Download Catabolism of the branched

Catabolism of the branched-chain
amino acids
• The branched-chain amino acids, isoleucine, leucine, and valine, are
essential amino acids.
• In contrast to other amino acids, they are metabolized primarily by
the peripheral tissues (particularly muscle), rather than by the liver.
• They are oxidized as fuels primarily in muscle, adipose, kidney, and
brain.
• These extrahepatic tissues contain an aminotransferase, absent in
liver, that acts on all three branched-chain amino acids to produce
the corresponding α-keto acids.
• These three amino acids have a similar route of catabolism.
• The initial steps in valine, leucine, and isoleucine degradation are
identical. All three are first deaminated to a-keto acids, which are
then oxidatively decarboxylated to form CoA derivatives.
1. Transamination: Removal of the amino groups of all
three amino acids is catalyzed by a single, vitamin
B6–requiring enzyme, branched-chain α-amino acid
aminotransferase.
2. Oxidative decarboxylation: Removal of the carboxyl
group of the α-keto acids derived from leucine,
valine, and isoleucine is catalyzed by a single
multienzyme complex, branched-chain α-keto acid
dehydrogenase complex.
• This complex uses five cofactors: thiamine
pyrophosphate, lipoic acid, FAD, NAD+, and CoA as
its coenzymes.
• Degradation of leucine, valine, and
isoleucine.
• TPP = thiamine pyrophosphate.
3. Dehydrogenation: Oxidation of the products formed in the
above reaction yields α-β-unsaturated acyl CoA derivatives.
4. End products:
•
isoleucine ultimately yields acetyl CoA and succinyl CoA,
rendering it both ketogenic and glucogenic.
•
Valine yields succinyl CoA and is glucogenic.
•
Leucine is ketogenic, being metabolized to acetoacetate and
acetyl CoA.
•
[Note: Branched-chain amino acid catabolism also results in
glutamine and alanine being sent out into the blood from
muscle.]
Maple syrup urine disease
• It is a hereditary defect in the oxidative decarboxylation of these
branched-chain a-keto acids.
• Due to the deficiency of branched-chain α-keto acid dehydrogenase
complex.
• The metabolic block created by this defect leads to elevated levels
of valine, leucine, and isoleucine (and their corresponding
branched-chain a-keto acids) in the blood and urine.
• The accumulation of the branched-chain α-keto acid substrates in
urine give their sweet odor and prompted the name maple syrup
urine disease.
• If untreated, the disease results in abnormal development of the
brain, mental retardation, and death in early infancy.
• Treatment by rigid control of the diet, limiting the intake of valine,
isoleucine, and leucine to the minimum required to permit normal
growth.
Catabolic pathways of three branched chain amino acids
Inherited Disorders of A.A
Catabolism
Inborn Errors Of Metabolism
Phenylketonuria
• Phenylketonuria (PKU), caused by a deficiency of phenylalanine
hydroxylase, PKU is the most common clinically encountered inborn
error of amino acid metabolism (prevalence 1:15,000).
• Hyperphenylalaninemia may also be caused by deficiencies in any
of the several enzymes required to synthesize BH4, or in
dihydropteridine (BH2) reductase, which regenerates BH4 from BH2.
• Biochemically, it is characterized by:
• accumulation of phenylalanine in blood & urine (and a deficiency
of tyrosine) [phenylalanine in the blood that is 30-50 times higher
than normal ].
• Excretion of large amounts of phe, phenylpyruvate, phenylacetate
and phenyllactate in urine.
• Phenylacetate gives a characteristic mousy odor to the urine.
Phenylketonuria
The most important symptoms of the disease are:
• 1) Mental retardation.
2) Hypopigmentation.
• Mental retardation results unless treatment
begins immediately after birth.
• Treatment consists of limiting phenylalanine
intake to levels barely adequate to support
growth. Tyrosine, an essential nutrient for
individuals with phenylketonuria, must be
supplied in the diet.
Alternative pathways for
catabolism of phenylalanine in
phenylketonuria:
• The high level of
phenylalanine leads to the
production of phenylalanine
metabolites such as
phenylpyruvate,
phenylacetate and
phenyllactate, all of which are
associated with the observed
neurological and
developmental problems.
PKU cont….
• Tyrosine is used not
only for protein
synthesis, but
tyrosine is also the
precursor for
neurotransmitter
dopamine, as well
as, skin pigments
(melanins) and
epinephrine.
• Why patients with
PKU have
hypopigmentation ?
Albinism
• Albinism refers to a group of conditions in which a defect in
tyrosine metabolism results in a deficiency in the
production of melanin.
• These defects result in the partial or full absence of
pigment from the skin, hair, and eyes.
• Albinism appears in different forms ,Complete albinism
(also called tyrosinase-negative oculocutaneous albinism)
results from a deficiency of tyrosinase, causing a total
absence of pigment from the hair, eyes, and skin.
• It is the most severe form of the condition. In addition to
hypopigmentation, affected individuals have vision defects
and photophobia (sunlight hurts their eyes). They are at
increased risk for skin cancer.
Alkaptonuria
• Alkaptonuria is a rare metabolic disease involving a deficiency in
homogentisic acid oxidase, resulting in the accumulation of homogentisic
acid. [This reaction occurs in the degradative pathway of tyrosine]
• There are three characteristic symptoms:
- homogentisic aciduria (the patient's urine contains elevated levels of
homogentisic acid, which is oxidized to a dark pigment on standing.
- Joint arthritis.
- Black ochronotic pigmentation of cartilage and collagenous tissue.
• Patients with alkaptonuria are usually asymptomatic until about age 40.
• Dark staining of the diapers sometimes can indicate the disease in infants.
• Diets low in protein—especially in phenylalanine and tyrosine—help
reduce the levels of homogentisic acid, and decrease the amount of
pigment deposited in body tissues.
Alkaptonuria:
It is characterized by dark color urine, large arthritis
with dark cartilage.