Amino Acids

Metabolism
GC-2-MS
(1427-108) 14.2 Amino Acids Biosynthesis
15.2 Amino Acids Degradation
Dr. Ahmed Almehdi 15.2 The Urea Cycle
15.2 Regulation of Urea Cycle
15.2 degradation of Carbon Skeleton
Biochemistry

Biochemistry, the molecular basis of life – McKee , 7th Ed (2020) , Oxford University Press
 14.2 Amino Acids Biosynthesis

▪ living organisms differ in their ability to

synthesize amino acids required for
protein synthesis
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▪ although plants and many microorganisms

can produce all their amino acids from
readily available precursors, other
organisms must obtain some preformed
amino acids from their environment
▪ human and animals can only produce half
of the amino acids required (nonessential
amino acids); the others must be obtained
from diet (essential amino acids)
 Cont. …14.2 Amino Acids Biosynthesis

▪ amino acids: serve a number of functions including: protein synthesis

and as a nitrogen source required in various synthetic reaction
pathways
▪ the nonnitrogen components of amino acids (the carbon skeleton) are
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a source of energy, as well as precursors in several reaction pathways

▪ therefore an adequate intake of amino acids, in the form of dietary
protein, is essential for human’s proper growth and development
▪ dietary protein sources differ in amino acid content of essential amino
acids, in general, complete proteins (those containing sufficient
quantities of EAA) are of animal origin (meat, milk, and eggs)
▪ Plant proteins often lack one or more EAA. for example gliadin (wheat
protein) has insufficient amounts of lysine, and zein (corn protein) is
low in both lysine and tryptophan)
 Cont. …14.2 Amino Acids Biosynthesis

▪ plant foods can provide a high-quality source of essential amino acids

only if they are eaten in appropriate combinations
▪ the amount of available amino acids (amino acid pool) is constantly
changing due to the metabolic state of the cell
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▪ healthy human adults are said to be in nitrogen balance, if his/her

nitrogen intake and usage are equal
❖ positive nitrogen balance: means nitrogen intake exceeds loss and is
common in children
❖ negative nitrogen balance: exists when an individual cannot replace
nitrogen losses from dietary sources (Kwashiorkor malnutrition)
▪ free amino acids (from digested proteins) are transported across
intestine into the blood to tissue cells (goes first to the liver)
 Cont. …14.2 Amino Acids Biosynthesis

▪ depending on metabolic requirements, certain amino acids are

synthesized or interconverted in the liver and then transported to
tissues
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▪ branched-chain amino acids (BCAA) valine, leucine and isoleucine, are

hydrophobic EAAs represent a major transport form of amino nitrogen
from the liver to other tissues, where they are used in the synthesis of
the NAAs required for protein synthesis
▪ amino acids that are immediately available for use in metabolic
processes are referred to as the amino acid pool
▪ in human and animals, amino acids in the pool are derived from the
breakdown of both dietary and tissue proteins
 Cont. …14.2 Amino Acids Biosynthesis

▪ Kwashiorkor is caused by a prolonged insufficient intake of protein. Its

symptoms include growth failure, liver enlargement, and decreased
mass and function of the heart and kidneys. Can be treated with high-
energy protein food
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▪ transport of amino acids into cells is mediated by specific membrane-

bound transport proteins (Na+-dependent amino acid transport)
▪ once amino acid molecules have entered cells, the amino groups are
available for many synthesis reactions
▪ two main groups of reactions are observed for amino acids synthesis:
1) Transamination reactions (requires the coenzyme pyridoxal-phosphate
(derivative of pyridoxine, derivative of vitamin-B6) and
2) direct reductive amination (direct incorporation of ammonium ions)
 Cont. …14.2 Amino Acids Biosynthesis

1) transamination:
▪ α-amino groups are transferred from α-amino acid (donator of
α-amino group) to α-keto acid (acceptor of α-amino group)
▪ catalyzed by a group of enzymes referred to as aminotransferases
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(earlier name was transaminases)

▪ eukaryotic cells have a large variety of aminotransferases, found in
cytoplasm and mitochondria
 Cont. …14.2 Amino Acids Biosynthesis

