Protein Turn Over

Protein Turn-Over &
amino-acid
catabolism
Dr. Mehwish Hamid
Protein turn over
• The amino acids are generated by the digestion of protein in the intestine the
degradation of proteins within the cell.
• Many cellular proteins are constantly degraded and resynthesized. To facilitate
this recycling, a complex system for the controlled turnover of proteins has
evolved.
• Damaged or unneeded proteins are marked for destruction by the covalent
attachment of chains of a small protein, ubiquitin.
• Proteins are degraded into amino acids and their turn over is tightly regulated
• Polyubiquitinated proteins are subsequently degraded by a large,
ATP-dependent complex called the proteasome.
• The primary uses of amino acids are as building blocks for protein and
peptide synthesis and as a source of nitrogen for the synthesis of
other amino acids and other nitrogenous compounds such as
nucleotide bases.
• Amino acids in excess of those needed for biosynthesis cannot
be stored, in contrast with fatty acids and glucose, nor are they
excreted.
• Rather, surplus amino acids are used as metabolic fuel.
• The a-amino group is removed, and the resulting carbon skeleton is converted
into a major metabolic intermediate.
• Most of the amino groups of surplus amino acids are converted into urea
through the urea cycle, whereas their carbon skeletons are transformed into
acetyl CoA, acetoacetyl CoA, pyruvate, or one of the intermediates of the citric
acid cycle.
• Hence, fatty acids, ketone bodies, and glucose can be formed from amino
acids.
• Protein digestion begins in the stomach, where the acidic
environment favors protein denaturation.
The Digestion • Protein degradation continues in the lumen of the intestine
and Absorption owing to the activity of proteolytic enzymes secreted by the
of Dietary pancreas.
Proteins • Dietary proteins are hydrolyzed to amino acids and
absorbed into the blood stream.
Cellular Protein Degradation
Cellular proteins are degraded at different rates.
• Ornithine decarboxylase has a half-life of 11 minutes.
• Hemoglobin lasts as long as a red blood cell.
• Υ-Crystallin (eye lens protein) lasts as long as the organism does.
Regulation of Protein
Turnover
How can a cell distinguish proteins that
are meant for degradation??
Ubiquitin
• Tags protein for destruction
• The –COOH terminal in gly residue in ubi
covalently attaches with the amino acid
group of Lys on a protein which needs to
be degraded.
• A large protease complex called the proteasome or the 26S
proteasome digests the ubiquitinated proteins.
• This ATP-driven multisubunit protease spares ubiq-uitin, which is then
recycled.
• The 26S proteasome is a complex of two components: a 20S
proteasome, which contains the catalytic activity, and a 19S
regulatory subunit.
Removal of Nitrogen
• The first step in amino acid degradation is the removal of the
nitrogen.
• The liver is the major site of protein degradation in mammals.
• Deamination produces α-keto acids, which are degraded to other
metabolic intermediates.
Conversion to Ammonium Ions
• α–Amino groups are converted to ammonium ions by the oxidative
deamination of glutamate.
• The a-amino group of many amino acids is transferred to a-ketoglutarate
to form glutamate, which is then oxidatively deaminated to yield
ammonium ion (NH4+).
Transamination
• Aminotransferases catalyze the transfer of an a-amino group from an
a-amino acid to an a-ketoacid. These enzymes, also called
transaminases
• Generally these enzyme funnel amino groups to α–ketoglutarate.
• Aspartate transaminase
• Alanine transaminase
• Aspartate aminotransferase, one of the most important of these
enzymes, catalyzes the transfer of the amino group of aspartate to a-
ketoglutarate.
• Alanine aminotransferase catalyzes the transfer of the amino group of

alanine to a-ketoglutarate.
Deamination
• The nitrogen atom that is transferred to a-ketoglutarate in the
transamination reaction is converted into free ammonium ion by
oxidative deamination. The reaction is catalyzed by Glutamate
dehydrogenase
• The reaction proceeds by dehydrogenation of the C-N bond, followed
by hydrolysis of the resulting Schiff base.
Deamination
• The sum of the reactions catalyzed by aminotransferases and
glutamate dehydrogenase is
• In most terrestrial vertebrates the ammonium ion is converted to

