DISORDERS OF PHENYLALANINE METABOLISM

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Disorders of tyrosine (phenylalanine) metabolismGandham.RajeevEmail:[email protected] (PKU)Enzyme defect: Deficiency of the hepatic enzyme, phenylalanine hydroxylase.A variant of PKU-due to a defect in dihydrobiopterin reductase (relatively less).This enzyme deficiency impairs the synthesis of tetrahydrobiopterin required for the action of phenylalanine hydroxylase.

Types of PKUThere are 5 types of PKU described. Type I is the classical one.Type I is due to phenylalanine hydroxylase deficiency. Types II & III are due to deficiency of dihydrobiopterin reductase. Type IV & V are due to the deficiency of the enzyme synthesizing biopterin. Tetrahydrobioptrerin is the co-enzyme required for serotonin & dopamine, the decreased level of these neurotransmitters may also result in the neurological symptoms. Phenylalanine hydroxylase gene is located in chromosome 12 & dihyro biopterin reductase gene in chromosome 4.

Phenylalanine metabolism in PKUPhenylketonuria primarily causes the accumulation of phenylalanine in tissues & blood. It results in 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 & phenylglutamine.AII these metabolites are excreted in urine in high concentration in PKU.Phenylacetate gives the urine a mousey odour.Phenylpyruvate is a keto acid excreted in urine in high amounts.

Alternate pathways in PKUBiochemical manifestations of PKUEffects on central nervous system:Mental retardation, failure to walk or talk, failure of growth & tremor are the characteristic findings in PKU.lf untreated, the patients show very low lQ (below50). The biochemical basis of mental retardation in PKU is not well understood.

Accumulation of phenylalanine in brain impairs the transport & metabolism of other aromatic amino acids.The synthesis of serotonin (an excitatory neurotransmitter) from tryptophan is insufficient. This is due to the competition of phenylalanine & its metabolites with tryptophan that impairs the synthesis of serotonin.Defect in myelin formation.Effect on pigmentation:Melanin is the pigment synthesized from tyrosine by tyrosinase.Accumulation of phenylalanine competitively inhibits tyrosinase & impairs melanin formation. The result is hypopigmentation that causes light skin colour, fair hair, blue eyes etc.Diagnosis of PKUNormal level is 1 mg/dl.In PKU, the level is >20 mg/dl. Carried out by Guthrie fest, which is a bacterial (Bacillus subtilis) bioassay for phenylalanine.Phenylpyruvate in urine can be detected by ferric chloride test (a green colour is obtained). It is not specific, many other compounds give a false positive test.Dietary intake of phenylalanine should be adjusted by measuring plasma levels.Early diagnosis (in the first couple of months of baby's life) & treatment for 4-5 years can prevent the damage to brain. The restriction to protein diet should be continued for many more years in life.Treatment of PKUIn seriously affected PKU patients, treatment includes administration of 5-hydroxytryptophan & dopa to restore the synthesis of serotonin & catecholamines.

Tyrosinemia type IIEnzyme defect: Tyrosine transaminase.This disorder-also known as Richner Hanhart syndrome. There is a blockade in the routine degradative pathway of tyrosine.Accumulation & excretion of tyrosine in urine.Tyrosine & its metabolites namely p-hydroxyphenylpyruvate, p-hydroxyphenyllactate, p-hydroxy phenylacetate, N-acetyltyrosine & tyramine are excreted.Characterized by skin (dermatitis) & eye lesions & rarely mental retardation. A diet low in protein is advised.

Neonatal tyrosinemia Enzyme defect: p-hydroxyphenylpyruvate dioxygenase.Cause transient hypertyrosinemia in the new-born.This condition respond to administration of ascorbic acid & dietary protein restriction.

17Alkaptonuria (Black urine disease)Enzyme defect: Homogentisate oxidase.Homogentisate accumulates in tissues & blood & is excreted into urine. Homogentisate, on standing, gets oxidized to the corresponding quinones, which polymerize to give black or brown colour. The urine of alkaptonuric patients resembles coke in colour.

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Biochemical manifestationsHomogentisate gets oxidized by polyphenol oxidase to benzoquinone acetate which undergoes polymerization to produce a pigment called alkapton.Alkapton is deposited in connective tissue, bones & various organs (nose, ear etc.) resulting in a condition known as ochronosis.

Many alkaptonuric patients suffer from arthritis.This is due to the deposition of pigment alkapton (in the joints), produced from homogentisate.Diagnosis:Urine becomes black on standing when it becomes alkaline.

Blackening is accelerated on exposure to sunlight & oxygen. The urine when kept in a test tube will start to blacken from the top layer.Ferric chloride test will be positive for urine.Benedict's test is strongly positive.Not a dangerous disorder & does not require any specific treatment.Protein diet with low phenylalanine content.Tyrosinosis or tyrosinemia type IEnzyme deficiency: Fumarylacetoacetate hydroxylase or maleylacetoacetate isomerase.Tyrosinosisis a rare & serious disorder.lt causes liver failure, rickets, renal tubular dysfunction & polyneuropathy.Tyrosine, its metabolites & many other amino acids are excreted in urine.In acute tyrosinosis, the infant exhibits diarrhea, vomiting, and 'cabbage-like' odor.Death may even occur due to liver failure within one year. Treatment: Diets low in tyrosine, phenylalanine and methionine are recommended.AlbinismAlbinism (Greek: albino-white) is an inborn error, due to the lack of synthesis of the pigment melanin.It is an autosomal recessive disorder with a frequency of 1 in 20,000.Tyrosinase is completely absent, leading to defective synthesis of melanin.

The ocular fundus is hypopigmented & iris may be grey or red. There will be associated photophobia & decreased visual acuity.The skin has low pigmentation & skin is sensitive to UV rays (skin cancer). Hair is also white.Manifestations are less severe in tyrosinase positive type, where the abnormality is in the uptake of tyrosine by melanocytes.

AlbinismCauses of albinismMelanocyte deficiency secondary to a failure of melanoblasts to colonize the skin.Failure of melanocytes to form melanosomes.Due to tyrosinase deficiency, melanin is not produced in the melanosomes.Failure of melanosomes to form melanin owing to substrate deficiency.Failure of melanosomes to store melanin or to transport melanin to keratinocytes.Excessive destruction of functional melanosomes.References Textbook of Biochemistry-U SatyanarayanaTextbook of Biochemistry-DM VasudevanThank You