FATE OF THE CARBON

SKELETON OF AMINO ACIDS

Dr. Daniel Gyamfi

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 Degradation of amino acids to one of seven
common metabolic intermediates
Glucogenic degradations
in green
Ketogenic degradations
in red

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 CATABOLISM OF BRANCHED CHAIN
AMINO ACIDS:
LEUCINE, ISOLEUCINE & VALINE
• The main site for the catabolism of the branched chain
amino acids (all essential AAs) is the skeletal muscle

• However, it has also been demonstrated in the

adipose, kidney and brain tissues

• The catabolism commences with a specific

aminotransferase (higher in muscles than liver)
which converts the respective amino acids into α-keto
acids in the cytosol where α-ketoglutarate is the
acceptor (transamination reaction) 3
Branched Chain Amino Acids Catabolism
3 common
steps
1 - Transamination

2 – Oxidative
decarboxylation

3 - Dehydrogenation

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 CATABOLISM OF LEUCINE,
ISOLEUCINE & VALINE
• The α-keto acids are then acted on by branched
chain α-keto acid dehydrogenase complex (which
is synonymous to the PDC/α-KDC) in the
mitochondria (oxidative decarboxylation reaction) to
produce the corresponding Acyl CoA thioesters

• 5 coenzymes used - TPP, CoASH, Lipoamide,

FAD, NAD+

• 3 enzymes decarboxylase, a transacylase, and a

dihydrolipoyl dehydrogenase 5
 CATABOLISM OF LEUCINE,
ISOLEUCINE & VALINE
• The α-keto acid dehydrogenase complex is
regulated by covalent modification

• This is in response to the presence of branched

chain amino acids in the diet

• The enzyme complex is inactivated by

phosphorylation and activated by
dephosphorylation (via kinase and phosphatase,
respectively)
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 Maple Syrup Urine Disease
• The deficiency of α-keto acid dehydrogenase complex
has been associated with the Maple Syrup Urine
Disease

• This condition is characterized by the accumulation of

α-keto acids in the blood and their excretion in the urine
– also called branched chain ketonuria

• The urine and sweat of affected individuals have the

odour of maple syrup (or burnt sugar)

• The accumulation of BCAAs impairs transport &

function of other AAs – even protein synthesis affected7
 Maple Syrup Urine Disease
• 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

• Diagnosis: urinary branched amino acids and keto

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acids & enzyme analysis
 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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 ISOVALERIC ACIDAEMIA
• This condition is due to the deficiency of Isovaleryl
CoA dehydrogenase required for the catabolism of
leucine (i.e. isovaleryl CoA to β-methylcrotonyl CoA is
impaired)

• The accumulation and excretion of isovalerate

(isovaleric acid) is high in urine

• The breath and urine (body fluids) of affected

subjects have a `cheesy’odour

• Affected subjects present with a mild mental

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retardation
 ISOVALERIC ACIDAEMIA
• 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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CATABOLISM OF PHENYLALANINE

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 CATABOLISM OF PHENYLALANINE

• Phenylalanine is usually hydroxylated to tyrosine in

a reaction catalyzed by phenylalanine hydroxylase
(present in the liver)

• The cofactor for this reaction is tetrahydrobiopterin

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 PHENYLKETONURIA
• The deficiency of the phenylalanine hydroxylase, the
cofactor or the dihydrobiopterin reductase (dihydrobiopterin
→ tetrahydrobiopterin) which regenerates the cofactor may
lead to PKU
Alternative pathway

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 PHENYLKETONURIA
• It is characterized by the accumulation of
phenylalanine and phenylketones (from alternative
pathway) in the blood and their excretion in the
urine

• The urine of affected subjects has a `mousey’

odour (due to phenylacetate)

• Affected subjects present with severe mental

retardation; a low IQ; failure to grow; and dilution of
hair and skin pigmentation (hypopigmentation)
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 PHENYLKETONURIA
• Management of the condition requires the restriction
of phenylalanine containing diets

• The diet of subjects should however be high in

tyrosine (essentail now)* for the first 4-5 years
(prevent the damage to brain)

• Protein diet restriction should be enforced for

several years

• The diets of subjects should contain high levels of

tetrahydrobiopterin 16
 PHENYLKETONURIA
• Diagnosis of PKU:

– Guthrie test: for phenylalanine in blood (bacterial

inhibition assay; β-2-thienylalanine inhibits
growth of Bacillus subtilis)

– Ferric chloride test: for phenylpyruvate in urine

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 METABOLISM OF TYROSINE

The metabolic fate of tyrosine are as follows:

Catecholamines

Thyroid Hormones

Melanin pigment

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 Catabolism of Tyrosine
• Tyrosine is catabolized through a series of reactions
leading to the synthesis of acetoacetate and
fumarate
• The reactions include transamination,
dioxygenation, isomerisation, hydrolysis reactions

• Occurs mostly in the liver

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Catabolism of Tyrosine

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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 (prematured
babies more affected)

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 TYROSINAEMIA
• 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

