Amino acid metabolism V.Enzymopathies related to amino acid

metabolism

Figures:

Lehninger-4ed; chapter: 18

(Stryer-5ed; chapter: 23)

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)

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

• 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

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)

Deficiencies of ornithine transcarbamoylase, argininosuccinase,

argininosuccinate synthetase are treated by supplementing

the diet with Arg!

In arginase deficiency (rare) Arg excluded from diet

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)

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.)

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

3.) Maple Syrup Urine Disease (MSUD)

• 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

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

5.) Histidinaemia

• Defect of histidase or histidine-amino lyase

(His degradation)

• Mental retardation (causal relationship not proven yet)

• Treatment:Controlled administration of His

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!)

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!

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:

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

8.) Tyrosinaemia III

• Defect of para hydroxyphenyl

pyruvate dioxygenase (Phe/Tyr

degradation)

• Mild mental retardation,

drowsiness, ataxia

9.) Alkaptonuria

• Defect of homogentisate dioxygenase (Phe/Tyr degradation)

• Urine darkens on standing (black), arthritis

• Treatment:Ascorbic acid diet poor in proteins

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

11.) Albinism

• Defect of the tyrosine 3-monooxygenase (tyrosinase)

(melanine synthesis from tyrosine)

• lack of pigmentation: white hair pink skin