
n
i
t
h
i
n
e
t
r
a
n
s
c
a
r
b
a
m
o
y
l
a
s
e
(
O
C
T
)
A
r
g
i
n
i
n
o
s
u
c
c
i
n
a
t
e
s
y
n
t
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a
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A
r
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o
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y
a
s
e
A
r
g
i
n
a
s
e
C
O
N
T
’
D
C
P
S
I
O
C
T
A
S
S
A
S
L
A
r
g
i
n
a
s
e
Urea Cycle: Regulation
R
a
t
e
-
l
i
m
i
t
i
n
g
e
n
z
y
m
e
o
f
u
r
e
a
c
y
c
l
e
:
C
a
r
b
a
m
o
y
l
p
h
o
s
p
h
a
t
e
s
y
n
t
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t
a
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I
(
C
P
S
I
)
A
l
l
o
s
t
e
r
i
c
a
c
t
i
v
a
t
o
r
o
f
C
P
S
I
:
N
-
A
c
e
t
y
l
g
l
u
t
a
m
a
t
e
N
-
A
c
e
t
y
l
g
l
u
t
a
m
a
t
e
i
s
s
y
n
t
h
e
s
i
z
e
d
b
y
:
N
-
A
c
e
t
y
l
g
l
u
t
a
m
a
t
e
s
y
n
t
h
e
t
a
s
e
(
N
A
G
S
)
i
n
p
r
e
s
e
n
c
e
o
f
a
r
g
i
n
i
n
e
N
A
G
S
d
e
f
i
c
i
e
n
c
y
i
s
e
f
f
i
c
i
e
n
t
l
y
t
r
e
a
t
e
d
w
i
t
h
C
a
r
b
a
g
l
u
e
,
a
C
P
S
1
a
c
t
i
v
a
t
o
r
Fate of Urea
U
r
e
a
K
i
d
n
e
y
s
a
n
d
e
x
c
r
e
t
e
d
i
n
u
r
i
n
e
I
n
t
e
s
t
i
n
e
N
H
3
+
C
O
2
L
o
s
t
i
n
f
e
c
e
s
R
e
a
b
s
o
r
b
e
d
i
n
t
o
b
l
o
o
d
T
h
e
a
c
t
i
o
n
o
f
i
n
t
e
s
t
i
n
a
l
u
r
e
a
s
e
t
o
f
o
r
m
N
H
3
i
s
c
l
i
n
i
c
a
l
l
y
s
i
g
n
i
f
i
c
a
n
t
i
n
r
e
n
a
l
f
a
i
l
u
r
e
:
Renal failure Blood urea Urea to intestine NH
3
blood level
U
r
e
a
s
e
U
r
e
a
s
e
B
l
o
o
d
(
A
c
q
u
i
r
e
d
h
y
p
e
r
a
m
m
o
n
e
m
i
a
)
Sources and Fates of Ammonia
N
o
r
m
a
l
b
l
o
o
d
l
e
v
e
l
o
f
a
m
m
o
n
i
a
:
5
–
5
0
µ
m
o
l
/
L
Hyperammonemia
Acquired hyperammonemia:
1. Liver diseases:
Acute: Viral hepatitis or hepatotoxic
Chronic: Cirrhosis by hepatitis or alcoholism
2. Renal failure
Inherited hyperammonemia:
Genetic deficiencies of any of the 5 enzymes of
urea cycle or the activator enzyme for CPSI:
o
CPSI, OTC, ASS, ASL, arginase or NAGS
Inherited Hyperammonemia
Ornithine transcarbamoylase deficency:
X-linked recessive
Most common of congenital hyperammonemia
Marked decrease of citrulline and arginine
Others: Autosomal recessive
Clinical Presentation of Hyperammonemia
Lethargy and somnolence
Tremors
Vomiting and cerebral edema
Convulsions
Coma and death
Management of Hyperammonemia
1.
Protein restriction
2.
Volume repletion to maintain renal function
Use 10% dextrose in water but
limit the use of
normal saline
3.
Ammonia removal by hemodialysis &/or drugs
4.
Avoid drugs that increase protein catabolism
(eg,
glucocorticoids
) or inhibit urea synthesis
(eg,
valproic acid
), or have direct hepatotoxicity
Drug Treatment of Hyperammonemia
A.