• There are three distinct types of tyrosinaemia

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Vit C

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 Type I Tyrosinaemia
• This condition is characterized by the deficiency of
fumarylacetoacetase (fumaryl acetoacetate hydrolase)

• It is associated with the accumulation of maleyl

acetoacetate and fumaryl acetoacetate

• Fumaryl acetoacetate accumulates in hepatocytes and

proximal renal tubal cells and causes oxidative damage
and DNA damage leading to cell death

• Some babies may present with the acute form and others
with the chronic form
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 Type I Tyrosinaemia
• The acute form manifests in the first few months
where as the chronic form manifests around one
year

• The symptoms of the acute form are:

– Poor appetite and stunted growth
– Vomiting
– A cabbage-like odour
– Inflammation of the liver (hepatitis)
– Jaundice
– Irritability
– lethargy 25
 Type I Tyrosinaemia
• The symptoms of the chronic form are:
– Cirrhosis of the liver
– Polyneuropathy
– Kidney problems

• It is otherwise referred to as hepato-renal

tyrosinaemia

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 Type II Tyrosinaemia
• This condition is characterized by the deficiency of
tyrosine aminotransferase

• Accumulation and excretion of tyrosine and its

metabolites - including p-hydroxyphenylpyruvate,
and p-hydroxyphenyllactate

• It is associated with eye and skin lesions as well as

mental retardation (rare)

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 Type II Tyrosinaemia
• The symptoms begin in early childhood and
include:
– 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
• It is characterized by the deficiency of para-
hydroxy phenylpyruvate dioxygenase

• Characteristic features include:

– Intellectual disability
– Seizures
– Periodic loss of balance and coordination (intermittent
ataxia)

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 HOMOGENTISIC ACIDURIA
(Alkaptonuria)
• 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 gets oxidized

to the corresponding quinones, which polymerize to
give alkapton (black or brown colour) and leads to
the darkening of napkins

• The urine of alkaptonuric patients resembles coke

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in colour
 HOMOGENTISIC ACIDURIA
• Alkapton is also deposited in the bones, connective
tissue and other organs leading to ochronosis

• Later in life affected subjects present with arthritis

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 HOMOGENTISIC ACIDURIA
• Diagnosis:
– Change in colour of the urine on standing to brown or
dark (T. Mtd);

– Ferric chloride – positive ((a green colour is obtained);

– Benedict’s test – positive (reducing ability of

homogentisate)

• Treatment: Consumption of protein diet with

relatively low phenylalanine
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 MELANIN SYNTHESIS
• Melanin (Greek: melan-black) is the pigment of skin,
hair and eye

• Melanin synthesis occurs in melanosomes present

in melanocyte (pigment-producing cells)

• It is synthesized from tyrosine catalyzed by only

one enzyme, tyrosinase

• Tyrosinase converts tyrosine to DOPA and DOPA to

dopaquinone, then ultimately to melanin (black and
red melanin polymers – separate pathways) 33
 ALBINISM
• Deficiency of tyrosinase enzyme results in
albinism

• It is characterised by defective synthesis of

melanin in the skin, hair and eyes

• Caused by autosomal recessive genetic mutation

in the tyrosinase gene

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 ALBINISM (cont.)
• Affected subjects are extremely sensitive to sunlight

• Lack of pigment in the eyes causes photophobia but

does not impaired eyesight

• They are also highly susceptible to sunburn and skin

cancer

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Albino phenotype
 CATABOLISM OF HISTIDINE
• The first irreversible step in histidine catabolism is
its conversion to urocanic acid and NH3 catalysed
by histidine ammonia lyase (Histidase) (mostly
present in the liver and skin*)

• The urocanic acid* is subsequentially converted to

Formiminoglutamate (FIGlu)

• FIGlu is also converted in the presence of

tetrahydrofolate (THFA) to glutamate and N5-
formimino THFA
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CATABOLISM OF HISTIDINE (cont)

Histidase Urocanase
4-imidazolone
5-propionate
Histidine Urocanate

imidazolone propionase

glutamate
formiminotransferase

Glutamate
N5-Formimino-THFA
N-Formiminoglutamate (FIGlu)
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 CATABOLISM OF HISTIDINE (cont)
• Deficiency of folic acid or vitamin B12 in humans
results in accumulation of FIGlu and its excessive
excretion in urine

• Histidine load test - excretion of FIGLU in urine is

used to assess folic acid deficiency

• Folate deficiency may be due to malnutrition or may

be drug induced

• Folate deficiency is characterized by biochemical

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and haematological changes
 CATABOLISM OF HISTIDINE (cont)
• Deficiency of folate results in inadequate synthesis
of DNA and abnormal cell division

• Can lead to macrocytic RBC formation

(megaloblastic anaemia)

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 HISTIDINAEMIA
• Histidine ammonia lyase (histidase) 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

• (A). Absence of: (1) urocanate detection in sweat or

(2) Histidase in skin biospy confirms the condition
OR (B). blood and urine levels of histidine 40
THE END

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