Cont. …1) transamination:

▪ most aminotransferases use glutamate as the amino

group donor
▪ transamination reactions require the coenzyme
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pyridoxal-5ʹ-phosphate (PLP), which is derived from

pyridoxine (vitamin B6)
▪ PLP is also required for other amino acid reactions such
as decarboxylation
▪ the amino acid-1 is converted toketo acid-2 and the keto
acid-1 is converted to amino acid-2

-1 -1 -2 -2
 Cont. …14.2 Amino Acids Biosynthesis
Cont. …1) transamination:

▪ transamination reactions dominate amino acid metabolism

▪ three molecules pairs are important in amino acids metabolism:
i) α-ketoglutarate/glutamate pair
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ii) oxaloacetate/aspartate pair

iii) pyruvate/alanine pair
▪ α-ketoglutarate/glutamate pair: (in addition to its role in transamination
reactions), is connected to the citric acid cycle
▪ oxaloacetate/aspartate pair: (in addition to its role in transamination reactions),
is involved in the disposal of nitrogen in the urea cycle (Chapter-15)
▪ pyruvate/alanine pair: (in addition to its role in transamination reactions), is
involved in the glucose–alanine cycle: (Chapter 8), (alanine (generated from
pyruvate in exercising muscle) as one of the substrates for gluconeogenesis,
[besides lactate (from anaerobic metabolism) and glycerol (from fat metabolism)
 Cont. …14.2 Amino Acids Biosynthesis

Cont. …1) transamination:

▪ alanine: is a glucogenic (converted to glycolysis intermediate)

▪ in exercise, large amount of pyruvate in the muscles, some is
converted to alanine, transported to the liver → reconverted back
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to pyruvate then to glucose

glucose–alanine
cycle
 Cont. …14.2 Amino Acids Biosynthesis

2) direct reductive amination:

▪ there are two ways ammonium ion (NH4+) is directly incorporated into
amino acids:
a) reductive amination: of α-keto acids: direct amination of a-ketoglutarate
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to glutamate (catalyzed by glutamate dehydrogenase)

b) formation of amides: direct animation of aspartate to asparagine and
glutamate to glutamine (catalyzed by glutamine synthytase)

a)

b)
 Cont. …14.2 Amino Acids Biosynthesis

Cont. …2) direct reductive amination:

▪ the brain is sensitive to the toxic effects of NH4+

▪ brain cells has glutamine synthetase and converts NH4+ + glutamate to
glutamine (nontoxic)
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▪ glutamine is then transported to the liver, where converted back to NH4+

+ glutamate , then NH4+ is disposed of by incorporation into urea (the
principal nitrogenous waste product in mammals)
▪ the carbon skeleton of all NAA molecules are derived from glycerate-3-P,
pyruvate, α-ketoglutarate, or oxaloacetate (except tyrosine is synthesized
from the EAA Phe, and histidine is synthesized from Ribose-5-P)
▪ on the basis of the similarities in their synthetic pathways, the amino
acids can be grouped into six families: glutamate, serine, aspartate,
pyruvate, the aromatics, and histidine family
 Cont. …14.2 Amino Acids Biosynthesis

the NAA Amino Acids Synthesis Family:

GC-2-MS McKee 2020
 Cont. …14.2 Amino Acids Biosynthesis

the Glutamate Family:

▪ this family includes glutamate, proline, arginine,
and glutamine
a-Ketoglutarate may be converted to glutamate by
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▪
direct amination or transamination
▪ in addition to its role in protein synthesis, glutamine
is a safe storage and transport form of NH4+
▪ glutamine is the amino group donor in numerous biosynthetic reactions
(nucleic acids and amino sugars)
▪ conversion of glutamate to glutamine is catalyzed by glutamine synthetase
in liver, brain, kidney, muscle, and intestine
▪ in the kidney and small intestine, glutamine is a major source of energy
 Cont. …14.2 Amino Acids Biosynthesis

the Serine Family:

