Ureacycle Conversion

O
H 2N C NH2
urea
Urea cycle
Dr. N. Sivaranjani
Asst. Prof.
Dr. N. Sivaranjani 1
Transport of Ammonia
* Ammonia is produced in most tissues – less than 1% is TOXIC
especially to CNS pKa = 9.3
Readily ionizes to ammonium ion NH4 +
NH4+ NH3 + H+
* It is immediately removed from the circulation and detoxified to

Urea in the LIVER.
* Three transport forms of NH3 from peripheral tissues to LIVER:

1. Glutamate – ALL tissues
2. Glutamine – Brain
3. Alanine - MuscleDr. N. Sivaranjani 3
Brain
Liver
Glutamine synthetase
COO-
COO- Mitochondria COO-
CH NH3+ NH3
Glutaminase
H2O CH CH NH3+
NH3+
CH2
CH2 CH2
CH2
CH2 CH2
ATP ADP+Pi NH3
COO-
CO-- NH2 COO-
Urea
Glutamate Glutamine Glutamate
cycle
Glutamine is a non-toxic carrier of ammonia from Brain . It is released into

blood circulation and carried to liver.
Glucose-Alanine cycle
• Glucose Alanine Cycle / Cahill
Cycle
Plays a dual role :
• Transports ammonia from

muscle to liver in a non-toxic
form (Alanine)
• Transports carbon skeleton to

liver for gluconeogenesis
Alanine is safe way to transport ammonia from muscle to liver via blood.
G All cells
L Liver
U
Amino acids T Glutamate dehydrogenase
A
Transamination M α Keto glutarate
A
T
E NH3
Glutamate Aspartate
NH3 Glutamine synthetase
Muscle Brain
Glutamine Aspargine
Alanine
Glutaminase Glutamate
Aspartate
Pyruvate
Liver
NH3 Liver
Urea
G All cells
L Liver
U Glutamate dehydrogenase
Amino acids T
A
Transamination α Keto glutarate
M
A
T NH3
E
Glutamate Aspartate
Glutamine synthetase
Muscle Brain
Glutamine Aspargine
Alanine
Glutaminase Glutamate
Aspartate
Pyruvate
Liver
NH3 Liver
Urea
Sources of Ammonia
Purine
Pyrimidine
GLUTAMATE Catabolism
Oxidative
Deamination GDH
Serine Threonine Histidine

NH4+
GLUTAMINE Glutamate
Pyruvate α KB Urocanate
ASPARGINE Aspartate
Non Oxidative Deamination
Oxidation of Monoamine
Bacterial
by MAO
Intestine degradation
Amino Sugars of Urea
Biochemical basis of Ammonia toxicity
• In Brain cell Mitochondria – excess NH3 reacts with αKG to

form GLUTAMATE by GDH – dec. αKG – dec. TCA cycle- dec.
Glucose utilization & ATP generation. not universally
accepted.
 Glutamate depletion – NH3 Inhibits glutaminase – depletes

glutamate which is a excitatory NT.
Glutamine is accumulated in neurons – osmotic shift of H2O
into the cell- Edema & swelling of Astrocytes.
 Neuronal dysfunction – inc.
permeability of K+ & Cl- ions
 Accumulation of Excito-
toxins – inc. transport of
Tryptophan across BBB – its
Metabolites are accumulated
– which are Excito-toxins.
Excretory forms of Nitrogen
The basic features of
nitrogen metabolism
were elucidated
initially in pigeons
Mammals including
human beings
Urea cycle
Krebs–Henseleit urea cycle / Ornithine cycle

Site – LIVER
Subcellular organelle – Mitochondria , cytoplasm – 2 steps occur in
mitochondria, remaining in the cytosol.
Converts NH3 into harmless Urea
• Disposable form of NH3
UREA
• Accounts for 90% of NPN in Urine
• 1 N – Ammonia
• 2 N – Aspartate
• C & O – CO2
NH3 + CO2 + H2O
Transporter 2 ATP
2 ADP + Pi
Carbamoyl PO4 synthetase I
Ornithine Trans Carbamoylase Carbamoyl Phosphate

