Phenylalanine metabolism disorders

Metabolic disorders of phenylalanine catabolism include phenylketonuria (PKU) and several hyper-phenylalaninemias. 

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

To diagnose or exclude inherited metabolic disorders in individual patients. In this situation the increased concentration of the key metabolite may be quite prominent and is typically at least one order of magnitude greater than the reference range (e.g. phenylalanine > 1000 pmol/1 compared with a reference range of 42-110 pmol/1 [4]. 

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... 

Inborn errors of metabolism are inherited metabolic disorders caused by the absence of an enzyme in a metabolic pathway. Alkaptonuria is caused by the lack of homogentisate oxidase and is harmless, whereas phenylketonuria, which is due to a lack of phenylalanine hydroxylase, can cause severe mental retardation. 

For the sake of persons with the metabolic disorder phenylketonuria, aspartame must carry the health warning Phenylketonurics Contains Phenylalanine . 

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

Answers (b), (c), and (e) are correct. Phenylketonuria is a metabolic disorder arising from an absence or deficiency in the enzyme phenylalanine hydroxylase or (more rarely) its cofactor tetrahydrobiopterin. It results in the build-up of phenylalanine in the body and is treated -with a diet low in phenylalanine. 

Brain Damage in Phenylalanine, Homocysteine and Galactose Metabolic Disorders... 

As described above, phenylalanine, homocysteine, and galactose metabolic disorders affect brain function, the latter being profoundly or partially avoided by early diagnosis and proper treatment. As the ancient Greek doctor Hippocrates said, Prevention is better than treatment . 

A new sweetener, named Alitame by its inventors in your Research Division, is a dipeptide amide of L-aspartic acid and D-alanine. In contrast, aspartame, the amino acid-based sweetener currently approved by the FDA, is a dipeptide ester and contains L-phenylalanine instead of D-alanine. The New Products Department has tested the new material in a variety of uses and claims that it is stable enough for use in baked goods and has a longer shelf life than aspartame. It is also 12 times as sweet as aspartame and would not be harmful to people with the metabolic disorder, phenylketonuria, who must limit the intake of substances containing phenylalanine. Use is projected in foods, beverages, toiletries, and pharmaceuticals. 

Paddon-Jones et al. reported optimal protein synthesis when dietary protein was provided three times per day compared with the same total amount of protein given in various amounts [26, 29]. In patients with PKU, providing amino acid-based medical food throughout the day compared to a single dose of similar protein equivalents had a positive effect on protein synthesis [30]. A positive effect on plasma phenylalanine concentrations was also reported [30]. For patients with a metabolic disorder, providing medical food along with limited whole protein foods is most beneficial to optimize synthesis. 

In inherited metabolic disorders, not only is total protein a major consideration, but also the balance of individual amino acids. Excessive or imbalanced plasma amino add concentrations negatively affect absorption, protein synthesis, and brain concentrations of indispensable amino acids. In PKU, high blood phenylalanine concentrations cause high phenylalanine concentrations on the brain [52, 53]. In organic acidemias and maple syrup urine disease, imbalances in several or more indispensable amino adds can significantly affect protein synthesis (Fig. 7.5) (Chap. 11). 

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. 

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 . 

The geometric structure of the chelation on Cu" is also essential as Cu 0 is less free on the electrode surface than the Cu metal ion in aqueous solution. Based on these mechanisms, the free amino acids would be more steadily accessible to the Cu 0 reachon site than would peptides and proteins and the density of functional -COO and -N termini, size and geometric folding of which could stericaUy hinder the Cu A2 structure at the Cu"SPE surface. Although not related directly to any medical diagnosis, this application may prove to be valuable in the diagnosis of congenital amino acid-associated disorders of tyrosine and phenylalanine metabolism. 

Phenylalanine (Phe or F) (2-amino-3-phenyl-propanoic acid) is a neutral, aromatic amino acid with the formula HOOCCH(NH2)CH2C6H5. It is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. Tyr and Phe play a significant role not only in protein structure but also as important precursors for thyroid and adrenocortical hormones as well as in the synthesis of neurotransmitters such as dopamine and noradrenaline. The genetic disorder phenylketonuria (PKU) is the inability to metabolize Phe. This is caused by a deficiency of phenylalanine hydroxylase with the result that there is an accumulation of Phe in body fluids. Individuals with this disorder are known as phenylketonurics and must abstain from consumption of Phe. A nonfood source of Phe is the artificial sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester), which is metabolized by the body into several by-products including Phe. The side chain of Phe is immune from side reactions, but during catalytic hydrogenations the aromatic ring can be saturated and converted into a hexahydrophenylalanine residue. ... 

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