AMINO ACID METABOLISM
Woduinndu“@gmail.com
By Wodu, Ebizimor (PhD)
Department of Biochemistry
OVERVIEW OF AMINO ACID METABOLISM
➢ All proteins are continuously synthesised and degraded at different
rates.
➢ Their degradation releases amino acids.
➢ Amino acids also come from the digestion of dietary proteins.
➢ The cellular proteins undergo continuous turnover to release amino
acids and then reutilize about 70-80% for synthesis of new proteins
and other nitrogen containing biomolecules (nucleotides, heme,
neurotransmitters, etc).
➢ Each day, humans turnover 1-2% of their total body protein,
principally muscle proteins.
➢ It is a reflection of the balance between protein synthesis and
protein degradation.
➢ Amino acids catabolism yields intermediates which serves a
variety of roles such as energy provision; synthesis of glucose, fatty
acids and ketone bodies or simply to replenish TCA cycle
intermediates.
➢ When protein intake exceeds our requirements carbohydrates and
fatty acids synthesis becomes the predominant fate.
➢ The excess amino acids (derived from dietary proteins) are not
stored but degraded.
➢ The major site of amino acid degradation in mammals is the liver
except for branched chain amino acids which are oxidised as fuels
primarily in muscle, adipose tissue, kidney and brain.
➢ The muscle generates >50% of the total body pool of free amino
acids.
Classification of Amino Acids Based on the Fate of the
Carbon Skeleton
➢ Amino acids are classified as either glycogenic, ketogenic or both.
✓ Amino acids whose carbon skeleton can be converted to glucose are
glycogenic
✓ Those which can be converted to ketone bodies or fatty acids are
ketogenic.
✓ A few amino acids are both glycogenic and ketogenic as their partial
degradation, one glycogenic products and one ketogenic products.
➢ This classification does not hold true for organisms that possess
the glyoxylate cycle.
➢ In that case there is strictly no ketogenic amino acid since they can
convert acetylCoA to glucose.
➢ Even in animal tissues, particularly liver, the enzymes of glyoxylate
cycle are expressed to some extent. Yet we still continue with this
classification despite this limitations.
Convergent Pathways of Amino Acid Catabolism
➢ A small percentage of amino acids released from proteins are
catabolised.
➢ It generally begins with a different set of enzymes for each amino
acid but some amino acids do have few shared steps, as in case of
branch chain amino acids.
➢ The degradation of amino acids yields intermediates which are
either directly fed to the Krebs cycle or after few modifications.
➢ Recall from carbohydrate metabolism that Krebs cycle is the
convergent cycle for the complete oxidation of carbon emerging
from all classes of biomolecules.
➢ The twenty amino acids are grouped according to the common
degradation product generated.
➢ intermediates are oxaloacetate, pyruvate, α-ketoglutarate, succinyl
CoA, fumarate, acetoacetate and acetylCoA.
➢ The classification is ambiguous as some amino acids are degraded
by more than one pathway which may not always end with the same
product.
➢ In addition some amino acids produce more than one product and
therefore can be placed in more than one group.
➢ The entry of amino acids into the TCA cycle is given below.
Conditions Favoring Catabolism of Amino Acids
➢ The release of amino acids from protein turnover varies considerably
depending on the situation.
✓ During normal turnover of cellular proteins, only a fraction of amino acids
are degraded.
✓ Consumption of protein rich diet enhances the rate of degradation as
excess amino acids are not stored.
✓ During starvation and uncontrolled diabetes mellitus (DM), when
carbohydrates are unavailable or improperly utilized, cellular proteins are
used as fuel.
Fate of Amino acids Catabolism in Mammals
Intracellular Proteins
Dietary Proteins
Amino Acids
Oxaloacetate
Carbon Skeleton
NH+4
Biosynthesis of
Amino acids,
Nucleotides,
Amines
Carbomyl phosphate
Urea Cycle
Urea Excretion
α- Keto acids
Citric acid Cycle
Oxaloacetate
CO2+H2O + ATP
Gluconeogenesis
Catabolism Steps of the Amino acids
➢Step1: Transport of amino acids in to the cells:
✓ The transport of amino acids occurs from the extracellular
fluids in to the cells by active transport systems, driven by the
hydrolysis of ATP.
✓ There are seven different transport systems are known for
amino acids in the cells .
➢Step 2: Transamination:
➢It is a very crucial steps of the catabolism, removing of the α-amino
group is essential for producing energy from any amino acid after
that removal of remaining carbon skeletons is being metabolized .
➢Mechanism:
✓The first step in the catabolism of most amino acids is the transfer
of their α-amino group to α-ketoglutarate .
✓The products are an α-keto acid and glutamate.
Note#: In addition to the glutamate dehydrogenase , the D- Amino acid
oxidase is an FAD-dependent peroxisomal enzyme that catalyzes the oxidative
deamination of these amino acid isomers, which are found in plants. D-Amino
acids are found in plants and in the cell walls of microorganisms.
