Tyrosine metabolic disorders

Inherited Metabolic Disorders Errors of Phenylalanine and Tyrosine Metabolism L. I. Woolf... 

An unaffected patient will have a negative DNPH result. Mildly affected or partially treated patients may also yield negative results. Patients with a blood phenylalanine level (indicative of PKU) over 1 mmol/1 should generate positive DNPH results. Patients with a blood leucine level (indicative of MSUD) of 0.8 mmol/1 or higher usually show a positive DNPH result. Patients with pyruvate metabolic disorders may also give positive results, as will patients with true and transient disorders of tyrosine degradation. 

Because enzymes are required in all metabolic pathway reactions, a missing or damaged enzyme may result in a metabolic disorder, meaning that the pathway can no longer produce what it should because there is an interruption in the series of required reactions. When this happens, cells may have too much of some substances or too little of others. For example, a disorder called phenylketonuria is caused by the lack of an enzyme called phenylalanine hydroxylase. The enzyme converts the amino acid phenylalanine to another amino acid, tyrosine. When the enzyme is missing, phenylalanine... 

A number of genetic disorders are associated with phenylalanine and tyrosine metabolism. The best known is the classic phenylketonuria, discovered in 1934 by Foiling. It is characterized by the virtual absence of phenylalanine hydroxylase from the organism. As a result, phenylalanine is converted to a large extent to phenylpyruvate, phenyllactate, and phenylacetate (Figure 20.22). Their levels and that of phenylalanine in the bloodstream are elevated. Hyper-phenylalaninemia may also result from the absence of dihydrobiopterin reductase or any enzyme required for dihydrobiopterin biosynthesis from GTP. Although the etiologies of such disorders differ from that of classic phenylke-... 

Additional errors of phenylalanine and tyrosine metabolism include tyrosinosis, or hereditary tyrosinemia, neonatal tyrosinemia, and alcaptonuria. In the first case, there is a probable defect in p-hydroxyphenylpyruvate oxidase. In neonatal tyrosinemia, the problem is transient and may be solved by the administration of ascorbic acid. Ascorbic acid is apparently a cofactor for p-hydroxy-phenylpyruvate oxidase. Alcaptonuria is a benign disorder in which homogen-tisic acid oxidase is inoperative and homogentisic acid is excreted in the urine. Air oxidizes the homogentisic acid to a pigment, giving urine a black color. This pigment also accumulates in the patient s tissues. 

W22. Woolf, L. I., Inherited metabolic disorders Errors of phenylalanine and tyrosine metabolism. Advan. Clin. Chem. 6, 97-230 (1963). 

Malfunction of the thyroid gland results in serious metabolic disorders, with cardiovascular consequences. The thyroid gland secretes thyroxin, an iodine derivative of tyrosine. The thyroid gland therefore concentrates iodine, and administration of iodine-123, which is a y-emitter, will allow direct observation of the radionuclides distribution in the gland, using radiation detection apparatus. Uneven distribution will reveal the presence and possibly the type of disorder. 

These disorders of tyrosine metabolism are described in Chapter 47. 

Fig. 4.1. Tyrosine degradation pathway. Metabolic markers are framed. Possible metabolic disorders are marked with boxes, 4.1, fumarylacetoacetase 4.2, tyrosine aminotransferase 4.3, 4-hydroxyphenylpyruvate dioxygenase 4.5, homogentisate dioxygenase. Inhibition by succinylacetone and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-l,3-cyclo-hexanedione) are indicated by crosses. 5-ALA, 5-aminolevulinate...

Whenever an exceedingly high tyrosine concentration is found, especially if it is accompanied by eye symptoms, it seems appropriate to reduce phenylalanine and tyrosine intake whether it is a transient tyrosinemia in the newborn or caused by an inherited disorder of tyrosine metabolism. Especially for tyrosinemia type II and III, positive confirmation of the diagnosis may be delayed considerably, and if a liver biopsy is considered, this should wait until persistency of the tyrosinemia has been established. 

Some inherited metabolic disorders are extremely damaging while the effects of others are so mild that they can hardly be called diseases. For example, alkaptonurics are usually quite healthy although in later life they are prone to a particular form of arthritis. Similarly the conditions of fructosuria and pentosuria, in which fructose and pentose sugars respectively appear in the urine, have no pathological consequences. At the other end of the scale is phenylketonuria in which the enzyme phenylalanine hydroxylase, which is responsible for converting phenylalanine to tyrosine, is lacking. In this condition phenylpyruvic acid and other intermediate products of phenylalanine metabolism accumulate in the blood and tissues and are so injurious to the central nervous system that, although physical development is essentially normal, there is severe mental retardation. 

