TUJUAN PEMBELAJARAN :

Mahasiswa mampu menjelaskan :

Organ yang berperan dan lokasi terjadinya
siklus urea
5 tahap siklus urea
Mekanisme regulasi siklus urea dan peranan
siklus urea dalam metabolisme tubuh

Sumber Pustaka
DB Marks. 2000. Biokimia Kedokteran Dasar. Jakarta.
EGC
DK Kusmiyati, Setyawati AN, Ngestiningsih D,
Kristina TN. 2011. Buku Ajar Biokimia. Bagian
Biokimia Fakultas Kedokteran Universitas
Diponegoro. Semarang.

SIKLUS UREA
Jalur Utama pembuangan amonia
Pembentukan urea hanya terjadi di
Hepar.
Hanya 2 reaksi pertama terjadi
mitokondria
Semua reaksi setelahnya terjadi di
sitosol.

Transport of
ammonia to liver

From most tissues

Urea

H2O

Glutamine

Glutaminase
NH3

Liver

Glutamate
dehydrogenase
Glutamate

-ketoglutarate

ALT
Alanine

Pyruvate
Glucose

From muscle

Alanine cycle

Steps of Urea Cycle

Mitochondrion

1
2 ATP + HCO3- + NH3

Carbamoyl phosphate + 2 ADP + Pi

Pi

Ornithine

Ornithine
Urea

Citrulline

Urea cycle

Citrulline
ATP

Aspartate

AMP + PPi

H2O

Argininosuccinate

Arginine

4
Cytosol
Fumarate

Malate

Oxaloacetate

REAKSI TAHAP 1
Enzim yang berperan
carbamoyl phosphate
synthetase-I
Membutuhkan 2
molekul ATP.
Enzim ini kunci siklus
urea
Diaktifkan oleh Nacetyl glutamate.

Mitochondrion

1
2 ATP + HCO3- + NH3

Carbamoyl phosphate + 2 ADP + Pi

Pi

Ornithine

Ornithine
Urea

Citrulline

Urea cycle

Citrulline
ATP

Aspartate

AMP + PPi

H2O

Argininosuccinate

Arginine

4
Cytosol
Fumarate

Malate

Oxaloacetate

REAKSI TAHAP 2
Reaksi terjadi di
mitokondria
Enzim yang berperan
ornithine
transcarbamoylase
Karbamoil fosfat +
ornithine sitrulin
Sitrulin keluar
menuju sitosol

Mitochondrion

1
2 ATP + HCO3- + NH3

Carbamoyl phosphate + 2 ADP + Pi

Pi

Ornithine

Ornithine
Urea

Citrulline

Urea cycle

Citrulline
ATP

Aspartate

AMP + PPi

H2O

Argininosuccinate

Arginine

4
Cytosol
Fumarate

Malate

Oxaloacetate

REAKSI TAHAP 3
Terjadi di sitosol
Enzim :
argininosuccinate
syntethase
Sitrulin + aspartat
arginino suksinat
Reaksi ini ATP
dependent,
menghasilkan AMP
dan P.

Mitochondrion

1
2 ATP + HCO3- + NH3

Carbamoyl phosphate + 2 ADP + Pi

Pi

Ornithine

Ornithine
Urea

Citrulline

Urea cycle

Citrulline
ATP

Aspartate

AMP + PPi

H2O

Argininosuccinate

Arginine

4
Cytosol
Fumarate

Malate

Oxaloacetate

REAKSI TAHAP 4
Enzim :
argininosuccinate
lyase
arginino suksinat
arginin + fumarat

Mitochondrion

1
2 ATP + HCO3- + NH3

Carbamoyl phosphate + 2 ADP + Pi

Pi

Ornithine

Ornithine
Urea

Citrulline

Urea cycle

Citrulline
ATP

Aspartate

AMP + PPi

H2O

Argininosuccinate

Arginine

4
Cytosol
Fumarate

Malate

Oxaloacetate

REAKSI TAHAP 5
Enzim : arginase
Arginin urea +
ornithine
Urea masuk aliran
darah ginjal
keluar lewat urin
Ornithine
mitokondria