Drugs that scavenge ammonia by creating an
alternate pathway to excrete N
2
- precursors:
1.
I.V. Sodium phenylacetate & sodium
benzoate
(Ammonul)
2.
Oral sodium phenyl butyrate
(Buphenyl)
3.
I.V. Arginine: for all UCDs except UCD due to
arginase deficiency (argininemia)
B.
Activators to CPSI
(Carglumic acid “Carbaglu”):
For hyperammoniemia due to NAGS deficiency
Sodium phenyl butyrate (Buphenyl)
S
o
d
i
u
m
p
h
e
n
y
l
b
u
t
y
r
a
t
e
(
B
u
p
h
e
n
y
l
)
:
P
r
o
d
r
u
g
t
h
a
t
i
s
c
o
n
v
e
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t
e
d
t
o
p
h
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n
y
l
a
c
e
t
a
t
e
.
P
h
e
n
y
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a
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a
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e
c
o
n
d
e
n
s
e
s
w
i
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h
g
l
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t
a
m
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f
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m
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d
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u
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e
References
Lippincott’s Illustrated Reviews in Biochemistry 6
th
Edition pages-253-258
Explore the intricate process of the urea cycle, its role in removing amino groups from amino acids, converting ammonia into urea in the liver, and managing hyperammonemia. Learn about transamination, oxidative deamination, and the importance of glutamine and alanine in ammonia transport. Discover the significance of pyridoxal phosphate in transamination reactions and the involvement of ALT and AST enzymes in amino acid metabolism.
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Presentation Transcript
Urea Cycle Urea Cycle Dr. Rana Hasanato Medical Biochemistry Unit Department of Pathology
Objectives: Objectives: Understand the reactions for removal of -amino group of amino acids and formation of ammonia Identify the importance of blood transport of ammonia to the liver in the form of glutamine/alanine Understand the importance of conversion of ammonia into urea by the liver through urea cycle Identify urea as the major form for the disposal of amino groups derived from amino acids Identify the causes (hereditary & acquired), clinical manifestations and management of hyperammonemia
Background: Background: Unlike glucose and fatty acids, amino acids are not stored by the body. Amino acids in excess of biosynthetic needs are degraded. Degradation of amino acids involves: Removal of -amino group Ammonia (NH3) Remaining carbon skeleton Energy metabolism
Removal of Removal of - -amino group, formation of amino group, formation of ammonia and its transport to liver ammonia and its transport to liver A: Removal of -amino group of amino acids and formation of ammonia: 1. Transamination to glutamate 2. Oxidative deamination of glutamate B: Blood transport of ammonia into liver: 1. in the form of glutamine (most tissue) 2. in the form of alanine (muscle)
A: Removal of A: Removal of - -amino group & formation of ammonia formation of ammonia amino group & Amino groups of amino acids are funneled to glutamate (Why?) by transamination reactions with -ketoglutarate Glutamate is unique. It is the only amino acid that undergoes rapid oxidative deamination Oxidative deamination of glutamate will release NH3 and re-generate -ketoglutarate
Transamination Transamination & PLP PLP: Pyridoxal phosphate, a co-enzyme that is derived from vitamin B6
Transamination Transamination by ALT & AST by ALT & AST & PLP ALT & PLP & PLP
Oxidative Oxidative Deamination Deamination Glutamate NAD NADH -ketoglutarate NH3 Glutamate Dehydrogenase
Summary: Removal of Summary: Removal of - -amino group of amino acid & formation of ammonia of amino acid & formation of ammonia amino group
B: Transport of NH B: Transport of NH3 3 from peripheral tissues into the liver peripheral tissues into the liver Ammonia is produced by all tissues and the main disposal is via formation of urea in liver from Blood level of NH3 must be kept very low, otherwise, hyperammonemia and CNS toxicity will occur (NH3 is toxic to CNS) To solve this problem, NH3 is transported from peripheral tissues to the liver via formation of: Glutamine (most tissues) Alanine (muscle)
Transport of NH Transport of NH3 3 from peripheral tissues into the liver peripheral tissues into the liver from Cont D Cont D From most peripheral tissues: NH3 is transported Into the liver through forming glutamine by glutamine synthetase
Transport of NH Transport of NH3 3 from peripheral tissues into the liver peripheral tissues into the liver from Cont D Cont D From the muscle: First, NH3 will be transferred into -ketoglutarate to form glutamate Then, glutamate will give its amino group to pyruvate to form alanine by ALT Therefore, NH3 is transported from muscle into the liver through forming alanine
Release of ammonia from glutamine Release of ammonia from glutamine and and alanine alanine in the liver In the Liver: in the liver 1. Glutamine is converted into glutamate by glutaminase. 2. Alanine will give its amino group to -ketoglutarate to form glutamate by ALT. 1 3 2 3. Glutamate is converted into -ketoglutarate and releasing NH3 by glutamate dehydrogenase.
