Kwame Nkrumah University of

Science & Technology, Kumasi, Ghana

FATE OF CARBON SKELETON IN

AMINO ACID CATABOLISM

Dr Max Efui Annani-Akollor

Dept of Molecular Medicine

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 LECTURE OUTLINE
• Catabolism of Branched Chain aa.
• Maple Syrup Urine Disease
• Intermittent Branched Chain Ketonuria
• Isovaleryl acidemia
• Catabolism of Phenylalanine
• Phenylketonuria
• Catabolism of Tyrosine
• Type I Tyrosinaemia
• Type II
• Type III
• Catabolism of Histidine
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 Lecture Objectives
•Identify the fate of the carbon skeletons of amino acids undergoing catabolism
•Identify in-born errors associated with enzyme catalyzed steps in catabolism of
amino acids.
•Enumerate some presentations of these in-born errors of amino acid carbon
skeleton catabolism.
•Explain the mechanism behind some common presentations in in-born errors of
amino acid catabolism

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 CATABOLISM OF BRANCHED-CHAIN AMINO ACID (BCAA)
LEUCINE, ISOLEUCINE AND VALINE
•A BCAA is an amino acid having an aliphatic side-chain with a branch (a
central carbon atom bound to three or more carbon atoms). Among
proteinogenic aa’s, there are three BCCAS leucine, isoleucine, and valine.
•Non-proteinogenic BCAAs include 2-aminoisobutyric acid.
•Not made by humans hence they are all essential in the diet.
•These amino acids serve as an alternate source of fuel for the brain especially
under conditions of starvation.
•The Pros and Cons of BCAA Supplements: Benefits and Risks (bestfornutrition.com)

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 CATABOLISM OF BCAA
•Their catabolism initiates in muscles and yields NADH and FADH2 which can be
utilized for ATP generation.
•Their catabolism uses the same enzymes in the first two steps. The first step in
each case is a transamination using a single BCAA aminotransferase, with α-
ketoglutarate as amine acceptor.
•The first three metabolic reactions are common to the branched chain amino
acids 1. Transamination 2. Oxidative decarboxylation 3. Dehydrogenation

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 CATABOLISM OF BCCA
LEUCINE, ISOLEUCINE AND VALINE

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 CATABOLISM OF BCCA
LEUCINE, ISOLEUCINE AND VALINE

•Three different α-keto acids are produced and are oxidized using a common
branched-chain α-keto acid dehydrogenase, yielding three different CoA
derivatives. Subsequently the metabolic pathways diverge, producing many
intermediates.
•The main site for the catabolism of the branched chain aa is the liver
•Demonstrated in the muscle, adipose , kidney and brain tissues
•The catabolism commences with a specific aminotransferase which converts the
amino acids to an α-keto acid

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 CATABOLISM OF BCCA
LEUCINE, ISOLEUCINE AND VALINE

The principal product from valine is propionyl CoA, the glucogenic precursor
of succinyl-CoA.
Isoleucine catabolism terminates with production of acetyl CoA and
propionyl CoA; thus isoleucine is both glucogenic and ketogenic.
Leucine gives rise to acetylCoA and acetoacetylCoA, and is thus classified as
strictly ketogenic.
Generally the oxidation of these amino acids is similar to fatty acid oxidation,
except for a debranching reaction for each intermediate.
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 CATABOLISM OF BCCA
LEUCINE, ISOLEUCINE AND VALINE
•The α-keto acids are then acted on by an α-keto acid dehydrogenase complex
which is synonymous to the Pyruvate dehydrogenase complex (PDC)
•The α-keto acid dehydrogenase complex isolated from the rate liver is regulated
by covalent modification
•This is in response to the presence of BCCA in the diet
•The enzyme complex is inactivated by phosphorylation and activated by
dephosphorylation
•The deficiency of α-keto acid dehydrogenase complex has been associated with
the Maple Syrup Urine Disease
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Summary of branched chain amino acid
metabolism ( –Defect in α-keto acid
dehydrogenase results in maple syrup urine
disease; HMG CoA–β-Hydroxy β-methyl-glutaryl
CoA; Valine is glycogenic, leucine is ketogenic,
while isoleucine is both).

