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Phenylalanine and Tyrosine Phenylalanine and Tyrosine MetabolismMetabolism

Dr. Mohammad AkramDr. Mohammad Akram

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PhenylalaninePhenylalanine

Phenylalanine is an essential amino acid Phenylalanine is an essential amino acid (building block for proteins in the body). It (building block for proteins in the body). It is essential to human health but cannot be is essential to human health but cannot be manufactured by the body. For this manufactured by the body. For this reason, phenylalanine must be obtained reason, phenylalanine must be obtained from food. The body converts from food. The body converts phenylalanine into tyrosine, another amino phenylalanine into tyrosine, another amino acid essential for making proteins, brain acid essential for making proteins, brain chemicals including dopamine and chemicals including dopamine and norepinephrine, and thyroid hormones. norepinephrine, and thyroid hormones.

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Phenylalanine and Tyrosine Phenylalanine and Tyrosine CatabolismCatabolism

Phenylalanine normally has only two fates: Phenylalanine normally has only two fates: incorporation into polypeptide chains, and incorporation into polypeptide chains, and

production of tyrosine via the production of tyrosine via the tetrahydrobiopterin-requiring tetrahydrobiopterin-requiring phenylalanine hydroxylase. phenylalanine hydroxylase.

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PathwayPathway

From tyrosine, there are further From tyrosine, there are further connections to the biosynthesis of connections to the biosynthesis of

catecholamines, melanin, hormones, etc. catecholamines, melanin, hormones, etc. Usually, dietary intake of Phe and Tyr, and Usually, dietary intake of Phe and Tyr, and

the body's demand for Phe and Tyr, are the body's demand for Phe and Tyr, are fairly closely balanced. However, when fairly closely balanced. However, when there is too much phenylalanine in the there is too much phenylalanine in the body's pool of amino acids, it must be body's pool of amino acids, it must be

eliminated, either by excretion or by eliminated, either by excretion or by biochemical reaction biochemical reaction

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PKUPKU

In 'classic PKU', the enzyme that breaks In 'classic PKU', the enzyme that breaks down phenylalanine, phenylalanine down phenylalanine, phenylalanine hydroxylase, happens in the liver cells, is hydroxylase, happens in the liver cells, is completely or nearly completely deficient. completely or nearly completely deficient. This enzyme normally converts This enzyme normally converts phenylalanine to another amino acid, phenylalanine to another amino acid, tyrosine. Without this enzyme, tyrosine. Without this enzyme, phenylalanine and its' breakdown phenylalanine and its' breakdown chemicals from other enzyme routes, chemicals from other enzyme routes, accumulate in the blood and body tissues. accumulate in the blood and body tissues.

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Cont.Cont.

Tyrosine is converted in turn to 3-4-Tyrosine is converted in turn to 3-4-dihydroxy phenylalanine (nick-named dihydroxy phenylalanine (nick-named DOPA) by another enzyme and DOPA DOPA) by another enzyme and DOPA serves as a precursor for the hormones serves as a precursor for the hormones adrenaline and noradrenaline and for the adrenaline and noradrenaline and for the black pigment, melanin. black pigment, melanin.

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Phenylalanine and Tyrosine Phenylalanine and Tyrosine CatabolismCatabolism

Therefore tyrosine is equally important for Therefore tyrosine is equally important for protein biosynthesis as well as an protein biosynthesis as well as an

intermediate in the biosynthesis of several intermediate in the biosynthesis of several physiologically important metabolites e.g. physiologically important metabolites e.g.

dopamine, norepinephrine and dopamine, norepinephrine and epinephrine.epinephrine.

