Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 22 Ammonia 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.
Learning Objectives
? Ammonia metabolism
? Ammonia Intoxication
? Biosynthesis of Urea cycle
? Disorders related to Urea cycle
Introduction
? Ammonia is produced by all tissues during the metabolism of variety
of compounds and is it disposed by formation of urea in the liver
? Blood ammonia level must be low because even slight elevation
leads hyperammonemia (toxic to CNS).
? Normal blood ammonia is 30-60M
? Therefore, mechanism required for transport of nitrogen from
peripheral tissues to liver for disposal as urea
Sources/Formation of Ammonia
From glutamine
? Catabolism of branched-chain aa in skeletal
muscle
? This glutamine is taken up by cells of intestine,
liver , and kidney
? Liver and kidneys generate ammonia from
glutamine by glutaminase and glutamate Fig 19.17. Lippincott's Illustrated Reviews, Biochemistry, 6th Ed
dehydrogenase
Cont--
? In kidneys, most of this ammonia is excreted into urine as NH4+,
provides an important mechanism for maintaining body's acid?base
balance through excretion of protons
? In liver, ammonia is detoxified to urea and excreted
From bacterial action in intestine
? Ammonia is formed from urea by bacterial urease in lumen of
intestine
? This ammonia is absorbed from intestine by way of portal vein, and
all is removed by liver via conversion to urea
Cont--
From amines
Amines obtained from the diet and monoamines that serve as
hormones or neurotransmitters give rise to ammonia by the
action of monoamine oxidase
From purines and pyrimidines
In the catabolism of purines and pyrimidines, amino groups
attached to the ring atoms are released as ammonia
Glutamine Transport Ammonia in Bloodstream
? Free ammonia produced in tissues is
combined with glutamate to yield
glutamine by glutamine synthetase
and it requires ATP
? Glutamate and ATP react to form
ADP and -glutamyl phosphate
intermediate which reacts with
ammonia to produce glutamine and
inorganic phosphate (Pi).
Fig18.8: Lehninger Principles of Biochemistry by David L Nelson
Cont--
? Glutamine is a nontoxic transport form of ammonia
? In microorganisms, the glutamine synthetase serves as an
essential portal for the entry of fixed nitrogen into biological
systems
Glucose-Alanine Cycle: Alanine transport ammonia from skeletal muscle to liver
Two mechanisms are available in humans for
transport of ammonia from peripheral tissues to
liver for its ultimate conversion to urea
1) Combine ammonia with glutamate to form
glutamine (nontoxic transport form of
ammonia) by glutamine synthetase
? Glutamine is transported in the blood to the
liver where it is cleaved by glutaminase to
produce glutamate and free ammonia which is
converted to urea
Fig 19.13. Alanine serves as a carrier of ammonia and of the carbon skeleton of
pyruvate from skeletal muscle to liver. The ammonia is excreted and the pyruvate
is used to produce glucose, which is returned to the muscle.
Lippincott's Illustrated Reviews, Biochemistry, 6th Ed
2) Formation of alanine by transamination of pyruvate produced
from both aerobic glycolysis and metabolism of succinyl CoA
generated by catabolism of branched-chain aa isoleucine and
valine
? Alanine is transported by blood to liver, where it is converted to
pyruvate by transamination
? Pyruvate is used to synthesize glucose, which can enter blood
and be used by muscle
Ammonia Metabolism
? Formation of urea in the liver is
quantitatively the most important
disposal route for ammonia
? Urea travels in blood from liver to
kidneys, where it passes into the
glomerular filtrate
? Glutamine provides a nontoxic storage
and transport form of ammonia
Fig 19.19. Lippincott's Illustrated Reviews, Biochemistry, 6th Ed
Cont-
? The ATP-requiring formation of glutamine from glutamate and
ammonia by glutamine synthetase occurs in skeletal muscle
and liver
? Its imp. in central nervous system (CNS), where it is major
mechanism for removal of ammonia in the brain
Ammonia Intoxication
? Ammonia produced by enteric bacteria and absorbed into portal
venous blood and ammonia produced by tissues are rapidly
removed from circulation by liver and converted to urea
? Only traces (10-20 g/dL) normally are present in peripheral
blood
? This is essential, since ammonia is toxic to CNS
? Should portal blood bypass liver, systemic blood ammonia may
attain toxic levels
Cont--
? This occurs in severely impaired hepatic function or development of
collateral links between portal and systemic veins in cirrhosis
? Symptoms of ammonia intoxication include tremor, slurred speech,
blurred vision, coma, and ultimately death
? Ammonia may be toxic to brain in part because it reacts with -
ketoglutarate to form glutamate
? Resulting depletion of levels of -ketoglutarate then impairs function
of tricarboxylic acid (TCA) cycle in neurons.
Cont--
Hyperammonemia: Elevated levels of ammonia in blood cause
symptoms of ammonia intoxication, which include tremor, slurring
of speech, and blurring of vision
? High levels result in coma and death
? There are two types of conditions: Acquired and Hereditary
Cont--
Acquired: Cirrhosis of liver may result in formation of collateral
circulation around liver
? As a result, portal blood is shunted directly into systemic
circulation and does not have access to liver
? Therefore, conversion of ammonia to urea is severely impaired,
leading to elevated levels of ammonia.
Cont--
Hereditary: Genetic deficiency of each of five enzymes in urea cycle
pathway
? X-linked ornithine transcarbamoylase/ornithine carbomyl transferase
deficiency is common of these disorders
? In each case, failure to synthesize urea leads to hyperammonemia
during first weeks of birth
? Treatment included restriction of dietary protein in presence of
sufficient calories to prevent catabolism
Urea Cycle
Introduction
? Urea is major disposal form of amino groups derived from aa.
? It accounts for about 86-90% of the nitrogen containing
components of the urine
? One nitrogen group of urea is supplied by free NH and the
3
other nitrogen from aspartate
Cont--
? Glutamate is the immediate precursor of both ammonia groups
by the 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.
Urea Biosynthesis
? Synthesis of 1 mol of urea
requires 3 mol of ATP, 1 mol
each of NH + and of aspartate,
This enz def. leads to hyperargininaemia
4
and five enzymes
CPS-1 def. leads to
Hyperammonemia
type I
This enz def. leads to Hyperammonemia
type II
? Of the six participating aa, N-
This enz def. leads to arginosuccinate
aciduria
acetylglutamate as an enzyme
activator, others serve as
This enz def. leads to citrullinemia
carriers of atoms that become
urea
Fig 28.16. Harper's Illustrated Biochemistry 30th Edition
Cont--
? While ammonium ion, CO2, ATP, and aspartate are consumed,
the 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 the
kidneys
? The enzymes of the urea cycle are induced if a high-protein diet
is consumed for several days
? When the nitrogen of aa is converted to urea in the liver, their
carbon skeletons are converted either to glucose (in the fasting
state) or to fatty acids (in the fed state)
Regulation of the 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 the urea cycle
Fig18.13: Lehninger Principles of Biochemistry by David L Nelson
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
the 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: The metabolic defect is in
argininosuccinate lyase
? Elevated levels of argininosuccinate in blood, CSF, and urine, is
associated with friable, tufted hair.
? Diagnosis by the measurement of erythrocyte argininosuccinate
lyase activity can be performed on umbilical cord blood or
amniotic fluid cells
Hyperargininemia: is an autosomal recessive defect in the 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 the enzymes of the
urea cycle is an area of active investigation
? Animal models using an adenoviral vector to treat citrullinemia
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
32
Group Discussion
? Subtopics of previous and today's class discussed in groups.
Thank you
This post was last modified on 05 April 2022