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 MAPLE SYRUP URINE DISEASE
•This condition is characterized by the accumulation of α-keto acids in the blood
and their excretion in the urine
•The urine and sweat of affected individuals has the odour of maple syrup
•There is an associated abnormal development of the brain leading to mental
retardation and death in infancy.
•The condition may be managed by restricting the intake of branched chain
amino acids
•Some cases respond to the administration of large doses of thiamine

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BCAA acids degraded
in brain, muscle,
kidney to α-keto acids.

Maple Syrup urine

disease, defective α-
keto acid
dehydrogenase: diet,
mental retardation

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 INTERMITTENT BRANCHED CHAIN KETONURIA

• This condition is a variant of MSUD

• It is characterized by a less severe deficiency of the α-keto acid
dehydrogenase complex
• In this variant, the symptoms appear later in life and occur only
intermittently
• Restriction of the intake of branched chain amino acids is more effective

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 ISOVALERYL ACIDAEMIA

•This condition is due to the deficiency of Isovaleryl CoA dehydrogenase

required for the catabolism of leucine
•The breath and urine of affected subjects has a ‘cheesy’ odour
•Affected subjects present with a mild mental retardation
•When affected subjects are fed with protein they may present with vomiting,
acidosis and coma
•It may be managed by the restriction of the intake of leucine

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 PHENYLKETONURIA (PKU)
•It is characterized by the accumulation of
phenylketones in the blood and their excretion in
the urine
• Phenylpyruvic acid in urine (musty odor) rises
2- 6 weeks after ↑ed blood PA.
• Monitor diet, screen pregnant PKU women, or
follow-up on questionable PKU test results
•Affected subjects present with severe mental
retardation, a low IQ and dilution of hair and skin
pigmentation
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 PKU IS AN AUTOSOMAL RECESSIVE GENETIC DISEASE
The phenylalanine hydroxylase gene is located on
chromosome 12 making it an autosomal recessive genetic
disease.

The probability that two PKU carriers will have a child with
the disease is 25% based on simple Mendelian genetics.

Since the frequency of PKU carriers in the general

population is ~2% (~1 in 50), then the probability that a
baby will be born with PKU by random chance is 0.02 x 0.02
x 0.25 = 0.0001, or 1 in 10,000, which is close to the
observed frequency of 1 in 15,000.
What would the probability be of having a PKU afflicted child if the mother was
normal (PP) and the father was a carrier (Pp)?
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 CATABOLISM OF PHENYLALANINE

•Phenylalanine is usually
hydroxylated to tyrosine under
the catalysis of phenylalanine
hydroxylase
•The cofactor for this reaction is
tetrahydrobiopterin
•The deficiency of the
hydroxylase, the cofactor or the
reductase which regenerates
the cofactor may lead to PKU
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 CATABOLISM OF PHENYLALANINE
•Management of the condition requires the restriction of phenylalanine
containing diets
•The diet of subjects should however be high in tyrosine for the first 4-5 years
•Protein diet restriction should be enforced for several years.
•The diets of subjects should contain high levels of tetrahydrobiopterin

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Since the symptoms of PKU are
caused by excess Phe and its
metabolites, and humans require Phe,
PKU treatment involves careful
monitoring of phenylalanine intake to
provide just enough for protein
synthesis without accumulating Phe .

