Download Metabolic fate of amino acid

METABOIC FATE OF AMINO
ACIDS
• Intracellular proteases hydrolyze internal peptide
bonds, of protein releasing peptides, which are then
degraded to free amino acids by peptidases.
• Endopeptidases cleave internal bonds, forming shorter
peptides.
• Amino peptidases and carboxy peptidases remove
amino acids sequentially from the amino acids.
• Extracellular, membrane-associated, and long-lived
intracellular proteins are degraded in cellular
organelles termed lysosomes by ATP- independent
processes.
• By contrast, degradation of abnormal and other occurs
in the cystol.
• Animals excrete nitrogen from amino acids and
other sources as one of three end products:
ammonia, uric acid, or urea.
• Teleostean fish, which are
excrete nitrogen as ammonia.
ammonotelic,
• Land animals convert nitrogen either to uric
acid
(uricotelic organisms)
or to urea
(ureotelic organisms)(Fig.11.1)
Overall amino acids metabolisms
• Urea biosynthesis is divided for discussion into 4
stages
• (1) transamination,
• (2) oxidative deamination of glutamate,
• (3) ammonia transport, and
• (4) reactions of the urea cycle.
• These areas to the overall catabolism of amino acid
nitrogen.
• Free amino acids released from dietary or intracellular
proteins are metabolized in identical ways.
• Following removal of the a -amino nitrogen by
transamination, the resulting carbon “Skeleton” is
then degraded
(1) Transamination
• Transamination interconverts a pair of amino acids and a pair
of keto acids, generally and a -amino acid and a a -keto acid
(Fig.11.2).
• While most amino acids undergo transmination, exceptions
inculde lysine, threonine, and the cyclic imino acids proline
and hydroxy proline.
• Since transminations are freely reversible, transaminases
(aminotransferases) can function both in amino acid
catabolism and biosynthesis.
• Pyridoxal phosphate resides at the catalytic site of all
transaminases.
• Alanine-pyruvate transaminase (alanine transaminase) and
glutamate a -ketoglutarate transaminase (glutamate
transaminase), present in most animals.
Transaminase Overall reaction
1. Aspartate donates its amino group, becoming the aketo acid oxaloacetate
2. a-Ketoglutarate accepts the amino group, becoming the
amino acid glutamate.
(2) Oxidative Deamination
• The a -amino groups of most amino acids
ultimately are transferred to a -ketoglutarate by
transamination, forming L-glutamate (Fig.11.3).
• Release of this nitrogen as ammonia is then
catalyzed by L- glutamate dehydrogenase that
uses either NAD+ or NADP+ as oxidant.
Oxidative deamination
(3)Ammonia Transport by L-amino acid
oxidases
• L-amnio acid oxidase is present in liver and
kideny tissue.
• These autoxidizable flavoproteins oxidize amino
acids to an a -imino acid that adds water and
decomposes to the corresponding a -keto acid
with release of ammonium ion (Fig.11.3).
• The reduced flavin is reoxidized directly by
molecular oxygen, forming hydrogen peroxide
(H2O2), which is split to O2 and H2O by the
enzyme catalase present in many tissues,
especially liver.
Ammonia transport by L-amino acid
oxidase
(4)Action of Glutamate Synthetase
• While ammonia is constantly produced in the
tissues, it is rapidly from the circulation by the liver
and converted to glutamate, glutamine, and
ultimately to urea.
• Formation of glutamine is catalyzed by glutamine
synthetase (Fig.11.5).
• Synthesis of the amide bond of glutamine is
accomplished at the expense of hydrolysis of one
equivalent of ATP to ADP and Pi.
Action of Glutamate synthetase
(5)Action of Glutaminase and
asparaginase
• Hydrolytic release of the amide nitrogen of glutamine as
ammonia, catalyzed by glutaminase, strongly favours
glutamate formation.
• Glutamine synthetase and glutaminase thus catalyze
inter conversion of free ammonium ion and glutamine
(Fig.11.6).
• An analogous reaction is catalyzed by L-asparaginase.
• These enzymes occur in liver, kidney and gills and also
in red and white muscles.
Action of Glutaminase and asparaginase
(6)Urea Synthesis
• Urea is the major end product of nitrogen
catabolism in humans.
• Urea is formed from ammonia, carbon
dioxide, and aspartate, synthesis of I mol
each of ammonium ion and the a -amino
nitrogen of aspartate.
• The biosythesis of urea involves 5 important
steps
1. Synthesis of carbomyl phosphate
Carbamoyl Phosphate Synthase
(Type I) catalyzes a three-step
reaction with carbonyl phosphate
and carbamate intermediates.
• Formation of carbamoy1 phosphate requires 2
mol of ATP
• One ATP serves as a source of phosphate.
• Conversion of the second ATP to AMP and
pyrophophate, together with the coupled
hydrolysis of pyrophophate to orthophosphate,
provides the driving force for synthesis of the
amide bond and the mixed acid anhydride bond
of carbamoy1 phosphate.
2.Synthesis of citrulline
• In the next step, carbamoy1 phosphate
donates its carbamoy1 to ornithine to form
citrulline and release phosphate in a reaction
catalyzed by ornithine transcarbamoylase, a
Mg2+ requiring enzyme.
• The citrulline thus formed leaves the
mitochondria and passes into the cytosol of
the liver cells.
3.Synthesis of arginosuccinate
• The transfer of the second amino group to citrulline
occurs by a condensation reaction between the amino
group of aspartate and the carbamoy1 carbon of
citrulline in the presence of ATP to form arginosuccinate,
catalyzed by the enzyme arginosuccinate synthetase.
• The second amino group is introduced in the form of L
aspartate, which in turn acquired it form L. glutamate by
the action of aspartate transaminase.
4.Formation of arginine
• In the next step, arginosuccinate is reversibly cleaved by
arginosuccinate lyase to form free arginate and
fumerate.
• The fumerate so formed returns to the pool of citric acid
cycle intermediates.
5. Formation of Ornithine
• In the last reaction arginase cleaves arginase to yield
urea and ornithine.
• Ornithine thus generated enters the mitochondria again
to initiate another round of urea cycle.
Overall reaction
• The overall equation of the urea cycle is
• 2NH 4+ + HCO3- + 3ATP4- + H2O
• Urea + 2AMP- + PPi3- + H+
• The urea cycle brings together two amino
and HCO3- to form a molecule of urea
which diffuses from the liver cells into the
blood thence to be excreted into the urine
by the kidneys.
• Thus the toxic ammonia is converted into
harmless urea in ureotelic animals.
• Two molecules of ATPs are required to make
carbamoy1 phosphate and
• Two more molecules of ATP is required to make
arginosuccinate.
• In these reactions ATP undergoes a pyrophosphate
cleavage to AMP and pyrophosphate, which may be
hydrolysed to yield two orthophosphates.
• Thus the ultimate cost for the formation of one
molecule of urea is four ATPs.