Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 86 Urea Cycle And Associated Disorders Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
Urea Cycle and associated disorders
Department of Biochemistry
Specific Learning Objectives
Describe factors affecting nitrogen balance in health and disease
Explain rationale of urea cycle in ammonia excretion
List two subcellular compartments used by urea cycle
Describe reactions of Urea Cycle, including specific enzymes, input substrates
(NH4, HCO3, ornithine, and aspartate), and energy requirements
Describe urea cycle regulation by allosteric effectors, substrate availability, and
enzyme levels
Outline steps of Urea cycle and inherited disorders associated with urea cycle
Identify connections and common intermediates between Urea Cycle and TCA
cycle
Urea cycle and reactions that feed amino groups into cycle
Fig18.10: Lehninger Principles of
Biochemistry by David L Nelson,
6th Ed.
Introduction
Urea is major disposal form of amino groups derived from aa.
It accounts for about 86-90% of the nitrogen containing components of
urine
One nitrogen group of urea is supplied by free NH3 and other nitrogen
from aspartate
Cont--
Glutamate is immediate precursor of both ammonia groups by
following reactions:
Transamination: transfer of ammonia to oxaloacetate to form aspartate
transaminase (AST)
Oxidative deamination: removal of free ammonia, glutamate
dehydrogenase
Cont--
Carbon and oxygen of urea are derived from CO2
Urea is produced by Liver and then transported in blood to kidneys for
excretion in kidneys
Blood urea level is measured as blood urea nitrogen (BUN). Levels are 8-
20 mg/dl
BUN is low in liver failure and is very high in patients with renal failure in
uremia.
Nitrogen Balance
Nitrogen balance occurs when synthesis of body protein equals degradation.
Amount of nitrogen excreted in urine each day equals amount of nitrogen
ingested each day
Positive nitrogen balance occurs when synthesis of body protein excess
compare to degradation.
Less nitrogen is excreted than ingested (growth, e.g. growing infants and
children, pregnant women, tissue repair)
Cont--
Negative nitrogen balance occurs when synthesis of body protein lesser
compare to degradation.
More nitrogen is excreted than ingested (malnutrition, absence of one or
more essential aa in diet)
It occurs in injury, stress response, malnutrition of essential aa
Urea Biosynthesis
? Synthesis of 1 mol of urea requires 3
mol of ATP, 1 mol each of NH4+ and of
This enz def. leads to hyperargininaemia
aspartate, and five enzymes
CPS-1 def. leads to
Hyperammonemia
type I
This enz def. leads to Hyperammonemia
type II
? Of
six
participating
aa,
N-
This enz def. leads to arginosuccinate
acetylglutamate
as
an
enzyme
aciduria
activator, others serve as carriers of
This enz def. leads to citrullinemia
atoms that become urea
Fig 28.16. Harper's Illustrated Biochemistry 30th Edition
Cont--
While ammonium ion, CO2, ATP, and aspartate are consumed,
ornithine consumed in reaction 2 is regenerated in reaction 5
Thus is no net loss or gain of ornithine, citrulline, argininosuccinate,
or arginine
Cont--
Ammonia, which is very toxic in humans, is converted to urea, which
is nontoxic, very soluble, and readily excreted by kidneys
Enzymes of urea cycle are induced if a high-protein diet is consumed
for several days
When nitrogen of aa is converted to urea in liver, their carbon
skeletons are converted either to glucose (in fasting state) or to fatty
acids (in fed state)
Regulation of urea cycle
? Carbamoyl phosphate synthetase I (CPS-I), is
allosterically activated by N-Acetylglutamate
? Steady-state levels of N-acetylglutamate are
determined by concentrations of glutamate and
acetyl-CoA and arginine
? Arginine is an activator of N-acetylglutamate
synthase, and thus an activator of urea cycle
Fig18.13: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed.
Disorders of Urea cycle
Urea cycle disorders are characterized by hyperammonemia,
encephalopathy, and respiratory alkalosis
Deficiencies of CPS-1, ornithine carbamoyl transferase, argininosuccinate
synthase, and argininosuccinate lyase, result in accumulation of
precursors of urea, principally ammonia and glutamine
Ammonia intoxication is most severe when metabolic block occurs at
reactions 1 or 2 of urea cycle
Leads to feeding difficulties, vomiting ataxia, lethargy, irritability, poor
intellectual development
Cont--
Hyperammonemia Type I: Deficiency of CPS-1, infants die in neonatal
period
Hyperammonemia Type II: Deficiency of ornithine transcarbamoylase,
Levels of glutamine are elevated in blood, cerebrospinal fluid, and
urine, result of enhanced glutamine synthesis in response to elevated
levels of tissue ammonia
Cont--
Citrullinemia: Patients who lack detectable argininosuccinate synthase
activity, citrulline levels elevated
Plasma and cerebrospinal fluid citrulline levels are elevated, and 1 to 2
g of citrulline are excreted daily.
Cont--
Argininosuccinic aciduria: Metabolic defect is in argininosuccinate lyase
Elevated levels of argininosuccinate in blood, CSF, and urine, is
associated with friable, tufted hair.
Diagnosis by measurement of erythrocyte argininosuccinate lyase
activity can be performed on umbilical cord blood or amniotic fluid cells
Hyperargininemia: is an autosomal recessive defect in gene for
arginase
Blood and CSF levels of arginine are elevated
Urinary aa pattern, which resembles that of lysine-cystinuria may
reflect competition by arginine with lysine and cysteine for
reabsorption in renal tubule
Gene Therapy for Correcting Defects in Urea Biosynthesis:
Gene therapy for rectification of defects in enzymes of urea cycle is
an area of active investigation
Animal models using an adenoviral vector to treat citrullinemia
Links between urea cycle and citric acid cycle
Fig18.12: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed.
20
Reference Books
1) Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th
Ed
2) Biochemistry, Lippincott's Il ustrated Reviews, 6th Ed
3) Harper's Il ustrated Biochemistry-30th Ed
4) Lehninger Principles of Biochemistry-6th Ed
Two Clinical-cases discussed
Group Discussion
Subtopics of previous and today's class discussed in group
discussion.
Thank you
This post was last modified on 05 April 2022