Tyrosine defective

Figure 1.2 Consequences of a metabolic block in pheylalanine-tyrosine Defective phenylalanine hydroxylase can lead to the accumulation of phenylalanine, which can cause damage to brain cells and mental retardation in phenylketonuric babies. Another metabolic blockage caused by a defective enzyme can lead to alcaptonuria.

Hibbs ML, Tarlinton DM. Armes J. Grail D. Hodgson G, Maghtto R, Stacker SA, Dunn AR Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 1995 83 301-311. Nishizumi H, Yamamoto T Impaired tyrosine phosphorylation and Ca + mobiUzation, but not degranulation, in Lyn-deficient bone marrow-derived mast cells. J Immunol 1997 158 2350-2355. 

Figure28-10. The phenylalanine hydroxylase reaction. Two distinct enzymatic activities are involved. Activity II catalyzes reduction of dihydrobiopterin by NADPH, and activity I the reduction of O2 to HjO and of phenylalanine to tyrosine. This reaction is associated with several defects of phenylalanine metabolism discussed in Chapter 30.

Figure 30-12. Intermediates in tyrosine catabolism. Carbons are numbered to emphasize their ultimate fate. (a-KG, a-ketoglutarate Glu, glutamate PLP, pyridoxal phosphate.) Circled numerals represent the probable sites of the metabolic defects in type II tyrosinemia neonatal tyrosinemia alkaptonuria and 0 type I tyrosinemia, or tyrosinosis.

The probable metabohc defect in type I tyrosine-mia (tyrosinosis) is at himarylacetoacetate hydrolase (reaction 4, Figure 30-12). Therapy employs a diet low in tyrosine and phenylalanine. Untreated acute and chronic tyrosinosis leads to death from liver failure. Alternate metabolites of tyrosine are also excreted in type II tyrosinemia (Richner-Hanhart syndrome), a defect in tyrosine aminotransferase (reaction 1, Figure 30-12), and in neonatal tyrosinemia, due to lowered y>-hydroxyphenylpyruvate hydroxylase activity (reaction 2, Figure 30-12). Therapy employs a diet low in protein. 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway. The electron donor for phenylalanine hydroxylase is tetrahydrobiopterin (BH4), which transfers electrons to molecular oxygen to form tyrosine and dihydrobiopterin (QH2 Fig. 40-2 reaction 2). BH4 is regenerated from QH2 in an NADH-dependent reaction that is catalyzed by dihydropteridine reductase (DHPR), which is widely distributed. In the brain, this... 

In rare instances, PKU is caused by defects in the metabolism of BH4, which is synthesized from GTP via sepiapterin (Fig. 40-2 reactions 3 and 4) [25]. Even careful phenylalanine restriction fails to avert progressive neurological deterioration because patients are unable to hydroxylate tyrosine or tryptophan, the synthesis of which also requires tetrahydrobiopterin. Thus, neurotransmitters are not produced in sufficient amount. 

These patients suffer from a genetic defect of dopamine synthesis, caused by reduced GTP cyclohydrolase activity. This enzyme is rate-limiting in the biosynthesis of tetra-hydrobiopterin, a cofactor of the dopamine-synthesizing enzyme tyrosine hydroxylase (see Fig. 40-2). 

A much more serious genetic disease, first described by Foiling in 1934, is phenylketonuria. Here the disturbance in phenylalanine metabolism is due to an autosomal recessive deficiency in liver phenylalanine hydroxylase (Jervis, 1954) which normally converts significant amounts of phenylalanine to tyrosine. Phenylalanine can therefore only be metabolized to phenylpyruvate and other derivatives, a route which is inadequate to dispose of all the phenylalanine in the diet. The amino acid and phenylpyruvate therefore accummulate. The condition is characterized by serious mental retardation, for reasons which are unknown. By the early 1950s it was found that if the condition is diagnosed at birth and amounts of phenylalanine in the diet immediately and permamently reduced, mental retardation can be minimized. The defect is shown only in liver and is not detectable in amniotic fluid cells nor in fibroblasts. A very sensitive bacterial assay has therefore been developed for routine screening of phenylalanine levels in body fluids in newborn babies. 

Faith A, Akdis CA, Akdis M, Simon H-U, Blaser K Defective TCR stimulation in anergized type 2 T helper cells correlates with abrogated p56(lck) and ZAP-70 tyrosine kinase activities. J Immunol 1997 159 53-60. 

Tyrosine (Tyr or Y) (4-hydroxyphenylalanine ((5)-2-amino-3-(4-hydroxyphenyl)-propanoic acid)) is a polar, neutral, aromatic amino acid with the formula H00CCH(NH2)CH2C6H50H and is the precursor of thyroxin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and the pigment melanin. Being the precursor amino acid for the thyroid gland hormone thyroxin, a defect in this may result in hypothyroidism. Tyr is extremely soluble in water, a property that has proven useful in isolating this amino acid from protein hydrolysates. The occurrence of tyrosine- 0-sulfate as a constituent of human urine and fibrinogen has been reported. ... 

Approximately 30 years ago, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. Evidence in favour of this hypothesis was provided by the observation that the antihypertensive drug reserpine, which depletes both the central and peripheral vesicular stores of catecholamines such as noradrenaline, is likely to precipitate depression in patients in remission. The experimental drug alpha-methyl-paratyrosine that blocks the synthesis of noradrenaline by inhibiting the rate-limiting enzyme tyrosine hydroxylase was also shown to precipitate depression in patients during remission. While such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression, more direct evidence is needed to substantiate the hypothesis. The most obvious approach would be to determine the concentration of noradrenaline and/or its major central... 

Chen Q, Huang NN, Huang JT, Chen S, Fan J, Li C, Xie FK (2009) Sodium benzoate exposure downregulates the expression of tyrosine hydroxylase and dopamine transporter in dopaminergic neurons in developing zebrafish. Birth Defects Res B Dev Reprod Toxicol 86 85-91... 

X-Linked agammaglobulinemia Defect in gene coding for Bruton tyrosine kinase responsible for B cell growth and maturation. 

Wilcken B, Hammond JW, Howard N, Bohane T, Hocart C, Halpern (1981) Hawkinsinuria a dominantly inherited defect of tyrosine metabolism with severe effects in infancy. N Engl J Med 305 865-868... 

Phenylketonuria was among the first inheritable metabolic defects discovered in humans. When this condition is recognized early in infancy, mental retardation can largely be prevented by rigid dietary control. The diet must supply only enough phenylalanine and tyrosine to meet the needs for protein synthesis. Consumption of protein-rich foods must be curtailed. Natural proteins, such as casein of milk, must first be hydrolyzed and much of the phenylalanine removed to provide an appropriate diet, at least through childhood. Because the artificial sweetener aspartame is a dipeptide of aspartate and the methyl ester of phenylalanine (see Fig. l-23b), foods sweetened with aspartame bear warnings addressed to individuals on phenylalanine-controlled diets. 

Tyrosine is normally a nonessential amino acid, but individuals with a genetic defect in phenylalanine hydroxylase require tyrosine in their diet for normal growth. Explain. 

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, and it may be inherited by one of several modes autosomal recessive, autosomal dominant, or X-linked. Complete albinism (also called tyrosinase-negative oculocutaneous albinism) results from a defi ciency of tyrosinase activity, causing a total absence of pigment from the hair, eyes, and skin (Figure 20.20). It is the most severe form of the condition. Affected people may appear to have white hair, skin, and iris color, and they may have vision defects. They also have photophobia (sunlight is painful to their eyes), they sun burn easily, and do not tan. 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

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