▪ serine, glycine, and cysteine derive their carbon
skeletons from the glycolytic intermediate
glycerate-3-phosphate
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▪ serine is a precursor of ethanolamine and sphingosine

▪ glycine is used in the purine, porphyrin, and
glutathione synthesis
▪ cysteine plays a significant role in sulfur metabolism
▪ conversion of serine to glycine is a pyridoxal phosphate
(derivative of vitamin B6) requiring reaction
 Cont. …14.2 Amino Acids Biosynthesis

the Aspartate Family:

▪ aspartate: is synthesized from oxaloacetate in a single AST
step by the enzyme aspartate aminotransferase (AST),
(also known as glutamic oxaloacetic transaminase or GOT)
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▪ this reaction is reversible and significantly influences the

flow of carbon and nitrogen within the cell
▪ aspartate: can be used as a nitrogen source for synthesis
of other amino acids : Lys, Met, Thr, Asn as well as a
source of the citric acid cycle intermediate (oxaloacetate)

AST
 Cont. …14.2 Amino Acids Biosynthesis

Cont. …the Aspartate Family:

▪ aspartate transaminase (AST) is the most active of the aminotransferases,

found in most cells
▪ aspartate: participate as a source of both nitrogen (for urea and
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nucleotide synthesis) and the citric acid cycle intermediate OAA

▪ asparagine, the amide of aspartate, is not formed directly from aspartate
and NH4+, instead, the amide group of glutamine is transferred to
aspartate by asparagine synthase
asparagine
synthase
Aspartate + Glutamine + Aspargine + Glutamate +
 Cont. …14.2 Amino Acids Biosynthesis

the Pyruvate Family:

▪ the pyruvate family consists of alanine, valine, leucine,
and isoleucine
▪ alanine: is synthesized from pyruvate in a single step
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by the enzyme alanine aminotransferase (ALT)

▪ the glucose–alanine cycle contributes to the
maintenance of blood glucose

ALT
 Cont. …14.2 Amino Acids Biosynthesis

the Aromatic Family:

▪ the aromatic family of amino acids includes
phenylalanine, tyrosine, and tryptophan
▪ tyrosine: is is considered nonessential in mammals
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▪ either Phe or Tyr is required for the synthesis of

dopamine, epinephrine, and norepinephrine, an
important class of biologically potent molecules
referred to as the catecholamines
▪ Tryptophan is a precursor in the synthesis of NADH,
NADPH, and the neurotransmitter serotonin
 Cont. …14.2 Amino Acids Biosynthesis

the Histidine Family:

▪ histidine is considered nonessential in healthy human
adults, but essential in human infants
▪ histidine contributes substantially to protein structure
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and function (such as binding to the heme prosthetic

group in hemoglobin)
▪ histidine is synthesized from phosphoribosylpyrophosphate
(PRPP), ATP, and glutamine
 15.2 Amino Acids Catabolism

▪ amino acid catabolism usually begins with the removal of the amino
group (disposed in urea synthesis , urea cycle)
▪ the remaining carbon skeletons are then degraded into one or more
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of seven possible metabolic products: acetyl-CoA, acetoacetyl-CoA,

pyruvate, α-ketoglutarate, succinyl-CoA, fumarate, or OAA
▪ these metabolic products can then be used to synthesize fatty acids
or glucose or to generate energy
▪ amino acids degraded to acetyl-CoA and acetoacetyl-CoA are referred
to as ketogenic amino acids because they can be converted to either
fatty acids or ketone bodies
▪ most amino acids are glucogenic, are degraded to pyruvate or a citric
acid cycle intermediate and can be used to synthesize glucose
 Cont. …15.2 Amino Acids Catabolism
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 Cont. …15.2 Amino Acids Degradation

Deamination:
▪ deamination: is the removal of the α-amino group from amino acids
▪ deamination: involves two types of reactions: transamination and
oxidative deamination (opposite direct reductive amination) (slide-6)
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▪ deamination reactions: are reversible, so the amino groups can be shifted

from abundant amino acids and used to synthesize those that are scarce
▪ when amino acids are in excess, the amino groups become available for
urea synthesis
 Cont. …15.2 Amino Acids Degradation
Cont. …Deamination:

▪ in muscle:
excess amino groups are transferred to α-ketoglutarate to form glutamate
▪ the amino groups of glutamate are transported in blood to the liver by the
alanine cycle (slide 10)
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▪ in Liver:
alanine is converted to glutamate and to α-Ketoglutarate by
oxidative deamination (most ammonia generated in amino acid degradation is
produced by the oxidative deamination of glutamate)

glucose–
alanine
cycle
 Cont. …15.2 Amino Acids Degradation

Cont. …Deamination:

▪ urea: is synthesized in especially large amounts when the diet is high in

protein or when there is massive breakdown of protein (during starvation)
▪ most of the ammonia (NH4+) generated in amino acid degradation is
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produced by the oxidative deamination of glutamate

▪ additional ammonia is produced in several other reactions catalyzed by
the following enzymes:
1. amino acids oxidase
2. serine and threonine dehydratase
3. bacterial urease in the intestine
4. adenosine (nucleotide) deaminase
 Cont. …15.2 Amino Acids Degradation

the Urea Cycle:

▪ the large amount of ammonia (NH4+) produced by oxidative deamination
are extremely toxic and must be removed from the body, regardless of
the energy required (hydrolysis of 3 ATP)
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▪ in human NH4+ is kept out of the blood and detoxified in the liver by
converting them to urea in the urea cycle pathway and excreted in the
urine
▪ in urea cycle, urea is formed from ammonia, CO2, and aspartate
▪ the urea cycle disposes of approximately 90% of surplus nitrogen
▪ overall urea cycle equation:

CO2 + NH4+ + Aspartate + 3 ATP + 2 H2O →

Urea + Fumarate + 2 ADP + 2 Pi + AMP + ppi + 5 H+
 Cont. …15.2 Amino Acids Degradation

Cont. …the Urea Cycle:

▪ urea synthesis: (in the liver) begins with the

formation of carbamoyl -P in the mitochondrial matrix
▪ Carbamoyl-phosphate reacts with ornithine to form
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citrulline
▪ citrulline is transported to the cytoplasm, binds to
aspartate forming arginosuccinate
▪ arginosuccinate splits into arginine and fumarate
▪ arginine releases urea and ornithine is regenerated,
which binds to another carbamoyl-P forming citrulline,
and the cycle continues
 Cont. …15.2 Amino Acids Degradation

Regulation of the Urea Cycle:

▪ urea diffuses out of the hepatocytes into the
blood stream
▪ urea is eliminated in the urine by the kidney
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▪ there is a relationship between the urea

cycle and the citric acid cycle (fumarate and
formation of aspartate from oxaloacetate )
▪ urea is toxic, so its synthesis is stringently
regulated
▪ urea synthesis is stimulated by a high-protein diet or fasting
▪ glucagon (a peptide hormone) and glucocorticoids (steroid hormone,
cortisone) activate urea cycle enzyme synthesis (transcription),
while insulin represses synthesis
 Cont. …15.2 Amino Acids Degradation

Catabolism of Amino Acid Carbon Skeletons:

▪ amino acids degradation can be

grouped into classes according to
their end products: pyruvate,
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acetyl-CoA, acetoacetyl-CoA, and

citric acid cycle intermediates
1) amino acids converted to
pyruvate are:
alanine, serine, glycine,
cysteine, and threonine
2) amino acids converted to
acetyl-CoA are:
pyruvate and isoleucine
 Cont. …15.2 Amino Acids Degradation

Cont. …Catabolism of Amino Acid Carbon Skeletons:

3) amino acids converted to

acetoacetyl-CoA are:
phenylalanine, tyrosine, and
tryptophan
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4) amino acids converted to

citric acid cycle intermediates are:
a) forming α-ketoglutarate:
aspartate, glutamate (glutamine),
arginine, proline, histidine,
b) forming succinyl-CoA:
methionine, threonine,
isoleucine, and valine
c) forming oxaloacetate: aspartate
 Cont. …14,15 Amino Acids Metabolism
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