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Phenylalanine and Tyrosine Phenylalanine and Tyrosine CatabolismCatabolism

As in As in phenylketonuriaphenylketonuria (deficiency of (deficiency of phenylalanine hydroxylase, PAH), deficiency of phenylalanine hydroxylase, PAH), deficiency of

tyrosine aminotransferase (TAT) leads to tyrosine aminotransferase (TAT) leads to hypertyrosinemia and the urinary excretion of hypertyrosinemia and the urinary excretion of

tyrosine and the catabolic intermediates tyrosine and the catabolic intermediates between phenylalanine and tyrosine. The between phenylalanine and tyrosine. The

adverse neurological symptoms are similar for adverse neurological symptoms are similar for PAH and TAT deficiencies. In addition, PAH and TAT deficiencies. In addition,

hypertyrosinemia leads to painful corneal hypertyrosinemia leads to painful corneal eruptions and photophobia. eruptions and photophobia.

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Main Route for Metabolism of Main Route for Metabolism of PhenylalaninePhenylalanine

Phenylalanine is converted by the mono-Phenylalanine is converted by the mono-oxygenase, phenylalanine hydroxylase, to oxygenase, phenylalanine hydroxylase, to

tyrosine. This REDOX reaction requires tyrosine. This REDOX reaction requires the cofactor the cofactor tetrahydrobiopterintetrahydrobiopterin, which in , which in the course of the reaction is converted to the course of the reaction is converted to

quinonoid dihydrobiopterin. The cofactor is quinonoid dihydrobiopterin. The cofactor is regenerated through the action of the regenerated through the action of the

enzyme dihydropteridine reductase, which enzyme dihydropteridine reductase, which in turn uses NADPH as a source of in turn uses NADPH as a source of

reducing power. reducing power.

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Phenylalanine and Tyrosine Phenylalanine and Tyrosine CatabolismCatabolism

The first inborn error in metabolism ever The first inborn error in metabolism ever recognized, recognized, alkaptonuriaalkaptonuria, was demonstrated to , was demonstrated to

be the result of a defect in phenylalanine and be the result of a defect in phenylalanine and tyrosine catabolism. Alkaptonuria is caused by tyrosine catabolism. Alkaptonuria is caused by

defective homogentisic acid oxidase. defective homogentisic acid oxidase. Homogentisic acid accumulation is relatively Homogentisic acid accumulation is relatively

innocuous, causing urine to darken on exposure innocuous, causing urine to darken on exposure to air, but no life-threatening effects accompany to air, but no life-threatening effects accompany the disease. The only untoward consequence of the disease. The only untoward consequence of

alkaptonuria is ochronosis (bluish-black alkaptonuria is ochronosis (bluish-black discoloration of the tissues) and arthritis.discoloration of the tissues) and arthritis.

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Phenylalanine metabolism

Reaction 1 is catalysed byPhenylalanine hydroxylase and

Reaction 2 is catalysed by phenylalanine transaminase.

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Oxidation of Phenylalanine and Oxidation of Phenylalanine and Biosynthesis of TyrosineBiosynthesis of Tyrosine

If there is sufficient phenylalanine in If there is sufficient phenylalanine in the the diet, then humans usually have no diet, then humans usually have no difficulty in synthesizing adequate difficulty in synthesizing adequate amounts of tyrosine from the dietary amounts of tyrosine from the dietary phenylalanine.  The reaction is phenylalanine.  The reaction is complex: complex: This reaction is also the first reaction in the normal route of catabolism of phenylalanine.

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Oxidation of Phenylalanine and Oxidation of Phenylalanine and Biosynthesis of Tyrosine cont.Biosynthesis of Tyrosine cont.

The enzyme catalyzing the reaction is The enzyme catalyzing the reaction is phenylalanine hydroxylase (PAH), a phenylalanine hydroxylase (PAH), a

mixed-function mono-oxygenase that uses mixed-function mono-oxygenase that uses molecular oxygen.  This enzyme also uses molecular oxygen.  This enzyme also uses

the cofactor the cofactor tetrahydrobiopterintetrahydrobiopterin (BH4) (BH4), , which is oxidized in the course of the which is oxidized in the course of the

reaction to dihydrobiopterin (BH2).  The reaction to dihydrobiopterin (BH2).  The cofactor must be regenerated by a cofactor must be regenerated by a

separate system of enzymes for PAH separate system of enzymes for PAH action to continue. action to continue.

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