Phenylketonuriacs also have to be

careful to avoid processed foods and
beverages containing the food
additive aspartame (aspartyl-
phenylalanine methyl ester).
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 METABOLISM OF TYROSINE
•Type I Liver Damage and Fanconi’s syndrome (generalized renal tubular failure)
•Type II defective tyrosine aminotransferase transaminase) deposits of tyrosine
affecting skin and eyes.
•Both types high level of tyrosine in blood and urine
The metabolic fate of tyrosine are as follows:
–Catabolism to Acetoacetyl CoA
–Synthesis of catecholamines
–Synthesis of melanin
–Synthesis of thyroid hormones
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 METABOLISM OF TYROSINE

Tyrosine is Oxidized by
tyrosine hydroxylase in a
reaction requiring the
enzyme cofactor
tetrahydrobiopterin to
form
dihydroxyphenylalanine
(L-DOPA), a metabolic
precursor to dopamine.

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 METABOLISM OF TYROSINE
Tyrosine - precursor to pigment molecules
called melanins that are produced from
dopaquinone.

The two primary melanins are eumelanins,

which are dark pigments having a brown or
black color, and pheomelanins that have red
or yellow color.

The yellow color of pheomelanin pigments

comes from the sulfur in cysteine that is
combined with dopaquinone.
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 CATABOLISM OF TYROSINE

•Tyrosine is catabolized through a

series of reactions leading to the
synthesis of acetoacetyl CoA
•The reactions include
transamination, dioxygenation,
isomerisation reactions

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 Tyrosinaemia
•This condition is characterized by the accumulation and excretion of tyrosine
and its metabolites.
•About 10% of neonates may have temporarily elevated levels of tyrosine.

•This temporary elevation may be due to Vit C deficiency or immature liver

enzymes due to prematurity.

•If untreated tyrosine and its metabolites may build up in tissues and organs
leading to serious medical problems.

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 TYROSINAEMIA
•This condition affects both males and females equally.

•There are three distinct types of this condition – Type I, II, and III

•If untreated tyrosine and its metabolites may build up in tissues and organs
leading to serious medical problems
•This condition affects both males and females equally

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 TYPE 1 TYROSINAEMIA

• This condition is characterized by

the deficiency of fumaryl
acetoacetase
• It is associated with the
accumulation of maleyl
acetoacetate and fumaryl
acetoacetate
• Some babies may present with the
acute form and others with the
chronic form
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 TYPE 1 TYROSINAEMIA
•The acute form manifests in the first few months where as the chronic form
manifests around year one
•The symptoms of the acute form are:
–Poor appetite and failure to grow normally

–Vomiting, Diarrhoea and bloody stools

–A cabbage-like odour, Jaundice & Inflammation of the liver (hepatitis)

–Irritability, lethargy

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 TYPE 1 TYROSINAEMIA
The symptoms of the chronic form are:
–Cirrhosis of the liver
–Polyneuropathy & kidney problems
–It is otherwise referred to as hepato-renal Tyrosinaemia
–Episodes of intense abdominal pain
–Heart muscle weakness
–ca

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 TYPE II TYROSINAEMIA
•This condition is characterized by the
deficiency of tyrosine aminotransferase
•It is associated with eye and skin lesions
as well as mental retardation
•The symptoms begin in early childhood
and include:

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 TYPE II TYROSINAEMIA
•Excessive tearing
•Abnormal sensitivity to light (photophobia)
•Eye pain and redness
•Painful skin lesions on the palms and soles
•About 50% of affected subjects have some degree of intellectual disability
•It is otherwise referred to as oculo-cutaneous tyrosinaemia or Richner-
Hanhart Syndrome

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 TYPE III TYROSINAEMIA

•It is characterized by the deficiency of 4-

hydroxy phenylpyruvate dioxygenase
•Characteristic features include:
•Intellectual disability
•Seizures
•Periodic loss of balance and coordination
(intermittent ataxia)

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 HOMOGENTISIC ACIDURIA
•This condition is characterized by
the deficiency of Homogentisate 1,
2 dioxygenase
•Affected subjects excrete large
amounts of homogentisic acid in
their urine hence the name
•On exposure to air, homogentisic
acid polymerizes to alkapton which
leads to the dark coloured
urine/darkening of napkins
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 HOMOGENTISIC ACIDURIA

