AMINO ACID SYNTHESIS

AND DEGRADATION

Dr. Adnan Riaz

Assistant Professor (Biochemistry)
IMDC, Sialkot
Glucogenic and Ketogenic
Amino acids
 Amino acids are classified as glucogenic, ketogenic,
or both based on which of the seven intermediates
are produced during their catabolism
 Amino acids whose catabolism yields pyruvate or
one of the intermediates of the citric acid cycle are
termed glucogenic or glycogenic
 Amino acids whose catabolism yields either
acetoacetate or one of its precursor, (acetyl CoA or
acetoacetylCoA) are termed ketogenic.
 Some amino acids are both glucogenic or ketogenic
 Ketone Bodies
 Ketone bodies are three water-soluble compounds that
are produced as by-products when fatty acids are broken
down for energy in the liver and kidney.
 The three ketone bodies are acetone, acetoacetic acid
and beta-hydroxybutyric acid.
 Ketone bodies are transported from the liver to other
tissues, where acetoacetate and beta-hydroxybutyrate
can be reconverted to acetyl-CoA to produce energy, via
the Krebs cycle.
 Excess ketone bodies accumulate, this abnormal (but not
necessarily harmful) state is called Ketosis
Glucogenic VS Ketogenic Amino acids
Amino acids that enter metabolism as oxaloacetate
(Aspargine and Aspartate)

 Asparagine is hydrolyzed by Asparginase, liberating

ammonia and Aspartate

 Aspartate loses its amino group by tranamination to

form oxaloacetate

 Oxaloacetate with acetyl CoA to form citrate in the

first reaction of the Krebs cycle (GLUCOGENIC)
 Aspargine and Aspartate
 Both these amino acids are non-essential and
glycogenic.
 Aspartate is formed from oxaloacetate (an
intermediate in TCA cycle) by transamination.
Aspartate transaminase(AST) is an important
enzyme for the interconversion of aspartate
 Asparagine is synthesized from aspartate by a
synthetase in an irreversible ATP-dependent
reaction. Asparaginase hydrolyses asparagine and
liberates ammonia
 Important functions of Aspartate
1. It donates one amino group for the synthesis of
urea (the other amino group in urea directly
comes from ammonia).
2. Aspartate forms a connecting link between urea
cycle and TCA cycle (via oxaloacetate).
3. It is utilized for the synthesis of purines and
pyrimidines.
4. Malate-aspartate shuttle is important for the
transfer of reducing equivalents( NADH) from
the cytosol to mitochondria.
 Amino acids that form α-ketoglutarate
(Glutamine, Proline, Arginine, Histidine)

 2) Proline: It is oxidized to glutamate. Glutamate is then oxidatively

deaminated to form α-ketoglutarate
 Amino acids that form α-ketoglutarate
(Glutamine, Proline, Arginine, Histidine)

 3) Arginine:This aa is cleaved by arginase to produce ornithine.

Ornithine is subsequently converted to α-ketoglutarate

 4) Histidine:
 Glutamate and glutamine

 Glutamate and glutamine are non-essential

glycogenic amino acids. Both are directly involved
in the final transfer of amino group for urea
synthesis.
 The amino acids histidine, proline and arginine
can be converted to glutamate.
 Glutamate for the synthesis of
specialized products
1. Glutathione is a tripeptide that contains
glutamate.
2. N-Acetylglutamate is an allosteric regulator of
carbamoyl phosphate synthase l, the first
enzyme in urea synthesis.
3. Glutamate is present in the clotting factors (ll,
Vll, lX, X) as y-carboxyglutamate" and is
involved in coagulation
4. GABA
 Arginine for the synthesis of
specialized products
1. Arginine is the substrate for the production of
nitric oxide (NO).
2. NO functions as a vasodilator, smooth muscles
relaxant, inhibitor of platelet aggregation and
neurotransmitter.
 Histidine for the synthesis of
specialized products
1. The metabolism of histidine is important for the
generation of one-carbon unit, namely formimino
group.
2. From N-formiminoglutamate (FIGLU) the
Tetrahydrofolate (THF) takes up the formimino
group to form N5-formimino THF.
Amino acids that enter as Pyruvate
(Alanine, Serine, Glycine, Cystine Threonine)

 Alanine loses its amino

group by transamination
to form pyruvate
 Alanine

 The non-essential amino acid alanine performs

two important functions in the body
1. Incorporation into the structure of proteins
2. Participation in transamination and NH3
transport
Alanine-pyruvate shuttle
Serine and Glycine

 Glycine is reversibly
converted to serine by
serine hydroxymethyl
transferase. Pyruvate is
then produced from serine
by serine dehydratase.
 Glycine can be
converted to glyoxylate,
which can be oxidized to
oxalate, or
transaminated to
glycine.
 Glycine undergoes
oxidative deamination by
glycine synthase to
liberate NH4+,CO2 and
one carbon fragment as
N5, N10-methylene THF
 Synthesis of glycine

 Glycine is synthesized from serine by the

enzyme serine hydroxymethyl transferase.
 Glycine can also be obtained from threonine,
catalyzed by threonine aldolase.
 Glycine synthase can convert a one-carbon unit
(N5, N1o-methylene THF), CO2 and NH3 to
glycine.
 Cystine and Threonine

 The sulfate released can be used to synthesize 3'-

phosphoadenosine-5'-phosphosulfate (PAPS), an activated sulfur
donor to acceptors such as glycosaminoglycans
 Amino Acids that enter metabolism as fumarate
(Phenylalanine and Tyrosine)

 Phenylalanine and tyrosine

are both glucogenic and
ketogenic

 Inherited deficiencies in the enzymes of phenylalanine and tyrosine

metabolism lead to the diseases phenylketonuria and alkaptonuria and
the condition of albinism
 Phenylketonurea
(Prevalence of 1:15,000)

 A deficiency of phenylalanine hydroxylase

 More than 400 mutations in gene that code for PKU
 Deficiency of enzymes required for the synthesis of BH4 and
dihydropterine (BH2) Reductase which regenerates BH4 from BH2
also leads to hyperphenylalaninemia.

