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
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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
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enzyme levels
Outline steps of Urea cycle and inherited disorders associated with urea cycle
Identify connections and common intermediates between Urea Cycle and TCA
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cycle
Urea cycle and reactions that feed amino groups into cycle
Fig18.10: Lehninger Principles of
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Biochemistry by David L Nelson,
6th Ed.
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IntroductionUrea is major disposal form of amino groups derived from aa.
It accounts for about 86-90% of the nitrogen containing components of
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urine
One nitrogen group of urea is supplied by free NH3 and other nitrogen
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from aspartateCont--
Glutamate is immediate precursor of both ammonia groups by
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following reactions:Transamination: transfer of ammonia to oxaloacetate to form aspartate
transaminase (AST)
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Oxidative deamination: removal of free ammonia, glutamate
dehydrogenase
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Cont--Carbon and oxygen of urea are derived from CO2
Urea is produced by Liver and then transported in blood to kidneys for
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excretion in kidneys
Blood urea level is measured as blood urea nitrogen (BUN). Levels are 8-
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20 mg/dlBUN is low in liver failure and is very high in patients with renal failure in
uremia.
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Nitrogen BalanceNitrogen balance occurs when synthesis of body protein equals degradation.
Amount of nitrogen excreted in urine each day equals amount of nitrogen
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ingested each day
Positive nitrogen balance occurs when synthesis of body protein excess
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compare to degradation.Less nitrogen is excreted than ingested (growth, e.g. growing infants and
children, pregnant women, tissue repair)
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Cont--
Negative nitrogen balance occurs when synthesis of body protein lesser
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compare to degradation.More nitrogen is excreted than ingested (malnutrition, absence of one or
more essential aa in diet)
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It occurs in injury, stress response, malnutrition of essential aa
Urea Biosynthesis
? Synthesis of 1 mol of urea requires 3
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mol of ATP, 1 mol each of NH4+ and of
This enz def. leads to hyperargininaemia
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aspartate, and five enzymesCPS-1 def. leads to
Hyperammonemia
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type I
This enz def. leads to Hyperammonemia
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type II? Of
six
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participating
aa,
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N-This enz def. leads to arginosuccinate
acetylglutamate
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as
an
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enzymeaciduria
activator, others serve as carriers of
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This enz def. leads to citrullinemia
atoms that become urea
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Fig 28.16. Harper's Illustrated Biochemistry 30th EditionCont--
While ammonium ion, CO2, ATP, and aspartate are consumed,
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ornithine consumed in reaction 2 is regenerated in reaction 5
Thus is no net loss or gain of ornithine, citrulline, argininosuccinate,
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or arginineCont--
Ammonia, which is very toxic in humans, is converted to urea, which
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is nontoxic, very soluble, and readily excreted by kidneysEnzymes of urea cycle are induced if a high-protein diet is consumed
for several days
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When nitrogen of aa is converted to urea in liver, their carbon
skeletons are converted either to glucose (in fasting state) or to fatty
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acids (in fed state)Regulation of urea cycle
? Carbamoyl phosphate synthetase I (CPS-I), is
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allosterically activated by N-Acetylglutamate
? Steady-state levels of N-acetylglutamate are
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determined by concentrations of glutamate andacetyl-CoA and arginine
? Arginine is an activator of N-acetylglutamate
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synthase, and thus an activator of urea cycle
Fig18.13: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed.
Disorders of Urea cycle
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Urea cycle disorders are characterized by hyperammonemia,
encephalopathy, and respiratory alkalosis
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Deficiencies of CPS-1, ornithine carbamoyl transferase, argininosuccinatesynthase, and argininosuccinate lyase, result in accumulation of
precursors of urea, principally ammonia and glutamine
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Ammonia intoxication is most severe when metabolic block occurs at
reactions 1 or 2 of urea cycle
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Leads to feeding difficulties, vomiting ataxia, lethargy, irritability, poorintellectual development
Cont--
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Hyperammonemia Type I: Deficiency of CPS-1, infants die in neonatal
period
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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
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levels of tissue ammonia
Cont--
Citrullinemia: Patients who lack detectable argininosuccinate synthase
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activity, citrulline levels elevated
Plasma and cerebrospinal fluid citrulline levels are elevated, and 1 to 2
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g of citrulline are excreted daily.Cont--
Argininosuccinic aciduria: Metabolic defect is in argininosuccinate lyase
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Elevated levels of argininosuccinate in blood, CSF, and urine, is
associated with friable, tufted hair.
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Diagnosis by measurement of erythrocyte argininosuccinate lyaseactivity can be performed on umbilical cord blood or amniotic fluid cells
Hyperargininemia: is an autosomal recessive defect in gene for
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arginaseBlood and CSF levels of arginine are elevated
Urinary aa pattern, which resembles that of lysine-cystinuria may
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reflect competition by arginine with lysine and cysteine for
reabsorption in renal tubule
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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
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Animal models using an adenoviral vector to treat citrullinemiaLinks between urea cycle and citric acid cycle
Fig18.12: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed.
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20Reference Books
1) Text Book of Medical Biochemistry by Chatterjee & Rana Shinde, 8th
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Ed
2) Biochemistry, Lippincott's Il ustrated Reviews, 6th Ed
3) Harper's Il ustrated Biochemistry-30th Ed
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4) Lehninger Principles of Biochemistry-6th EdTwo Clinical-cases discussed
Group Discussion
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Subtopics of previous and today's class discussed in groupdiscussion.
Thank you
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