HO HO
Transamination O
NH3+
•Alkapton is also deposited CH2CHCO2- CH2CCO2-
Tyrosine
in the bones, connective p-Hydroxyphenyl-
pyruvate
tissue and other organs Deficient in O2
leading to ochronosis. alkaptonuria

OH
•Later in life affected Homogentisate
Cleavage of dioxygenase
subjects present with aromatic ring CO2

arthritis O2 CH2 CO2-

Fumarate + acetoacetate OH
Homogentisate
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 ALBINISM
•Deficiency of tyrosinase
•Defective synthesis of melanin in the
skin, hair and eyes
•Extremely sensitive to sunlight.
•They have poor eyesight
•Highly susceptible to sunburn and
skin cancer

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 TYPE 1 ALBINISM IS AN AUTOSOMAL RECESSIVE
GENETIC MUTATION IN THE TYROSINASE GENE
A deficiency in tyrosinase will result in loss
of hair and skin pigments which explains
the albino phenotype.

Interestingly, individuals with

phenylketonuria can have light skin and
hair at birth because of low levels of
tyrosine.

However, phenylketonuriacs are not albinos

because they obtain sufficient amounts of
tyrosine in their diets to support melanin
biosynthesis.
Why is PKU treatable, but albinism is not, even
though both are the result of genetic mutations in
enzymes?www.knust.edu.gh
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 ALBINISM
HO
HO
Tyr hydroxylase
NH3 +
NH3+
CH2CHCO2 - O2 HO CH2 CHCO2-
Tyrosine DOPA
Tyrosinase

O
Melanin Highly colored
(Black polymer) polymeric
intermediates O CH2 CHCO2-
Dopaquinone NH
+ 3

•Melanin formed in skin (melanocytes), eyes, and hair

•In skin, protects against sunlight
•Albinism: genetic deficiency of tyrosinase
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 CATABOLISM OF HISTIDINE

•Histidine ammonia lyase is

deficient in individuals
presenting with histidinaemia
•Histidinaemia is associated with
elevated blood and urine levels
of histidine
•In some affected individuals
there are speech defects and
mental retardation
•Humans deficient in folic acid or
vitamin B12 excrete excessive amounts
of formiminoglutamate (FIGLU)
•Hydantoin 5 propionate is excreted in
the urine
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 ALKAPTONURIA

•Enzyme defect homogentisic acid oxidase

•Increased homogentisic acid in blood, urine, and tissues
•Urine darkens after becoming alkaline on standing at room temperature
•Oxidation of homogentisic acid
•Asymptomatic in childhood
•Tendency toward arthritis in adulthood
•Doesn't show up until later childhood. Later brown pigment deposits in tissues
may lead to arthritis and liver and heart disorders

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 ALKAPTONURIA
HO HO
Transamination O
NH3+
CH2 CHCO2 - CH2 CCO2-
Tyrosine
p-Hydroxyphenyl-
pyruvate
Deficient in O2
alkaptonuria p-Hydroxyphenyl-
pyruvate
OH
Homogentisate dioxygenase
dioxygenase (ascorbate-dep.)
Cleavage of
aromatic ring CO2
CH2CO2-
O2
Fumarate + acetoacetate OH
Homogentisate

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 CATECHOLAMINE BIOSYNTHESIS
HO HO Catechol
Tyr hydroxylase
NH3 + NH3+
CH2CHCO2- O2 HO CH2CHCO2-
Tyrosine
Dihydroxyphenylalanine
(DOPA)

HO Epinephrine DOPA
(Adrenaline) decarboxylase
CO2
HO CHCH2 NHCH3
HO
OH Methyl Dopamine
transferase hydroxylase