Treatment: replacement therapy with BH4 or generated product

Pathways of phenylalanine metabolism
 Pathways of phenylalanine metabolism in normal
individuals and in patients with phenylketonuria.

 Characteristics of classic PKU:

 1) Elevated phenylalanine, phenyl pyruvate, phenyl lactate and
phenyl acetate in tissues, plasma and urine.
 2) CNS symptoms: Mental retardation, failure to walk or talk,
seizures, tremor etc.
 3) Hypo pigmentation: deficiency in the formation of Melanin lead
to the deficiency of pigmentation (fair hair, light skin, color, and
blue eyes.
 Treatments: Synthetic nutrient with low
phenylalanine content supplemented with
tyrosine
Alkaptonuria
deficiency in homogentisic acid oxidase, enzyme
in tyrosine degradation pathway.

 Characteristics:
 1)Results in accumulation of
homogentisic aciduria.
 2) Large joint arthritis
 3) Dense, black pigments deposited
on the intravetebral disks of the
vertebrae.
 Treatment: Low protein (low in
phenylalanine and tyrosine) diet
Help reduce the levels of
homogenistic acid
Amino acids that enter metabolism
as succinyl CoA
(Methionine, Valine, Isoleucine,
Threonine)
 Homocysteine and vascular
disease
 Elevations in plasma homocysteine levels promote
oxidative damage, inflammation, and endothelial
dysfunction, and are an independent risk factor for
vascular disease.
 Homocysteine levels are inversely related to
plasma levels of folate, B12, and B6.
 Supplementation with these vitamins has been
shown to reduce circulating levels of homocysteine.
Homocystinuria
The disease is due to a deficiency in cystathionine
synthase.
 Characteristics:
 1) High levels of homocysteine and methionine
in plasma and urine and low levels of cysteine
in plasma.
 2) ectopia (displacement of the lens)

 3) Skeletal abnormalities

 4) Premature arterial disease

 5) Osteoporosis

 6) Mental retardation

 Treatment: Restriction of methionine intake and

supplementation with VitB6, B12, and folate
Threonine

 Threonine is dehydrated to α-
ketobutyrate, which is converted to
propionyl CoA and then to succinyl CoA.
Valine and Isoleucine
 Maple syrup urine disease (MSUD)
(rare, prevalence of 1:185,000)
 Autosomal recessive disease in which there is a partial or
complete deficiency of Branched chain α-keto acid
dehydrogenase.
 Disease leads to accumulation of these amino acids and
branched chain α-ketoacid substrates causing abnormalities in
brain functions.
 Patients show feeding problems, vomiting, dehydration, severe
metabolic acidosis and Classic maple syrup odor to the urine.
 Treatments: Giving a synthetic formula that contains limited
amount of leucine, Isoleucine, and Valine.
Amino acids that form acetyl CoA or acetoacetyl CoA
(Leucine, isoleucine, lysine, and tryptophan)
Lysine and Tryptophan (Cont..)

 3. Lysine
 An exclusively ketogenic amino acid, this amino
acid is unusual in that neither of its amino groups
undergoes transamination as the first step in
catabolism. Lysine is ultimately converted to
acetoacetyl CoA.

 4. Tryptophan
 This amino acid is both glucogenic and ketogenic
because its metabolism yields alanine and
acetoacetyl Co
Serotonin (5-hydroxytryptamine)

 Found in the cells of intestinal mucosa

 Also found in CNS were it functions as
a neurotransmitter
 It has roles in pain perception,
affective disorders, regulation of sleep,
temperature, and blood pressure.
 Serotonin is converted to melatonin in
the pineal gland via acetylation and
methylation.
 Degradation of catecholamines

MAO [monoamine oxidase]

COMT [catechol-O-
methyltransferase]

MAO: inactivates catecholamines by oxidative deamination to yield the corresponding

aldehyde
COMT: inactivates catecholamines by methylation using S-adenosylmethionine (SAM)
MAO Inhibitors:
MAO inhibitors may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter
molecules to escape degradation and responsible for the antidepressant action of these
drugs.
 Histamine
 A chemical messenger that
mediates a wide range of cellular
responses, including allergic and
inflammatory reactions, gastric acid
secretion, and as neurotransmiter.
 It is secreted by mast cells as a
result of allergic reactions or trauma.
 Antihistamine are used to block
histamine during allergic reactions.
 Creatine
 Found in muscle
 High energy compound that can
donate phosphate group to ADP to
form ATP
 Creatine is reversibly phosphorylated
to creatine phosphate by
creatinekinase.
 Creatine phosphate serves as a
reserve of high-energy phosphates
that can be used to maintain ATP
levels
 Levels of creatine kinase in plasma is
an indicator of tissue damage and is
used in the diagnosis of myocardial
infarction
 Degradation of Creatine to
Creatinine
 Creatine and creatine phosphate spontaneously
cyclize at a slow but constant rate to form creatinine,
which is excreted in the urine.
 The amount of creatinine excreted is proportional to
the total creatine phosphate content of the body, and
thus can be used to estimate muscle mass.
 In addition, any rise in blood creatinine is a sensitive
indicator of kidney malfunction, because creatinine
normally is rapidly removed from the blood and
excreted.