Nitisinone (26, Orfadin ) is the first drug approved in Europe for the treatment of hereditary tyrosinemia type 1 (HT-1), a rare genetic metabolic disorder caused by a deficiency of fumarylacetoacetate hydrolase (FAH), an enzyme involved in the metabolism of tyrosine [69]. Nitisinone is a derivative of leptospermone (27), an effective herbicide present in the bottlebrush... 

The most widely known metabolic disorders are those which result in impairment of the intermediary metabolism of nutrients such as proteins, carbohydrates and lipids. For example, phenylketonuria is due to a genetic deficiency of phenylalanine hydroxylase, an enzyme involved in the conversion of phenylalanine to tyrosine. As a result, when ingested in amounts normally encountered in the diet, phenylalanine accumulates in blood and cerebrospinal fluid along with its pyruvate, lactate and acetate derivatives. (See review by McBean and Stephenson. ) The toxic response takes the form of severe mental retardation, neural and dermal lesions and premature death. But phenylalanine is an essential dietary amino acid and cannot be rigorously excluded from the diet, even of sufferers from phenylketonuria, though fortunately they do respond to reduced dietary intakes. Clearly, phenylalanine hydroxylase deficiency narrows the gap between the required intake and that which elicits a toxic response because this pathway is more readily overloaded . 

Disorders of L-tyrosine metabolism tyrosinaemia, tyrosinosis, tyrosyluria... 

Tyrosyluria (the excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyl-lactate and 4-hydroxyphenylacetate with hypertyrosinaemia) occurs in some normal newborn babies, particularly premature babies, scurvy (ascorbate or vitamin C deficiency), tyrosinosis (Medes, 1932), hepatic cytosol tyrosine transaminase deficiency (oculo-cutaneous tyrosinaemia) (Kennaway and Buist, 1971), in hereditary tyrosinaemia ( inborn hepatorenal dysfunction with tryosyluria ) (LaDu and Gjessing, 1978) and as a secondary phenomenon to a number of liver diseases, including several inherited metabolic diseases unassociated directly with tyrosine metabolism (for example, propionic acidaemia) or involving disorders of carbohydrate metabolism (for example, galactosaemia and fructosaemia). 

Buist, N.R.M., Kennaway, N.G. and Fellman, J.H. (1974), Disorders of tyrosine metabolism. In Heritable Disorders of Amino Acid Metabolism (ed. W.L. Nyhan), J. Wiley Sons, New York, pp. 160-176. 

The metabolism of norepinephrine is reported to be altered by other drugs used in the treatment of the affective disorders and a number of studies have shown a change in the metabolism of norepinephrine as a result of Li+ treatment. In rat brain, acute Li+ treatment enhances the uptake of norepinephrine in synaptosomes [151] and the enhanced turnover of this neurotransmitter may be due to an increase in its deamination in the brain, although Li+ also causes a slight increase in the levels of the amino acid precursor, tyrosine, in the brain and plasma of rats [152]. Also, acute Li+ treatment induces a decrease in the release of norepinephrine after electrical stimulation of rat brain [153]. Interest-... 

BH4 is an obligatory cofactor for both tyrosine and tryptophan hydroxylase. Consequently, the inborn errors of BH4 metabolism are associated with impaired dopamine and serotonin turnover, which is reflected by decreased concentrations of HVA and 5HIAA in the CSF. Whilst such a pattern is particularly true for the autosomal recessive disorders of BH4 metabolism, an autosomal dominant disorder of BH4 metabolism, (autosomal dominant GTP cyclohydrolase deficiency) is not always associated with marked decreases in the CSF concentration of HVA and 5HIAA [1]. 

The option to remove the toxin from the environment of susceptible persons is taken in hemochromatosis, a common disorder of iron metabolism(101) that affects 1 in 300 persons of northern European descent. Most cases of hereditary hemochromatosis are attributed to a polymorphism of HFE, which results in substitution of tyrosine for cysteine at codon 282. The disease, untreated, causes liver cirrhosis, heart failure, diabetes and arthritis and leads to early death treatment by phlebotomy to remove excess iron allows affected persons to live a normal life span. 

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