PLP
PLP
MECHANISM OF AMINOTRANSFERASES
➢The coenzyme pyridoxal phosphate (vit B6), is linked to the ε-amino
group of lysine at the active site of the enzyme.
➢Aminotransferases transfer amino group to the pyridoxal part of the
coenzyme to generate pyridoxamine phosphate.
➢The pyridoxamine form of the coenzyme then reacts with an α-keto
acid to form an amino acid, at the same time regenerating pyridoxal
phosphate.
Important facts about Aminotransferases
➢ There are two most important aminotransferases: alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) catalyzed transamination reactions.
➢ Alanine aminotransferase (ALT) is present in many tissue. It transfer amino group of
alanine to α-ketoglutarate, resulting in the formation of pyruvate. ALT is normally found
inside liver cells .
➢ Aspartate aminotransferase (AST) is transfers amino groups from aspartate to glutamate ,
forming to oxaloacetate. AST is found in the liver, heart, skeletal muscle, kidneys, brain,
and red blood cells
➢ Both ALT and AST have lots of clinical significance . The high level of plasma concentration
indicates liver dysfunction, myocardial infarction and muscle disorders. Moreover, ALT is
more specific than AST for liver disease because normally found inside liver cells.
Step3.
Oxidative deamination:
➢The amino groups of most amino acids are ultimately funneled to
glutamate by means of transamination with α-ketoglutarate.
➢Oxidative deamination catalyzed by glutamate dehydrogenase
results in the liberation of the amino group as free ammonia from
Glutamate.
➢ The α-keto acids enter the central pathway of energy metabolism
and ammonia in urea synthesis, liberated after oxidative
deamination.
➢Glutamate is the only amino acid that undergoes oxidative
deamination, a reaction catalyzed by glutamate dehydrogenase.
➢ The glutamate dehydrogenase of mammalian liver has the unusual
capacity to use either NAD+ or NADP+ as cofactor.
Mechanism of Oxidative deamination
Mechanism of Transport of ammonia to the Liver
➢ Since the ammonia is highly toxic in nature which is liberated
through oxidative deamination, and can’t transport directly to the
liver alone.
➢ Therefore, there are two mechanisms are available in humans for
the transport of ammonia from peripheral tissues to the liver for
conversion to urea.
➢ The first: it is found in most tissues, where uses glutamine
synthetase to combine ammonia with glutamate to form Glutamine
(a nontoxic transport form of ammonia).
➢ Then the glutamine is transported from blood to the liver, where it
cleaved by Glutaminase to produce glutamate and free ammonia.
➢ The second: In form of Alanine in muscle. The transport of ammonia
in muscle pathway is called the glucose-alanine cycle.
GLUCOSE ALANINE CYCLE AND ROLE OF GLUTAMATE
➢ The transport of amino group of amino acids also takes place in
the form of Alanine.
➢ The glucose-alanine cycle represents a critical link between
carbohydrate and amino acid metabolism and
➢ Comprises a series of reactions in which pyruvate, derived mostly
from intramyocellular glycolysis, is transaminated with ammonia,
derived from muscle protein catabolism, to form L-alanine.
➢ 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
transported to the liver where alanine and converts it back to
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.
The Fate of the Carbon Skeleton
➢ The 20 catabolic pathways converge to form only six major
products, all of which enter the citric acid cycle .
➢ From here the carbon skeletons are diverted to
gluconeogenesis or ketogenesis or are completely oxidized
to CO2 and H2O
➢ Six amino acids are ultimately broken down to acetyl-CoA.
Five amino acids are converted to -ketoglutarate, four to
succinyl-CoA, two to fumarate, and two to oxaloacetate.
Six Amino Acids Are
Degraded to Pyruvate
Six Amino Acids
Are Degraded to
Acetyl-CoA or
Acetoacetyl CoA
Five Amino Acids Are Converted
to α-alpha-Ketoglutarate
Four Amino Acids
Are Converted to
Succinyl-CoA
Asparagine and
Aspartate are converted
to oxaloacetate
Catabolism of Branched Chain Amino Acids
➢ Extrahepatic tissues contain an aminotransferase, absent in liver,
that acts on all three branched-chain amino acids to produce the
corresponding keto acids .
➢ The branched chain-keto acid dehydrogenase complex then
catalyzes oxidative decarboxylation of all three α–keto acids,
✓ in each case releasing the carboxyl group as CO2 and producing
the acyl-CoA derivative.
Study Questions
➢ Steps in catabolism of the amino acids --------,------------ and ------------
➢ When protein intake exceeds the body’s requirements the predominant fate of
proteins becomes ------------➢ Mention the intermediate in the TCA cycle through which amino acids are completely
oxidised
➢ Aminotransferases with clinical significance are -------- and -------➢ Why does consumption of protein rich diet enhance the rate of degradation amino
acids?
➢ A common precursor to aromatic amino acids is ----------➢ The products of the first step in the catabolism of most amino acids which is the
transfer of their α-amino group to α-ketoglutarate are ------- and ------------
➢ When cellular proteins undergo continuous turnover they release -------------➢ Asparagine is synthesized by amidation of aspartate, with glutamine donating --------