The document discusses the urea cycle and its role in removing toxic ammonia from the body. The urea cycle occurs primarily in the liver and involves several steps to convert ammonia and carbon dioxide into urea, which is excreted in urine. First, carbamoyl phosphate is formed in the mitochondria using ammonia, bicarbonate, and ATP. Carbamoyl phosphate then reacts with ornithine to form citrulline. Further reactions involving aspartate, ATP hydrolysis, and other enzymes ultimately yield arginine and then urea, which is excreted, along with regenerated ornithine to continue the cycle. Defects in this cycle can cause toxic hyperammonemia in

1. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
A.N. Emami R.

2. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle

3. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
amino acids The carbon chains are broken
Most mammals convert amino-
acid nitrogen to urea for down to molecules that feed
excretion into the TCA cycle.
NH4+
Some animals
excrete NH4+ or
uric acid.
most terrestrial fish & other aquatic birds & reptiles
vertebrates vertebrates
O
O NH4+ H
HN N
H2N-C-NH2 ammonium ion O
urea
N N
uric acid O H H
June 26, 2012 Total slide : 50 3

4. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Major fate of waste nitrogen
O
H2N C NH2
urea
June 26, 2012 Total slide : 50 4

5. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Why Urea?
Non toxic
Water soluble
Combines two waste products into one
molecule:
CO2
NH3
June 26, 2012 Total slide : 50 5

6. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Ammonia is highly toxic
Main reason to form urea is to reduce levels
of ammonia
“Ammonia” often refers to (NH3 + NH4+)
NH3 is really ammonia
NH4+ is the ammonium ion
pKa = 9.3
NH4+ NH3 + H+
June 26, 2012 Total slide : 50 6

7. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Ammonia rapidly equilibrates across membranes
NH4+ NH4+
pKa = 9.3
NH3 NH3
Lipid Bilayer
June 26, 2012 Total slide : 50 7

8. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Production of ammonia
Amino acids α-Ketoglutarate
α-Keto acids Glutamate GDH
Other reactions
Oxaloacetate NH+
α-Ketoglutarate 4
Aspartate Urea Urea
cycle
June 26, 2012 Total slide : 50 8

9. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Reaction catalyzed by glutamate dehydrogenase (GDH).
COO- COO-
+ NAD(P)+ NAD(P)H
H3 N C H C O
CH2 CH2
+
CH2 NH4 CH2
COO- COO-
June 26, 2012 Total slide : 50 9

10. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Most of the ammonia is produced by other
reactions…
H H
N N
N N
H H H H
CH2 C
H C NH3 histidase C H
+ NH4
COO C
L-histidine O O
urocanate
June 26, 2012 Total slide : 50 10

11. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Most of the ammonia is produced by other
reactions…
COO serine COO
H dehydratase C O + NH4
H3N C
CH2OH CH3
L-serine pyruvate
COO COO
serine
H 3N C H dehydratase
C O + NH4
H C OH CH2
CH3 CH3
L-threonine 2-ketobutyrate
June 26, 2012 Total slide : 50 11

12. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
O
C NH2 COO O
CH2 H2O NH4 CH2 C NH2 H2O NH4 COO
CH4 CH4 CH4 CH4
glutaminase asparaginase
H C NH3 H C NH4 H C NH4 H CH4NH4
COO COO CHOO CHOO
Gln Synthetase
L-glutamine L-glutamate L-asparagine L-aspartate
glutamine synthetase
ATP ADP +Pi
+
NH4 + glutamate glutamine
glutaminase
June 26, 2012 Total slide : 50 12

13. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Summary of sources of ammonia for urea cycle
June 26, 2012 Total slide : 50 13

14. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Closer look at transport of waste N from peripheral tissue
to liver via alanine and glutamine
Waste N funnelled to pyruvate Glucose – Alanine Cycle
via transaminations
Net: N (muscle)  Urea (liver)
June 26, 2012 Total slide : 50 14

15. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Synthesis of Glutamine in Peripheral Tissue and
Transport to the Liver
June 26, 2012 Total slide : 50 15

16. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
UREA FORMATION
June 26, 2012 Total slide : 50 16

17. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Overview
Occurs primarily in liver; excreted by kidney
Principal method for removing ammonia
Hyperammonemia:
Defects in urea cycle enzymes (CPS, OTC, etc.)
Severe neurological defects in neonates
Treatment:
Stop protein intake
Dialysis
Increase ammonia excretion: Na benzoate,
Na phenylbutyrate, L-arginine, L-citrulline
June 26, 2012 Total slide : 50 17

18. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Overview
Key reaction: hydrolysis of arginine
Arginine + H2O ==> urea + ornithine
arginase
Resynthesis of Arginine
June 26, 2012 Total slide : 50 18

19. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Blood Urea Nitrogen
Normal range: 7-18 mg./dL
Elevated in amino acid
catabolism
Glutamate N-
acetylglutamate
CPS-1 activation
Elevated in renal insufficiency
Decreased in hepatic failure
June 26, 2012 Total slide : 50 19

20. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Urine
urea NH2
C O
NH2
NH2 H2O
Mitochondrion C NH
5
CO2 + NH4 + Cytosol CH2 NH
CH2NH2
2 ATP carbamoyl CH2
phosphate CH2
synthetase I CH2
CH2 CH2NH2
2ADP + Pi (CPSI) H C NH2
H C NH2 CH2
1 COOH COOH
COOH CH2
O O Arginine
Ornithine HC
H C NH2
H2N C O P O- 2 ornithine
COOH CH
- transcarbamoylase 4
Carbamoyl O Ornithine COOH
NH2 argininosuccinase
phosphate NH2 Fumarate
C O
C O
Pi CH2 NH NH COOH
CH2 NH
CH2 C NH CH
CH2
CH2 CH2 NH
CH2 CH2
H C NH2 CH2
H C NH2 COOH
CH2
COOH
COOH 3
Citrulline argininosuccinate H C NH2
Citrulline
synthetase COOH
COOH
Argininosuccinate
ATP AMP + PPi
H2N C H
CH2
COOH
Aspartate
June 26, 2012 Total slide : 50 20

21. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
The urea cycle
HCO3- 2 ATP 2 ADP + Pi
carbamoyl mitochondria
O O
phosphate
NH4+ H2N-C-O-P-O-
O-
citrulline
ornithine NH3+ Pi O NH3+
H2N-CH2CH2CH2CH-CO2- H2N-C-NH-CH2CH2CH2CH-CO2-
cytosol ATP CO2- Asp
O
H2N-C-NH2
-
O2C-CH2CH-NH3+
AMP + PPi
urea
CO2- NH2+ NH3+
H2O -
O2C-CH2CH-NH-C-NH-CH2CH2CH2CH-CO2-
argininosuccinate
arginine NH2+ NH3+
H2N-C-NH-CH2CH2CH2CH-CO2-
-
O2C-CH=CH-CO2- fumarate
June 26, 2012 Total slide : 50 21

22. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Incorporation of ammonia into urea begins with
formation of carbamoyl phosphate
O O
NH4+ + HCO3- H2N-C-O-P-O-
carbamoyl
O- phosphate
2 ATP 2 ADP + Pi
This occurs in the mitochondrial matrix. Carbamoyl-phosphate
synthetase-1 catalyzes the reaction in three steps, using two
molecules of ATP:
(1)
O O
carbonic-
HCO3- HO-C-O-P-O- phosphoric acid
O- anhydride
ATP ADP NH4+
(2)
Pi
ATP ADP
O O O
carbamate H2N-C-O- H2N-C-O-P-O-
(3) O-
June 26, 2012 Total slide : 50 22

23. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Carbamoyl phosphate reacts with ornithine to form
citrulline
O O NH3+
H2N-C-O-P-O- +
H3N-CH2CH2CH2CH-CO2- ornithine
O-
carbamoyl
phosphate O NH3+
Pi H2N-C-NH-CH2CH2CH2CH-CO2-
+ H+ citrulline
This step also occurs in the mitochondrial matrix.
June 26, 2012 Total slide : 50 23

24. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Combination of citrulline with aspartate to form
argininosuccinate is driven by breakdown of ATP to AMP
CO2- O NH3+
-
O2C-CH2CH-NH3+ H2N-C-NH-CH2CH2CH2CH-CO2-
ATP citrulline
aspartate
AMP + PPi + H2O
argininosuccinate
CO2- NH2+ NH3+
-
O2C-CH2CH-NH-C-NH-CH2CH2CH2CH-CO2-
This reaction occurs only in the cytosol, so citrulline first must
leave the mitochondria. A transporter exchanges ornithine for
citrulline plus a proton across the mitochondrial inner membrane.
June 26, 2012 Total slide : 50 24

25. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Argininosuccinate splits into arginine and fumarate
CO2- NH2+ NH3+
-
O2C-CH2CH-NH-C-NH-CH2CH2CH2CH-CO2-
argininosuccinate
-
O2C-CH=CH-CO2-
fumarate NH2+ NH3+
H2N-C-NH-CH2CH2CH2CH-CO2-
arginine
This reaction occurs in the cytosol.
June 26, 2012 Total slide : 50 25

26. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Hydrolysis of arginine releases urea and regenerates
ornithine
NH2+ NH3+
H2N-C-NH-CH2CH2CH2CH-CO2-
arginine
H2O
O NH3+
H2N-C-NH2 H2N-CH2-CH2-CH2-CH-CO2-
urea H+ ornithine
This reaction occurs in the cytosol. To continue the
cycle, ornithine must return to a mitochondrion.
June 26, 2012 Total slide : 50 26

27. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
HCO3- 2 ATP 2 ADP + Pi
carbamoyl
O O phosphate
NH4+ H2N-C-O-P-O-
O-
Pi citrulline
O NH3+
ornithine H2N-C-NH-CH2CH2CH2CH-CO2-
2 Pi ATP CO2-
O -
O2C-CH2CH-NH3+
H2N-C-NH2 PPi + AMP
Asp
urea H2O
CO2- NH2+ NH3+
-
O2C-CH2CH-NH-C-NH-CH2CH2CH2CH-CO2-
argininosuccinate
Formation of urea consumes 4 phosphate anhydride bonds
June 26, 2012 Total slide : 50 27

28. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Input-Output
1. NH4+ + CO2 + 2 ATP carbamoyl phosphate + 2 ADP + Pi
2. carbamoyl phosphate + ornithine citrulline + Pi
3. citrulline + aspartate + ATP argininosuccinate + AMP + PPi
4. AMP + ATP 2 ADP
5. PPi + ATP 2 ADP
6. argininosuccinate arginine + fumarate
7. arginine + H2O urea + ornithine
SUM: NH4+ + CO2 + 4 ATP + aspartate urea + fumarate + 4 ADP + 4 Pi
June 26, 2012 Total slide : 50 28

29. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
The aspartate consumed in the urea cycle can be
regenerated from the fumarate that is produced
2 ATP 2 ADP + Pi
HCO3- + carbamoyl
phosphate α-keto acids amino acids
NH4+
Pi
aspartate-
oxaloacetate
ornithine
aminotransferase
citrulline
Urea oxaloacetate
ATP
cycle
urea aspartate
AMP + PPi malate
dehydrogenase
arginine argininosuccinate NADH
malate
NAD+
fumarate
This process also uses
H2O both cytosolic and
mitochondrial enzymes
June 26, 2012 Total slide : 50 29

30. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Oxidation of malate in mitochondria generates ATP
2 e- to O2 via NADH dehydrogenase
2 ATP 2 ADP + Pi
generates ~ 2.5 ATP
HCO3- carbamoyl NADH
mitochondrion oxaloacetate
phosphate
+ NH4+ NAD
Pi
aspartate glutamate
ornithine citrulline malate
α-ketoglutarate
ornithine citrulline α-ketoglutarate glutamate
ATP
aspartate
urea
AMP + PPi
amino acids α-ketoacids
arginine argininosuccinate
malate
cytosol
fumarate H2O
NADH, NAD and oxaloacetate can’t cross the mitochondrial inner membrane, but
+
there are transporters for malate, aspartate, glutamate and α-ketoglutarate.
June 26, 2012 Total slide : 50 30

31. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Transport systems in the mitochondrial inner membrane
exchange aspartate for glutamate and a-ketoglutarate for
malate
mitochondrion
aspartate- glutamate- + H+ α-ketoglutarate malate
aspartate- glutamate- + H+ α-ketoglutarate malate
cytosol Because the Asp/Glu transporter also moves a proton across the
membrane, it can be driven by an electrochemical potential gradient.
Mutations in this transporter have been linked to autism.
June 26, 2012 Total slide : 50 31

32. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Alpha--ketoglutarate/malate and aspartate/glutamate transporters also
participate in oxidation of cytosolic NADH
mitochondrion 2 e- to electron-
transport chain
NADH NAD+
oxaloacetate
aspartate glutamate α-ketoglutarate malate
aspartate glutamate α-ketoglutarate malate
oxaloacetate
cytosol NADH NAD+
glycolysis
June 26, 2012 Total slide : 50 32

33. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Well Fed State
a.a.'s
Asp
a.a.'s αKG
urea fumarate
αKAs Glu NH+ 4
cycle
urea
OAA Mal malate
CO2 + H2O
Net: 2 NH4+ + CO2 + 4 ATP  urea + 4 ADP + 4 Pi
June 26, 2012 Total slide : 50 33

34. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Fasted State
ala
Asp
ala αKG Gluconeogenesis
urea fumarate
pyr Glu NH+4
cycle
urea
OAA malate
OAA
2 ala + CO2  1 urea + 1 glucose
Glucose
June 26, 2012 Total slide : 50 34

35. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Balancing the levels of ammonia and
aspartate for entry into urea cycle
(a) NH3 in excess (b) Aspartate in excess
NH3 NH3
NADH α-Ketoglutarate
NADH
Glutamate Glutamate α-Ketoglutarate
dehydrogenase dehydrogenase
NAD NAD
Glutamate Glutamate
Aspartate Aspartate
transaminase transaminase
Oxaloacetate Aspartate Oxaloacetate Aspartate
Citrulline Citrulline
Carbamoyl Carbamoyl
phosphate phosphate
Urea Urea
Cycle Cycle
Urea Urea
Η 2Ο Η 2Ο
June 26, 2012 Total slide : 50 35

36. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
The urea cycle is regulated in two ways
1. Allosteric activation of carbamoylphosphate synthetase-1 by N-acetylglutamate
CO2- CO2-
+
H3N C H + acetyl-CoA CH3CO-NH C H N-acetylglutamate
CH2 CH2
CH2 CoA-SH CH2
Glu
CO2- CO2-
In mammals, N-acetylGlu appears to play only a
regulatory role. Carbamoylphosphate synthetase-1
is completely inactive in its absence. A genetic
carbamoyl-
deficiency in the enzyme that forms N-acetylGlu
2 ATP 2 ADP + Pi phosphate
can cause a lethal defect in the urea cycle.
O O
NH4+ + HCO3- H2N-C-O-P-O-
O-
2. A high-protein diet or starvation leads to increased synthesis of all five
enzymes used in the urea cycle, including carbamoylphosphate synthetase-1.
Expression of the enzyme that synthesizes N-acetylglutamate also increases.
June 26, 2012 Total slide : 50 36

37. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Urea Cycle Disorders
Deficiency of any of the five enzymes in the urea cycle results in the
accumulation of ammonia and leads to encephalopathy.
Episodes of encephalopathy and associated systems are unpredictable
and, if untreated, are lethal or produce devastating neurologic sequelae
in long-term survivors.
Although these disorders do not produce liver disease, the
consequences of hyperammonemia resemble those seen in patients
with hepatic failure or in a transient interference with the urea cycle,
as seen in some forms of organic acidemias.
Investigate for hyperammonemia in any infant or child with altered
mental status
June 26, 2012 Total slide : 50 37

38. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
The urea cycle
Asterisk = N-acetyl glutamate synthetase; 1 = carbamyl phosphate
synthetase; 2 = ornithine transcarbamylase; 3 = argininosuccinate
synthetase; 4 = argininosuccinate lyase; 5 = arginase
June 26, 2012 Total slide : 50 38

39. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
UREA CYCLE DISORDERS
Disorder Deficient Enzyme Inheritance Pattern
Carbamyl phosphate Carbamyl phosphate Autosomal recessive
synthetase deficiency synthetase
Ornithine Ornithine X-linked
transcarbamylase transcarbamylase
deficiency
Citrullinemia Argininosuccinate Autosomal recessive
synthetase
Argininosuccinic aciduria Argininosuccinate lyase Autosomal recessive
Argininemia Arginase Autosomal recessive
June 26, 2012 Total slide : 50 39

40. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Case
The patient is a full-term newborn boy from a normal vaginal delivery.
The pregnancy was uncomplicated. At 36 hours the baby became
lethargic, irritable, and was hyperventilating. Over the next 24 hours
lethargy increased and progressed to coma requiring mechanical
ventilation. Hemodialysis was started at 5 days. Patient died
at one week of age.
Laboratory Results
At 36 hours arterial blood pH was 7.50 (7.35-7.45), carbon dioxide was
25 torr (35-45), and blood urea nitrogen was 2 mg/dl (5-20). Sepsis
workup was negative. On day 5 plasma ammonium was 1800 :mol/l
(<35). Plasma glutamine was 1500 :mol/l (550-650),arginine was
below normal, and citrulline undetectable. Orotic acid in the urine was
extremely elevated.
Family History
Two of the mother’s four brothers had died shortly after birth. Cause of
death was given as encephalitis.
Biochemical Basis of Disorder , same as..
Diagnosis: ornithine transcarbamoylase deficiency
June 26, 2012 Total slide : 50 40

41. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Biochemical explanations for ornithine
transcarbamoylase deficiency
Low BUN
Low blood arginine
Undetectable blood citrulline
Elevated blood ammonia
Elevated blood glutamine
Elevated orotic acid
June 26, 2012 Total slide : 50 41

42. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Urine
NH4+ + Glu  Gln urea NH2
C O
NH2
NH2 H2O
Mitochondrion C NH
5
CO2 + NH4+
Cytosol CH2 NH
CH2NH2
2 ATP carbamoyl CH2
phosphate CH2
CH2
synthetase I CH2
(CPSI) CH2NH2
ADP + Pi H C NH2
H C NH2 CH2
1 COOH COOH
COOH CH2
O O Arginine
Ornithine HC
H C NH2
H2N C O P O- 2 ornithine
COOH CH
- transcarbamoylase 4
Carbamoyl O Ornithine COOH
NH2 argininosuccinase
phosphate NH2 Fumarate
C O
C O
Pi CH2 NH NH COOH
CH2 NH
CH2 C NH CH
CH2
CH2 CH2 NH
CH2 CH2
H C NH2 CH2
H C NH2 COOH
CH2
COOH
COOH 3
Citrulline argininosuccinate H C NH2
Citrulline
synthetase COOH
COOH
Argininosuccinate
ATP AMP + PPi
H2N C H
Carbamoyl P  orotic acid CH2
COOH
Aspartate
June 26, 2012 Total slide : 50 42

43. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Carbamoyl P synthetase deficiency
June 26, 2012 Total slide : 50 43

44. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Urine
NH4+ + Glu  Gln
urea NH2
C O
NH2
NH2 H2O
Mitochondrion C NH
5
CO2 + NH4 + Cytosol CH2 NH
CH2NH2
2 ATP carbamoyl CH2
phosphate CH2
synthetase I CH2
CH2 CH2NH2
ADP + Pi (CPSI) H C NH2
H C NH2 CH2
1 COOH COOH
COOH CH2
O O Arginine
Ornithine HC
H C NH2
H2N C O P O- 2 ornithine
COOH CH
- transcarbamoylase 4
Carbamoyl O Ornithine COOH
NH2 argininosuccinase
phosphate NH2 Fumarate
C O
C O
Pi CH2 NH NH COOH
CH2 NH
CH2 C NH CH
CH2
CH2 CH2 NH
CH2 CH2
H C NH2 CH2
H C NH2 COOH
CH2
COOH
COOH 3
Citrulline argininosuccinate H C NH2
Citrulline
synthetase COOH
COOH
Argininosuccinate
ATP AMP + PPi
H2N C H
CH2
Carbamoyl P  orotic acid COOH
Aspartate
June 26, 2012 Total slide : 50 44

45. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Autism is a neurodevelopmental genetic disorder
 Deficits in verbal & nonverbal communication and social interactions
 Repetitive or stereotyped behaviors
 Incidence ~1 per 1000 people (possibly higher)
 Strong evidence for heritability
 Polygenic - between 5 & 10 genes may be involved
Single-nucleotide polymorphisms (SNPs) in the gene for a mitochondrial,
Ca2+-dependent Asp/Glu exchanger increase the risk by a factor of 3 to 4.
This is the main form of the Asp/Glu exchanger that is expressed in the
brain. Mutations in the gene impair the urea cycle.
N. Ramoz et al., Am. J. Psychiatry 161: 662 (2004)
L. Palmieri et al., EMBO J. 20: 5060 (2001)
June 26, 2012 Total slide : 50 45

46. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Urea Cycle Disorders
(Diagnosis)
Cultured skin fibroblasts may be desirable if
prenatal diagnosis is considered in future
pregnancies.
Carbamyl phosphate synthetase I and ornithine
transcarbamylase (OTC) are not expressed in
cultured fibroblasts.
The enzymatic diagnosis of CPSD and OTCD
requires liver biopsy.
Biopsy should be done when establishing the
diagnosis of the first case in a family.
June 26, 2012 Total slide : 50 46

47. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Urea Cycle Disorders
(Treatment)
Once hyperammonemia is demonstrated in an infant,
protein-containing feedings should be discontinued
immediately,
appropriate supportive care, (mechanical ventilation)
Maximal calories should be provided in the form of
intravenous glucose and lipids in an effort to reduce
catabolism.
Plans should be immediately made to initiate hemodialysis
in infants who are encephalopathic and have plasma
ammonia levels over 10 times the upper limit of normal.
June 26, 2012 Total slide : 50 47

48. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Urea Cycle Disorders
(Treatment)
Maintenance therapy
dietary protein restriction+supplementation with citrulline or
arginine+ the use of drugs
The primary drug now used( provides an alternate pathway
for waste nitrogen excretion) for maintenance therapy in
patients with urea cycle disorders is sodium
phenylbutyrate (Buphenyl).
The drug is typically administered four times a day in a
dose of 0.4 to 0.6 g/kg/day. It is supplied as a powder,
which can be mixed with food or formula, or as a tablet.
June 26, 2012 Total slide : 50 48

49. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Urea Cycle Disorders
(Treatment)
Liver transplantation for
Severe neonatal OTC and CPS deficiency.
Liver failure and cirrhosis in ASL deficiency.
Failed medical-pharmacologic treatment.
Pretransplant care by
aggressively managing intercurrent hyperammonemia,
vaccinations and prophylaxis are given against
infectious
appropriate caloric intake
Gene replacement
June 26, 2012 Total slide : 50 49

50. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
Genetic deficiencies in some of the urea-cycle enzymes can be
treated pharmacologically
CO2-
benzoate CO2- phenylacetate
ATP + CoA-SH ATP + CoA-SH
AMP + PPi AMP + PPi
O
S-CoA S-
benzoyl-CoA CoA
O phenylacetyl-CoA
glycine glutamine
CoA-SH O CoA-SH
H
N CO2-
N CO2 -
phenylacetyl-
hippurate H
O glutamine
(benzoylglycine)
O
NH2
The amide products of these reactions (hippurate and phenylacetylglutamine) are excreted in the
urine. Replenishing the Gly or Gln removes ammonia.
June 26, 2012 Total slide : 50 50

51. Metabolic & Molecular Basis of Inherited Disease Metabolic Disorders of
Urea Cycle
THE END