H3N-CO-O-PO3
Argininosuccinate synthetase
Argininosuccinate lyase Citrulline Aspartate
Ornithine
Arginase
H2N-CO-NH2 UREA Cytosol
H2O Argininosuccinate
Significance Of Urea Cycle
2 N of urea ( H2N-CO-NH2) – NH3 , amino N of Aspartate
Disposes 2 waste products – NH3, HCO3-
Arginase E – only in LIVER
Forms SEAA – Arginine
Ornithine is regenerated – Polyamine syn. , NEAA syn. - proline
Fumarate is the link b/w UREA & TCA cycle – Kreb’s bi cycle
Relationship b/w Urea cycle & TCA cycle
Fumarate Arginine
Urea
Malate
TCA Arginino Urea Ornithine

cycle Succinate cycle
Carbamoyl PO4
Oxaloacetate
Aspartate Citrulline
α-amino acid
α-keto acid
Difference b/w CPS 1 and CPS 11
CPS -I CPS-II
Location Mitochondria Cytosol
Nitrogen donor NH3 Glutamine
Pyrimidine
Participates Urea Cycle
Biosynthesis
Activated – NAG
Regulated (N-Acetyl glutamate) Inhibited - CTP
Over all reaction
NH3 + CO2 + Aspartate + 3 ATP
UREA
Energetics of Urea Cycle
2 ATP 2 ATP TCA cycle

Via Fumarate
• Reaction 1 • Reaction 3
Malate – OAA
1 NADH=3ATP
4 ATP (UREA CYCLE) – 3 ATP (TCA CYCLE) = 1 ATP

Regulation
• Feed forward mechanism / Coarse regulation –

regulated by substrate availability
 High PROTEIN diet – induces CPS-I
 Prolonged starvation – inc. Catabolism of proteins -
induces GDH- inc. NH3 – urea cycle.
* Allosteric mechanism – CPS -I stimulated by N-Acetyl

Glutamate (NAG)
Allosteric Mechanism
Glutamate + Acetyl - CoA

Acetyl
Glutamate
synthase
+
CPS – I of
High protein diet, N-Acetyl Glutamate +
Urea Cycle
Glutamate ,
Arginine,
Prolonged Starvation Dr. N. Sivaranjani 21
Fate of UREA
Disorders of UREA cycle
• Genetic defect have been described in all enzymes of urea
cycle - results in ammonia intoxication
• These are extremely rare – 1 in 30,000 live births
• Autosomal Recessive , except OTC defect – X linked
• Defect in reaction 1 and 2 – accumulation of Ammonia directly
• Defect of later enzymes - accumulation of intermediates
 Common features seen are – severity varies
 Feeding difficulties , Lethargy , irritability ,

protein induced vomiting and poor intellectual
development – MR ,cerebral edema, seizures
 leads to COMA and death
Disorders Defective Products Clinical features
Enzyme Accumulated
Hyperammonaemia CPS – I Ammonia Severe hyperammonemia

type – I Mental retardation ,
developmental delay
Variant of N acetyl Ammonia Neonatal Hyperammonemia –

hyperammonemia glutamate Fatal.
type I synthase Rx -N-carbamoyl-L-glutamate
– activates CPS-I
Hyperammonaemia OTC , X- Ammonia Orotic aciduria -channeling of

type – II linked CP to Pyrimidine syn.
Disorders Defective Enzyme Products Clinical features
Accumulated
Hyperornithinemia Defective ornithine Ornithine & NH3 HHH syndrome -
transporter protein. Hyperornithinemia,
ORNT1 gene defect. hyperammonemia &
homocitrullinuria - carbamoylates
lysine
Citrullinemia Argino - succinate Citrulline Citrullinuria,

syntethase breast milk is to be avoided
Argininosuccinic Argininoauccinate Argininosuccinate Metabolic acidosis,

aciduria Lyase Friable brittle
tufted hair - Trichorrhexis
Nodosa
Argininemia Arginase Arginine Instead of arginine, Cysteine &

