Disposal of Nitrogen

Intro

Aminoacids cannot be stored in the body

It is synthesized, taken in diet or obtained
from degradation of protein
Any amino acids in excess of the biosynthetic
needs is rapidly degraded.
 Catabolism occurs in sequence:
1. Transamination and Deamination

2. Formation of Urea

3. Oxidation of Carbon skeleton via TCA cycle

Protein Turnover

Proteins are constantly synthesized and

degraded
1. Rate of Turnover:

300-400g of protein/day

Short- lived Proteins

Long lived Proteins

 2. Protein Degradation
A. Ubiquitin Mediated Degradation
B. Lysosomal degradation
Disposal of Ammonia-Urea Cycle

Transport of Ammonia to Liver

There are two mechanisms
1. Formation of Glutamine (Most Peripheral tissues)
Glucose- Alanine Cycle (Muscle)
Urea Cycle

Kidney glutaminase was responsible for the

formation of ammonia
However, about 80% of the excreted nitrogen
is in the form of urea which is also largely
made in the liver, in a series of reactions that
are distributed between the mitochondrial
matrix and the cytosol.
The series of reactions that form urea is
known as the Urea Cycle or the Krebs-
Henseleit Cycle.
Key Features

Arginine from the diet or from protein

breakdown is cleaved by the cytosolic
enzyme arginase, generating urea and
ornithine
In subsequent reactions of the urea cycle a
new urea residue is built on the ornithine,
regenerating arginine and perpetuating the
cycle
Regulation

Regulated at Gene level

1. High Protein Diet
2. Low Protein Diet
Short term Regulation
Regulatory Enzyme is CPS-I
Activated by N-Acetyl Glutamate, allosteric activator
Acetyl CoA + Glutamate
N-Acetyl Glutamate
 UCDs
Type I Carbamoyl with 24h - 72h after birth infant
Hyperammonemi phosph becomes lethargic, needs
a ate stimulation to feed, vomiting,
synthet increasing lethargy, hypothermia
ase I and hyperventilation; without
measurement of serum ammonia
levels and appropriate intervention
infant will die: treament with
arginine which activates N-
acetylglutamate synthetase
N-acetylglutamate N- severe hyperammonemia, mild
synthetase acetylgl hyperammonemia associated with
Deficiency utamate deep coma, acidosis, recurrent
synthet diarrhea, ataxia, hypoglycemia,
ase hyperornithinemia: treatment
includes administration of
carbamoyl glutamate to activate
CPS I
 Type 2 Ornithine most commonly occurring UCD, only X-
Hyperammonemia transcar linked UCD, ammonia and amino
bamoyla acids elevated in serum, increased
se serum orotic acid due to
mitochondrial carbamoylphosphate
entering cytosol and being
incorporated into pyrimidine
nucleotides which leads to excess
production and consequently excess
catabolic products: treat with high
carbohydrate, low protein diet,
ammonia detoxification with sodium
phenylacetate or sodium benzoate
Classic Citrullinemia Argininosuc episodic hyperammonemia, vomiting,
cinate lethargy, ataxia, siezures, eventual
syntheta coma: treat with arginine
se administration to enhance citrulline
excretion, also with sodium benzoate
for ammonia detoxification
Argininosuccinic Argininosu episodic symptoms similar to classic
aciduria ccinate citrullinemia, elevated plasma and
lyase cerebral spinal fluid
(arginin argininosuccinate: treat with
osuccin arginine and sodium benzoate
ase)

Hyperargininemia Arginase rare UCD, progressive spastic

quadriplegia and mental
retardation, ammonia and arginine
high in cerebral spinal fluid and
serum, arginine, lysine and
ornithine high in urine: treatment
includes diet of essential amino
acids excluding arginine, low
protein diet
Significance of Urea Cycle

Detoxication of Ammonia

Biosynthesis of Arginine
Ammonia and Neurotoxicity

Ammonia is converted to Glutamate by

Glutamate dehydrogenase
Depletion of Alpha-KG
Disturbance in the TCA cycle
Increased glutamate forms glutamine
Neural glutamine concentration leads to
cerebral edema.
Clinical Significance of Urea

Average Excretion of Nitrogen/day by an

healthy adult is 16.5g.

95% is excreted in Urine

5% in Feces

Normal Blood Urea Level ranges from 20-

40mg/dL
Fate of Carbomyl Phosphate

Formation of CP is committed step and

branch point in a metabolic pathway

Urea formation is restricted only to liver-

differentiated

Pyrimidine synthesis is carried out by all

tissues- undifferentiated
 In a regenerating Liver tissue
OT level decreases, AT activity increases and
CPS-II also increased
After regeneration, OT level increases and CPS-I
activity increases whereas AT and CPS-II activity
decreases
Classical example for biochemical
dedifferentiation.
Formation of Glutamine and its functions

Reservoir of Ammonia Nitrogen

Synthesized from Glutamate with the help of
Glutamine Synthetase
Synthesis takes place, Liver, Kidney, Brain
and Retina
Normal Blood level is 6-12mg/dL.
Hydrolysed by the enzyme glutaminase to
form Ammonia and Glutamate
 This reaction is specifically important in Renal
Tubular Epithelial cells

Exchanges Sodium from Sodium Chloride

Functions

1.Transamidation
Formation of Glucosamine-6-Phosphate
Formation of GMP
Formation of 5-Phosphoribosyl 1- amine
Formation of N-Formyl glycinamidine
ribonucleotide
Synthesis of Aspargine
 2. Formation of Carbomyl Phosphate
3.Role in Acid-Base Balance in Kidney
4. Role in Brain
5.Role in conjugation reaction
6. Role in cancer