S-Adenosyl- HO CH2CH2NH2
HO
homocysteine
Dopamine
SAM

HO CHCH2 NH2
DOPA, dopamine, norepinephrine, and epinephrine Norepinephrine
are all neurotransmitters OH
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 CATECHOLAMINES
• Epinephrine, Norepinephrine, Dopamine
• Amine derivatives of catechol
Reactions:
– Tyr  L- DOPA
• Tyr hydroxylase
– L-DOPA  Dopamine + CO2
• Aromatic acid decarboxylase

– Dopamine  Norepinephrine
• Dopamine β-hydroxylase
– Norepinephrine  Epinephrine
• Requires SAM
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 TRYPTOPHAN METABOLISM: SEROTONIN FORMATION
+
Indole ring NH3 +
NH3
CH2CHCO2-
CH2CHCO2- CH2CH2NH2
Trp
hydroxylase HO HO
Decarboxylase
N
H O2 N
N
H H
Tryptophan 5-Hydroxy- CO2 5-Hydroxy-
(Trp) tryptophan tryptamine (5-HT);
Serotonin

• Trp  5-hydroxytryptophan - Requires 5,6,7,8 tetrahydrobiopterin

• 5-HT  Serotonin + CO2 – Requires Aromatic acid decarboxylase
• Serotonin causes smooth muscle contraction
– Brain neurotransmitter
– Melatonin synthesized in pineal gland
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 SEROTONIN
Serotonin formed in:
• Brain (neurotransmitter; regulation of sleep, mood, appetite)
• Platelets (platelet aggregation, vasoconstriction)
• Smooth muscle (contraction)
• GIT (enterochromaffin cells - major storage site)

Drugs affecting serotonin actions used to treat:

• Depression - Serotonin-selective reuptake inhibitors (SSRI)
• Migraine
• Schizophrenia
• Obsessive-compulsive disorders
• Chemotherapy-induced emesis

• Some hallucinogens (e.g., LSD) act as serotonin agonists

 SEROTONIN METABOLISM: MELATONIN
CH2 CH2 NH2 CH2 CH2 NHCOCH3
HO H3 CO
2 Steps

N N
H H
Serotonin Melatonin

Melatonin:
• Formed principally in pineal gland
• Synthesis controlled by light, among other factors
• Induces skin lightening
• Suppresses ovarian function
• Possible use in sleep disorders
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TRYPTOPHAN METABOLISM : BIOSYNTHESIS OF NICOTINIC ACID

+
NH3
CH2CHCO2- CO2 H
Several steps

N
H N
Nicotinic acid
Tryptophan (Niacin)

Nicotinamide adenine
dinucleotide (NAD)

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 FORMATION OF SERINE

CO 2 - CO 2 -
Dehydrogenase
Glucose Glycolysis
H C OH C=O
NAD+ NADH +
CH2 OPO3-2 H+
CH2 OPO3-2
3 Steps 3-Phospho- 3-Phospho-
glycerate hydroxypyruvate
Pyruvate
Inhibits Glutamate
Transaminase
a-Ketoglutarate
CO 2 - CO 2 -

Phosphatase
H C NH3 +
H C NH3+

CH2 OH CH2 OPO3-2

Serine (Ser) 3-Phosphoserine
 CONVERSION OF SERINE TO GLYCINE
H
Dihydrofolate H2 N N
N
reductase
Folate CO 2 -
N
N CH2 NHR
H C NH3 +
OH
H Serine
Tetrahydrofolate CH2 OH
(FH4)
Serine hydroxymethyl
transferase (PLP-dep.)
H
N
Key intermediate
CO 2 -
in biosynthesis of
purines and N CH2 Glycine
H C NH3 +
formation of N
H2C H
thymine
N5, N10-Methylene FH4 Important in
biosynthesis of
Heme,
porphyrins,
and purines
• Illustrate how dopamine, epinephrine GABA,, are related
in amino acid metabolism.

Illustrate how MOA inhibitors serotonin, melanin and

melatonin are related in amino acid metabolism.

How will you account for allergies with reference to

histidinaemia.

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