inc. - CSF. lysine are lost in urine.
Hepatic Coma (Acquired Hyperammonemia)
Portal systemic Encephalopathy
/ Hepatic encephalopathy
Hepatic failure –finally lead to
hepatic coma and death
Hyperammonemia –
characteristic feature of liver
failure
C/F - Altered sensorium,

convulsions, ascites, jaundice,
hepatomegaly, cerebral edema, Urine
hemorrhage, spider naevi. Dr. N. Sivaranjani 27
Treatment
• Dietary restriction of protein – Mainstay of management
Replacement of EAA by their corresponding α-Keto acids –
dec. N disposal – without causing EAA deficiencies.
• Maximal calories should be provided in the form of I.V glucose
& lipids to reduce catabolism.
• Promote N excretion in forms other than Urea

Block due to Argininosuccinate lyase defect – supplement
Arginine diet – Argininosuccinate is excreted.
First 2 blocks – supplement diet with Benzoate & Phenylacetate

Citrulline Aspartate
Ornithine Argininosuccinate
Urea
Arginine Arginine supplements
Treatment for first 2 defects

 Benzyl CoA + Glycine = Hippuric acid Excreted in URINE
 Phenylacetyl CoA + Glutamine = Phenylaceylglutamine

Treatment
• Gene therapy is in experimental stage
• Neonatal Hyperammonaemia – Medical emergency

- requires rapid lowering of NH3
- Hemodilaysis ,
- Exchange Transfusion ,
- Peritoneal dialysis
• Hepatic Encepahalopathy
- sterilization of Gut – Lactulose laxative
- liver transplantation
- Treat the underlying cause.

Ureacycle Conversion

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O

* It is immediately removed from the circulation and detoxified to

* Three transport forms of NH3 from peripheral tissues to LIVER:

Glutamine is a non-toxic carrier of ammonia from Brain . It is released into

Plays a dual role :

• Transports ammonia from

• Transports carbon skeleton to

Serine Threonine Histidine

• In Brain cell Mitochondria – excess NH3 reacts with αKG to

 Glutamate depletion – NH3 Inhibits glutaminase – depletes

Krebs–Henseleit urea cycle / Ornithine cycle

Ornithine Trans Carbamoylase Carbamoyl Phosphate

H2N-CO-NH2 UREA Cytosol

Disposes 2 waste products – NH3, HCO3-

Arginase E – only in LIVER

Forms SEAA – Arginine

Ornithine is regenerated – Polyamine syn. , NEAA syn. - proline

TCA Arginino Urea Ornithine

NH3 + CO2 + Aspartate + 3 ATP

2 ATP 2 ATP TCA cycle

4 ATP (UREA CYCLE) – 3 ATP (TCA CYCLE) = 1 ATP

• Feed forward mechanism / Coarse regulation –

* Allosteric mechanism – CPS -I stimulated by N-Acetyl

Glutamate + Acetyl - CoA

• These are extremely rare – 1 in 30,000 live births

• Autosomal Recessive , except OTC defect – X linked

• Defect in reaction 1 and 2 – accumulation of Ammonia directly

• Defect of later enzymes - accumulation of intermediates

 Feeding difficulties , Lethargy , irritability ,

Hyperammonaemia CPS – I Ammonia Severe hyperammonemia

Variant of N acetyl Ammonia Neonatal Hyperammonemia –

Hyperammonaemia OTC , X- Ammonia Orotic aciduria -channeling of

Citrullinemia Argino - succinate Citrulline Citrullinuria,

Argininosuccinic Argininoauccinate Argininosuccinate Metabolic acidosis,

Argininemia Arginase Arginine Instead of arginine, Cysteine &

C/F - Altered sensorium,

• Promote N excretion in forms other than Urea

First 2 blocks – supplement diet with Benzoate & Phenylacetate

Arginine Arginine supplements

Treatment for first 2 defects

 Phenylacetyl CoA + Glutamine = Phenylaceylglutamine

• Neonatal Hyperammonaemia – Medical emergency

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