Guide,

INTRODUCTION
z
 Living organism excretes the excess of nitrogen arising from the metabolic
break down of amino acid .

 Many aquatic animals simply excrete ammonia. In the other way birds and
some terrestrial reptiles excretes ammonia which convert into less toxic waste
product called Uric acid.

 Urea cycle was out lined in 1932 by “Hans krebs” and “kurt Henseleit”. It is
first known as ‘metabolic cycle’.
 Enzymes involved in the urea cycle

 Carbamoyl phosphate synthetase (CPS)

 Ornithine transcarbamoylase (OTC)

 Argininosccinate synthetase

 Argininosuccinase

 Arginase release urea

0verview of the urea cycle
 Regulation of the Urea Cycle

 Short-term regulation of the cycle occurs principally at Carbamoyl Phosphate

Synthetase-I,
 which is inactive in the absence of its obligate activator N-acetylglutamate in
the steady-state concentration of N-acetylglutamate is set by the concentration
of its components acetyl-CoA and glutamate and by arginine, positive
allosteric effector of N-acetylglutamate synthase.
 Urea Cycle Disorders (UCDs)

 A complete lack of any one of the enzymes of the urea cycle will result in death
shortly after birth.
However, deficiencies in each of the enzymes of the urea cycle, including N-
acetylglutamate synthase. A common thread to most UCDs is hyperammonemia
leading to ammonia intoxication
 The most dramatic presentation of UCD symptoms occurs in neonates
between 24 and 48 hours after birth. Afflicted infants exhibit progressively
deteriorating symptoms due to the elevated ammonium levels.

 When making a diagnosis of neonatal UCD based upon presenting symptoms and
observed hyperammonemia
Defficiency of Urea cycle enzymes

N-acetylglutamate synthase deficiency:

 Deficiency or genetic mutation of enzyme (autosomal recessive) → urea cycle
failure.
 A severe neonatal disorder with fatal consequences, if not detected immediately upon
birth.
 Early symptoms include lethargy, vomiting, and deep coma.
 Treatment with structural analog N-carbamoyl-L-glutamate – activates CPS-I,
mitigates the intensity of the disorder :

Carbamoyl phosphate synthetase (CPS I) deficiency

 autosomal recessive metabolic disorder, associated with mental retardation and

developmental delay.
 Hyperammonemia has been observed in 0 – 50% of normal level of CPS-I
synthesis in the liver.
 Treatment with benzoate and phenylacetate → hippurate and Phe-Ac-Gln are
excreted in the urine:
 Ornithine transcarbamoylase (OTC) deficiency
 The most common urea cycle disorder, resulting in a mutated and ineffective form of
the enzyme.
 X-linked recessive disorder caused by a number of different mutations in the OTC
gene – males are generally more seriously affected than females (males are
asymptomatic as heterozygotes).

Argininosuccinate lyase deficiency (argininosuccinate aciduria)

Rare autosomal recessive disorder, argininosuccinate is excreted large amount in urine
 The severity of symptoms varies greatly, it is hard to evaluate the effect of therapy –
useful is dietary restriction of nitrogen.
Arginase deficiency (argininemia).
 Accumulation and excretion of arginine in urine and arginine precursors and products of
arginine metabolism.
 Therapy – low nitrogen compounds diet (including essential aminoacids
 Summary
 As we came to known about 80% of the excreated nitrogen in the form of
urea which produced exclusively in the liver

 In a series of reaction that are distributed between the mitochondrial matrix

and the cystol .Hence the reaction is called Urea cycle.

 The urea cycle disorder caused by the deficiency in the particular enzyme.

 The urea cycle reaction and their metabolic regulation are follows protein
breakdown is cleaved by the cystotic enzymes.The new urea cycle residue is
built on the ornithine, regeneration and pre-petuating the cycle.
 References
 Donald voet, JudithG, voet. Gharlert e w. Pralte. Text book of
Principle of biochemistry 2013 Fourt edition. International student
version

 Chatlerjee MN & Rana shinde 2007 Textbook of biochemistry 7th

Jaypee brwthers medical publisher (p) New Delhi

 Jain J.H, Sunjay Jain & Nithin Jain 2004 Fundamental of biochemistry
2, Eterliser S.Chandh & company Ltd . Ram nagar .New Delhi 1110055

 Satyanarayana v. 2005 biochemistry 2nd roal books & Allies (P)Ltd

kolkatta India.

 Robert yaskshi 1996 biochemistry, A Division of Itarcort bore &

Company.