Mitochondrion

1
2 ATP + HCO3- + NH3

Carbamoyl phosphate + 2 ADP + Pi

Pi

Ornithine

Ornithine
Urea

Citrulline

Urea cycle

Citrulline
ATP

Aspartate

AMP + PPi

H2O

Argininosuccinate

Arginine

4
Cytosol
Fumarate

Malate

Oxaloacetate

FUMARAT
Dikonversi
menjadi aspartat
Enzim : malate
dehydrogenase
Terbentuk
oksaloasetat

RINGKASAN SIKLUS UREA

Aspartate + NH3 + CO2 + 3ATP

Urea + fumarate +

2ADP + AMP + 2 Pi +PPi

4 ATP dibutuhkan untuk membentuk 1 molekul Urea.
Siklus Urea merupakan Reaksi Irreversibel
Penting untuk membuang amonia dari tubuh
Hiperamonia toksik

Sources of
urea nitrogen

Sources of urea
nitrogen
One nitrogen of the
urea molecule is
supplied by free NH3,
and the other
nitrogen by
aspartate.
Glutamate is the
immediate precursor
of both ammonia
which in turn,
gathers nitrogen
from other amino
acids

NAD+
-ketoacids

Glutamate

Amino acids

-ketoglutarate
NADH +

NH3

Urea
CO2

Arginine
Fumarate
Urea
cycle

Argininosuccinate

Citrulline
Amino acids

-ketoacids

-ketoacids

Glutamate

Aspartate

Oxaloacetate

Ornithine

Carbamoyl
phosphate

Regulation of
urea cycle

Fine regulation

Gross regulation

I- Fine regulation
N-Acetylglutamate is an essential allosteric activator for
carbamoyl phosphate synthetase- I, the rate-limiting step in the
urea cycle. N-Acetylglutamate is synthesized from acetyl-CoA and
glutamate, in a reaction for which arginine is an activator.

Acetate
Hydrolase

Glutamate
Synthetase
N-Acetylglutamate

Acetyl CoA
Arginine

CoA

II- Gross regulation

An increase in the supply of amino acids to the liver, such as
occurs on a high protein diet, during the administration of the
protein catabolic hormones, and during prolonged starvation,
increases the synthesis of the urea cycle enzymes 10-20-fold. This
increases urea formation.

Fate of urea

The urea formed by the liver goes, via the blood (plasma level
10-50 mg/dL), to the kidneys to be excreted in the urine.

In renal failure the plasma level of urea increases.

In hepatic failure ammonia remains in the blood, leading to

hyperammonemia and ammonia intoxication.

Hyperammonemia

Mechanism of ammonia toxicity

The toxicity is thought to result, in

part, from a shift in the equilibrium
of the glutamate dehydrogenase
reaction towards the direction of
glutamate formation.
This depletes -ketoglutarate, an
essential intermediate in the citric
acid cycle, resulting in a decrease in
cellular oxidation and ATP
production. The brain is particularly
sensitive to hyperammonemia,
because it depends on the citric acid
cycle to maintain its high rate of
energy production.

Glucose

Glycolysis

Pyruvate

Oxaloacetate

Acetyl CoA

Citrate
TCA
NAD

NH3

NH3
Glutamine

-ketoglutarate

Glutamate
ADP ATP

NADH

NAD

NADH

Isocitrate

Major types of hyperammonemia

1. Acquired hyperammonemia:
Cirrhosis of the liver caused by alcoholism, hepatitis, or biliary
obstruction may result in formation of collateral circulation around the
liver.
2. Hereditary hyperammonemia (metabolic disorders of the urea cycle):
Deficiencies of each of the 5 enzymes of the urea cycle have been
reported (with an overall incidence of 1 in 30,000 live births).

 However, when the liver function is compromised, due

either to genetic defects of the urea cycle, or liver disease,
blood levels can rise above 1000 mmol/L.
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, vomiting, cerebral
edema, and blurring of vision.

At high concentrations, ammonia can cause coma and

death.