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Amino acid metabolism V.Enzymopathies related to amino acid
metabolism
Figures:
Lehninger-4ed; chapter: 18
(Stryer-5ed; chapter: 23)
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I. Urea Cycle Defects (UCD’s)
• Lack or defect of urea cycle (or any of its enzymes) is crucial
for life
• A typical result of UCD’s (except arginase defect) is
hyperammonemia or the build-up of one or more urea cycle
intermediates (depending on the missing enzyme)
• Permanent activation of glutamate dehydrogenase also cause
hyperammonemia (hyperinsulinism-hyperammonemia
syndrome)
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Possible treatments:
• low protein diet (strict dietary control and supplements
of essential amino acids)
• removal of excess ammonia
• refill of urea cycle intermediate pools
• careful administration of aromatic acids (benzoate and
phenylbutyrate) in the diet can help lower the level of NH3
in the blood
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• Gly and Gln used up must be regenarated in reactions that take upNH3
• hippurate and phenylacetylglutamineare nontoxic and are excreted in theurine
• this pathways become prominentwhen aromatic acids are ingested
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N-acetylglutamate synthase deficiency:
• results in the absence of N-acetylglutamate (normal activator of
carbamoyl phosphate synthetase I)
• treatment: administering carbamoyl glutamate
(activator of carbamoyl-P synthetase I)
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Deficiencies of ornithine transcarbamoylase, argininosuccinase,
argininosuccinate synthetase are treated by supplementing
the diet with Arg!
In arginase deficiency (rare) Arg excluded from diet
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Neurotoxic effects of hyperammonemia
• Hepatogenic encephalopathy• Ammonia easily crosses blood-brain barrier• It is annihilated or scavenged in glutamate dehydrogenase
reaction, while consuming -ketoglutarate• Abnormal depletion of -ketoglutarate decreases the rate
of TCA cycle, in an extreme case to 0 energy production slows down or may even stop
• (Excess ammonia consumes glutamate, a precursor of GABA - an important neurotransmitter - in the glutaminase reaction)
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II. Genetic disorders of the amino acid degradation
1.) Nonketotic hyperglycinemia
● Defect of the glycine cleavage enzyme(Gly degradation)
● Elevated serum levels of Gly severe mental deficiencies anddeath in very early childhood
(Gly is an inhibitory neurotransmitter, perhaps explaining theneurological effects of the disease.)
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2.) Methylmalonic aciduria
• Defect of methylmalonylCoA isomerase
(methylmalonylCoA succinyl-CoA)
• Ketoacidosis, mental retardation, early death
• Treatment:
Vitamin B12, administration of controlled amounts of
the amino acids involved
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3.) Maple Syrup Urine Disease (MSUD)
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• Defect of the branched-chain -keto acid dehydrogenase complex
(degradation of Leu, Ile and Val)
• Lethal in days after birth (vomit, spleen) if not, it causes mental
retardation
• Urine has a characteristic odor after day 6-7 (the -keto acids
accumulate in the blood urine)
• Treatment:
Administration of a diet with strictly controlled amounts of Leu, Ile, Val
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4.) Homocystinuria I.
• Defect of cystathionine -synthase
(Met degradation)
• Mental retardation, thrombosis in arteries and veins
• Treatment:
Vitamin B6, diet rich in Cys and poor in Met
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5.) Histidinaemia
• Defect of histidase or histidine-amino lyase
(His degradation)
• Mental retardation (causal relationship not proven yet)
• Treatment:Controlled administration of His
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Genetic disorders of phenylalanine degradation
6.) Phenylketonuria (PKU)
• Defect of phenylalanine hydroxylase(Phe degradation)
• Mental retardation(phenylpyruvate inhibits pyruvate decarboxylase in the brain and the formation of myelin; it has influence on the levels of different neurotransmitters as well)Inhibits Trp metabolism as well
• Treatment:Diet poor in Phe and Tyr (only for protein synthesis!)
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Defect of dihydrobiopterinreductase can also causePKU!
Tetrahydrobiopterin is required for the formation of L-dopa and 5-hydroxy-tryptophan (precursors ofnorepinephrin and serotonin)
In this type of PKU, theseprecursors must be supplied in the diet!
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Phenylpyruvate, phenylacetateand phenyllactate can accumulatein tissues, blood, and urine.
The characteristic odor of theurine is due to the phenylacetate.
Alternative pathway for catabolism of Phe in PKU:
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7.) Tyrosinaemia II (Richner-Hanhart Syndrom)
• Defect of cytosolic (soluble) tyrosine aminotransferase (Phe/Tyr degradation)
• Ulcers, keratosis, keratitis, mental retardation, p-hydroxy phenyllactate accum. in urine
• Treatment:Diet poor in Phe and Tyr
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8.) Tyrosinaemia III
• Defect of para hydroxyphenyl
pyruvate dioxygenase (Phe/Tyr
degradation)
• Mild mental retardation,
drowsiness, ataxia
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9.) Alkaptonuria
• Defect of homogentisate dioxygenase (Phe/Tyr degradation)
• Urine darkens on standing (black), arthritis
• Treatment:Ascorbic acid diet poor in proteins
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10.) Tyrosinaemia I (tyrosinosis)
• Defect of fumarylaceto-
acetase
(Phe, Tyr degradation)
• Hepatic cyrrhosis,
dilatation of microtubules
in the kidney, urine with
characteristic odor
• Treatment: diet poor in
Phe and Tyr
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11.) Albinism
• Defect of the tyrosine 3-monooxygenase (tyrosinase)
(melanine synthesis from tyrosine)
• lack of pigmentation: white hair pink skin
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