urea.
Transporting Nitrogen to Liver
• Most amino acid degradation takes place in tissues other than the liver.
• For instance, muscle uses amino acids as a source of fuel during prolonged
exercise and fasting.
• As in the liver, the first step is the removal of the nitrogen from the amino
acid. However, muscle lacks the enzymes of the urea cycle, so the nitrogen
must be released in a form that can be absorbed by the liver and converted
into urea.
• Nitrogen is transported from muscle to the liver in two principal transport
forms. Glutamate is formed by transamination reactions, but the nitrogen
is then transferred to pyruvate to form alanine, which is released into the
blood.
• The alanine cycle is used to transport nitrogen to the liver.
Alanine Cycle
Nitrogen is transported from muscle to the liver in two principal transport

forms. Glutamate is formed by transamination reactions, but the nitrogen is
then transferred to pyruvate to form alanine, which is released into the
blood. The liver takes up the alanine and converts it back into pyruvate by
transamination. The pyruvate can be used for gluconeogenesis and the
amino group eventually appears as urea. This transport is referred to as the
alanine cycle.
Urea Cycle
Link to Citric Acid Cycle
• The urea cycle is linked to the citric acid cycle: Kreb’s Bi-cycle!!
Defects in the Urea Cycle
• Inherited defects in urea cycle cause hyperammonemia which can
lead to brain damage.
Carbon Atoms of Degraded Amino Acids
• The Carbon Atoms of Degraded Amino Acids Emerge as Major
Metabolic Intermediates. Degradation of the 20 amino acids funnel
into 7 metabolic intermediates
• Of the basic set of 20 amino acids, only leucine and lysine are solely
ketogenic. Isoleucine, phenylalanine, tryptophan, and tyrosine are both
ketogenic and glucogenic. Some of their carbon atoms emerge in acetyl
CoA or acetoacetyl CoA, whereas others appear in potential precursors
of glucose.
• The other 14 amino acids are classed as solely glucogenic. This
classification is not universally accepted, because different quantitative
criteria are applied.
• Whether an amino acid is regarded as being glucogenic, ketogenic, or
both depends partly on the eye of the beholder. We will identify the
degradation pathways by the entry point into metabolism.
Fates of the Carbon Skeletons of Amino Acids. Glucogenic amino acids are shaded red, and ketogenic amino
acids are shaded yellow. Most amino acids are both glucogenic and ketogenic.
Inborn Errors in Metabolism
• Alcaptonuria is an inherited metabolic disorder caused by the
absence of homogentisate oxidase.
Tyrosinemia
• Absence of activity of fumarylacetoacetase.
• Weakness, liver damage
• Leads to mental retardation
Phenylketonuria
• Absence of phenylalanine hydroxylase activity

• Phenylketonuria is caused by an absence or deficiency of phenylalanine
hydroxylase or, more rarely, of its tetrahydrobiopterin cofactor.
Phenylalanine accumulates in all body fluids because it cannot be
converted into tyrosine.
• Normally, three-quarters of the phenylalanine is converted into tyrosine,
and the other quarter becomes incorporated into proteins. Because the
major outflow pathway is blocked in phenylketonuria, the blood level of
phenylalanine is typically at least 20-fold as high as in normal people.
Minor fates of phenylalanine in normal people, such as the formation of
phenylpyruvate, become major fates in phenylketonurics.
• Almost all untreated phenylketonurics are severely mentally retarded.
In fact, about 1% of patients in mental institutions have
phenylketonuria. The brain weight of these people is below normal,
myelination of their nerves is defective, and their reflexes are
hyperactive.
• The life expectancy of untreated phenylketonurics is drastically
shortened. Half are dead by age 20 and three-quarters by age 30. The
biochemical basis of their mental retardation is an enigma.
Inborn errors of amino acid metabolism

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Protein Turn-Over &

• Alanine aminotransferase catalyzes the transfer of the amino group of

• In most terrestrial vertebrates the ammonium ion is converted to

Nitrogen is transported from muscle to the liver in two principal transport

• Absence of phenylalanine hydroxylase activity

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