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 NH 3 in the blood

Gly and Gln used up must be regenarated in reactions that take up NH 3 hippurate and phenylacetylglutamine are nontoxic and are excreted in the urine this pathways become prominent when 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 and death in very early childhood (Gly is an inhibitory neurotransmitter, perhaps explaining the neurological effects of the disease.)

2.) Methylmalonic aciduria Defect of methylmalonylCoA isomerase (methylmalonylCoA  succinyl-CoA) Ketoacidosis, mental retardation, early death Treatment: Vitamin B 12, 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 B 6, 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 dihydrobiopterin reductase can also cause PKU! Tetrahydrobiopterin is required for the formation of L-dopa and 5-hydroxy- tryptophan (precursors of norepinephrin and serotonin) In this type of PKU, these precursors must be supplied in the diet!

Phenylpyruvate, phenylacetate and phenyllactate can accumulate in tissues, blood, and urine. The characteristic odor of the urine 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