NETAJI SUBHAS CHANDRA BOSE INSTITUTE OF PHARMACY

Tatla, Roypara, Chakdaha, Dist. Nadia, PIN 741222, W.B.Affiliated to

MAULANA ABUL KALAM AZAD UNIVERSITY OF TECHNOLOGY (MAKAUT)BF 142, Sector 1, Salt Lake City, Kolkata 700064, West Bengal

INTRODUCTION:

Urea cycle is the first metabolic cycle to be elucidated.

The cycle is known as Krebs-Henseleit Urea cycle.

Ornithine is the first member of the reaction, it is also called as Ornithine cycle.

Urea is the major end product of protein metabolism (amino acid metabolism) in

humans and mammals.

Urea has two amino (-NH2) groups, one derived from NH3 and the other from

aspartate.

Urea is synthesized in the liver.

Than secreted into blood stream.

And taken up by the kidneys for excretion in the urine.

Urea synthesis is a five step cyclic process, with five distinct enzymes.

The first two enzymes are present in mitochondria while the rest are localized in

cytosol.

CHARACTERISTICS:

Urea is the major disposal form of amino groups.

It accounts for 90% of the nitrogen containing components of urine.

The urea cycle is the sole source of endogenous production of arginine.

Urea formation takes place in liver.

Urea excretion occurs through kidney.

SYNTHESIS:

STEP I: - Formation of carbamoyl phosphate

CO2 + NH4 + 2 ATP Carbamoyl Phosphate + 2ADP + 2Pi

Carbamoyl Phosphate Synthase-I

N-Acetyl Glutamic acid

STEP II: - Formation of citrulline

Ornithine + Carbamoyl Phosphate Citrulline + PiOrnithine Transcarbamoylase

STEP III: - Formation of Arginosuccinate

Citrulline + Aspartate + ATPArginosuccinate synthase

Arginosuccinate + AMP + PPi

STEP IV: - Formation of Arginine

STEP V: - Formation of Urea

Arginosuccinate Arginine + FumarateArginosuccinase

Arginine + H2OArginase

Urea + Ornithine

This Ornithine again bind with Carbamoyl Phosphate to form Citrulline. That’s why it is a cyclic process.

Overall reaction and energetic:

The urea cycle is irreversible and consumes 4 ATP. Two ATP are utilized for the synthesis of

carbamoyl phosphate. One ATP is converted to AMP and PPi to produce arginosuccinate which

equals to 2 ATP. Hence 4 ATP are actually consumed.

Regulation of Urea Cycle: -

Carbamoyl phosphate synthase (CPS-I) is rate limiting enzyme in Urea cycle.

CPS–I is allosterically activated by N–acetylglutamate (NAG).

It is synthesized from glutamate and acetyl CoA by synthase and degraded by a hyrolase.

The rate of Urea synthesis in liver is correlated with the concentration of N–acetylglutamate.

Formation and degradation of N-acetylglutamate

Interrelation between Urea cycle and TCA cycle: -

Metabolic disorders of Urea cycle: -

Disorders Defective Enzymes Product accumulated

Hyperammonemia-I Carbamoyl Phosphate Synthase-I

Ammonia

Hyperammonemia-II Ornithine Transcarbamoylase Ammonia

Citrullinemia Arginosuccinate Synthase Citrulline

Arginosuccinic aciduria Arginase Arginosuccinate

Argininemia Arginase Arginine

Blood Urea Significance: -

Normal blood Urea concentration is 10-40 mg/dl.

About 15-30 gm of Urea (7-15 gm nitrogen) is excreted in Urine per day.

Blood Urea estimation is a screening test for the evaluation of kidney(renal) function.

Elevation in blood Urea may be broadly classified into three categories.

Blood Urea Significance (continued): -

Renal:

In renal disorders like acute glomerulonephritis, chronic nephritis, nephrosclerosis, polycystic

kidey, blood Urea is increased.

Post-renal:

Due to obstruction in the Urinary tract (e.g. tumors, stones, enlargement of prostate gland

etc.) blood Urea is elevated.

This is due to increased reabsorption of Urea from the tubules.

Pre-renal:

This is associated with increased protein breakdown, leading to a negative nitrogen balance.

Observed after major surgery, prolonged fever, diabetic coma, thyrotoxicosis etc.

In leukemia & bleeding disorders also, blood Urea is elevated.

REFERENCES

1. Book of Biochemistry, by U. Satyanarayana & U. Chakrapani, Third

Edition, Page no. 337-341.

2. www.slideshare.net

3. www.fppt.com