Summary Blood transport of NH3 from peripheral tissues (in the form of glutamine and alanine) into the liver and the release of NH3 back in the liver to start the urea cycle
Urea Cycle Urea Cycle Urea is the major form for disposal of amino groups derived from amino acids Urea cycle occurs in the liver One nitrogen of urea is from NH3 and the other nitrogen from aspartate Urea is transported in the blood to the kidneys for excretion in urine
Urea Cycle Urea Cycle CONT D Arginase ASL The five enzymes of urea cycle: Carbamoyl phosphate synthetase I OCT Ornithine transcarbamoylase (OCT) ASS Argininosuccinate synthase CPSI Argininosuccinate lyase Arginase
Urea Cycle: Regulation Urea Cycle: Regulation Rate-limiting enzyme of urea cycle: Carbamoyl phosphate synthetase I (CPSI) Glutamate Allosteric activator of CPSI: N-Acetylglutamate NAGS N-Acetylglutamate is synthesized by: N-Acetylglutamate synthetase (NAGS) in presence of arginine N-Acetylglutamate NAGS deficiency is efficiently treated with Carbaglue, a CPS1 activator
Fate of Urea Fate of Urea Urea Kidneys and excreted in urine Blood Urease Intestine NH3 + CO2 Reabsorbed into blood Lost in feces The action of intestinal urease to form NH3 is clinically significant in renal failure: Urease Renal failure Blood urea Urea to intestine NH3 blood level (Acquired hyperammonemia)
Sources and Fates of Ammonia Sources and Fates of Ammonia Normal blood level of ammonia: 5 50 mol/L
Hyperammonemia Hyperammonemia Acquired hyperammonemia: 1. Liver diseases: Acute: Viral hepatitis or hepatotoxic Chronic: Cirrhosis by hepatitis or alcoholism 2. Renal failure Inherited hyperammonemia: Genetic deficiencies of any of the 5 enzymes of urea cycle or the activator enzyme for CPSI: oCPSI, OTC, ASS, ASL, arginase or NAGS
Inherited Hyperammonemia Inherited Hyperammonemia Ornithine transcarbamoylase deficency: X-linked recessive Most common of congenital hyperammonemia Marked decrease of citrulline and arginine Others: Autosomal recessive
Clinical Presentation of Hyperammonemia Clinical Presentation of Hyperammonemia Lethargy and somnolence Tremors Vomiting and cerebral edema Convulsions Coma and death
Management of Management of Hyperammonemia Hyperammonemia 1. Protein restriction 2. Volume repletion to maintain renal function Use 10% dextrose in water but limit the use of normal saline 3. Ammonia removal by hemodialysis &/or drugs 4. Avoid drugs that increase protein catabolism (eg, glucocorticoids) or inhibit urea synthesis (eg, valproic acid), or have direct hepatotoxicity
Drug Treatment of Drug Treatment of Hyperammonemia Hyperammonemia A. Drugs that scavenge ammonia by creating an alternate pathway to excrete N2- precursors: 1. I.V. Sodium phenylacetate & sodium benzoate (Ammonul) 2. Oral sodium phenyl butyrate (Buphenyl) 3. I.V. Arginine: for all UCDs except UCD due to arginase deficiency (argininemia) B. Activators to CPSI (Carglumic acid Carbaglu ): For hyperammoniemia due to NAGS deficiency
Sodium phenyl butyrate Sodium phenyl butyrate( (Buphenyl Buphenyl) ) Sodium phenyl butyrate (Buphenyl): Prodrug that is converted to phenylacetate. Phenylacetate condenses with glutamine forming phenylacetylglutamine that is excreted in urine
References Lippincott s Illustrated Reviews in Biochemistry 6th Edition pages-253-258
