Question

L-Phynelalanine

Answer 1

Phenylalanine ( Phe ,F ),is an essential aromatic amino acid . The only function of Phenylalanine is its conversion to tyrosine .For this reason, ingestion of tyrosine can reduce the dietary requirement of phenylalanine. This phenomenon is referred to as 'sparing action' of tyrosine on phenylalanine. The predominant metabolism of phenylalanine occurs through tyrosine. Tyrosine is incorporated into proteins and is involved in the synthesis of a variety of biologically important compounds-epinephrine, norepinephrine, dopamine (catecholamines), thyroid hormones and the pigment melanin . During the course of degradation, phenylalanine and tyrosine are converted to metabolites which can serve as precursors for the synthesis of glucose and fat. Hence, these amino acids are both glucogenic and ketogenic . Phenylalanine is hydroxylated at para-position by phenylalanine hydroxylase to produce Tyrosine ( p-hydroxy phenylalanine) . This is an irreversible reaction and requires the participation of a specific coenzyme biopterin . The active form of biopterin is tetrahydrobiopterin (Ha-biopterin). In the phenylalanine hydroxylase reaction, tetrahydrobiopterin is oxidized to dihydrobiopterin (H2-biopterin). Tetrahydrobiopterin is then regenerated by an NADPH-dependent dihydrobiopterin reductase .The enzyme phenylalanine hydroxylase is present in the liver. In the conversion of phenylalanine to tyrosine, the reaction involves the incorporation of one atom of molecular oxygen (O2) into the para position of phenylalanine while the other atom of O2 is reduced to form water. lt is the tetrahydrobiopterin that supplies the reducing equivalents which, in turn, are provided by NADPH. Due to a defect in phenylalanine hydroxylase, the conversion of phenylalanine to tyrosine is blocked resulting in the disorder phenylketonuria (PKU).
Pheny!ketonuria :
Phenylketonuria ( PKU) is the most common metabolic disorder in amino acid metabolism. The incidence of PKU is 1 in 10,000 births. lt is
due to the deficiency of the hepatic enzyme, phenylalanine hydroxylase, caused by an autosomal recessive gene. In recent years, a variant of PKU-due to a defect in dihydrobiopterin reductase (relatively less)-has been reported. This enzyme deficiency impairs the synthesis of tetrahydrobiopterin required for the action of phenylalanine hydroxylase . The net outcome in PKU is that phenylalanine is not converted to tyrosine. Phenylalanine metabolism in PKU : Phenylketonuria primarily causes the accumulation of phenylalaninein tissues and blood, and results in its increased excretion in urine. Due to disturbances in the routine metabolism,phenylalanine
is diverted to alternate pathways, resulting in the excessive production of phenylpyruvate phenylacetate phenyllactate and phenylglutamine. . AII these metabolites are excreted in urine in high concentration in PKU. Phenylacetate gives the urine a mousey odour .The name phenylketonuria is coined due to the fact that the metabolite phenylpyruvate is a keto acid (C6H5CH2-CO-COO-) excreted in urine in high amounts.
Clinical/biochemical manifestations of PKU :The disturbed metabolism of phenylalanine resulting in the increased concentration of phenylalanine and its metabolites in the body causes many clinical and biochemical manifestations . Effects on central nervous system : Mental retardation, failure to walk or talk, failure of growth ,seizures and tremor are the characteristic findings in PKU. lf untreated , the patients will have very low lQ (below 50). The biochemical basis of mental retardation in PKU is not well understood. There are, however, many explanations offered . Accumulation of phenylalanine in brain impairs the transport and metabolism of other aromatic amino acids (tryptophan and tyrosine). The synthesis of serotonin (an excitatory neurotransmitter) from tryptophan is insufficient. This is due to the competition of phenylalanine and its metabolites with tryptophan that impairs the synthesis of serotonin. Defect in myelin formation is observed in PKU patients. Effect on pigmentation : Melanin is the pigment synthesized from tyrosine by tyrosinase Accumulation of phenylalanine competitively inhibits tyrosinase and impairs melanin formation. The result is hypopigmentation that causes light skin colour, fair hair, blue eyes etc.
Diagnosis of PKU : PKU is mostly detected by screening the new born babies for the increased plasma levels of phenylalanine( PKU, 20-65 mg/dl; normal 1-2mg/dl). This is usually carried out by Guthrie fest, which is a bacterial (Bacillus subtilis) bioassay for phenylalanine. The test is usually performed after the baby is fed with breast milk for a couple of days. All the babies born in USA are screened for PKU by testing elevated levels of phenylalanine Phenylpyruvate in urine can be detected by ferric chloride test (a green colour is obtained). This test is not specific, since many other compounds give a false positive test .
Treatment of PKU : The maintenance of plasma phenylalanine concentration within the normal range is a challenging task in the treatment of PKU. This is done by selecting foods with low phenylalanine content and/or feeding synthetic amino acid preparations, low in phenylalanine. Dietary intake of phenylalanine should be adjusted by measuring plasma levels. Early diagnosis (in the first couple of months of baby's life) and treatment for 4-5 years can prevent the damage to brain. However, the restriction to protein diet should be continued for many more years in life. Since the amino acid tyrosine cannot be synthesized in PKU patients, it becomes essential and should be provided in the diet in sufficient quantity. In some seriously affected PKU patients, treatment includes administration of 5-hydroxytryptophan and dopa to restore the synthesis of serotonin and catecholamines .
Food containing phenalalanine is contradicted during pregnancy .