PHENYLALANINE METABOLISM

PHENYLALANINE METABOLISM

1. Metabolism of Phenyl alanine Gandham.Rajeev Email:[email protected]

2. It is aromatic & essential amino acid. Both Glucogenic & Ketogenic . Phenylalanine is converted to tyrosine. Referred to as 'sparing action' of tyrosine on phenylalanine. Phenyl alanine

3. Predominant metabolism of phenylalanine occurs through tyrosine. Tyrosine is incorporated into proteins & is involved in the synthesis of variety of biologically important compounds-epinephrine, norepinephrine , dopamine, thyroid hormones & the pigment melanin.

4. Conversion of phenylalanine to tyrosine Degradation of phenylalanine mostly occurs through tyrosine. Phenylalanine is hydroxylated at para -position by phenylalanine hydroxylase to produce tyrosine. This reaction is irreversible, & requires specific coenzyme biopterin , which is structurally related to folate .

5. Active form of biopterin is tetrahydrobiopterin . Tetrahydrobiopterin is oxidized to dihydrobiopterin . Tetrahydrobiopterin is then regenerated by an NADPH-dependent dihydrobiopterin reductase . Phenylalanine hydroxylase is present in liver.

6. In the conversion of phenylalanine to tyrosine, the reaction involves incorporation of one atom of molecular oxygen into para -position of phenylalanine while the other atom O2 is reduced to form water. Tetrahydrobiopterin supplies reducing equivalents.

7. Conversion of phenylalanine to tyrosine

8. D egradation of tyrosine (Phenylalanine) Phenylalanine is converted to tyrosine , a single pathway is responsible for the degradation of both these amino acids. Occurs mostly in liver. Tyrosine first undergoes transamination to P- hydroxyphenyl pyruvate , catalyzed by tyrosine transaminase (PLP dependent)

9. p- hydroxy phenylpyruvate hydroxylase (or dioxygenase ) is a copper-containing enzyme. It catalyzes oxidative decarboxylation as well as hydroxylation of the phenyl ring of p- hydroxy phenyl pyruvate to produce homogentisate . Production of Homogentisic acid

10. This reaction involves a shift in hydroxyl group from para position to meta position & incorporates a new hydroxyl group at para position to give 2,5-dihydroxyphenylacetic acid or homogentisic acid. This step requires ascorbic acid.

11. Homogentisate oxidase (iron metallo -protein) cleaves the benzene ring of homogentisate to form 4-maleylacetoacetate . Molecular oxygen is required for this reaction to break the aromatic ring. Cleavage of aromatic ring

12. 4-Maleylacetoacetate undergoes isomerization to form 4-fumaryl acetoacetate. Catalyzed by maleylacetoacetate isomerase . Isomerization

13. Fumaryl acetoacetase ( fumaryl acetoacetate hydrolase) brings about the hydrolysis of fumaryl acetoacetate to liberate fumarate & acetoacetate . Fumarate is an intermediate in citric acid cycle & can serve as precursor for gluconeogenesis. Isomerization

14. Acetoacetate is a ketone body from which fat can be synthesized. Phenylalanine & tyrosine are both glucogenic & ketogenic amino acids.

15. Degradation of Phe and Tyr

16. Synthesis of melanin Melanin is a pigment of skin, hair & eye. The synthesis of melanin occurs in melanosomes present in melanocytes , the pigment producing cells. Tyrosine is precursor for melanin & only one enzyme, namely tyrosinase (a copper containing oxygenase ), is involved in its formation.

17. Tyrosinase hydroxylates tyrosine to form 3,4-dihydroxy-phenylalanine (DOPA). DOPA can act as a cofactor for tyrosinase . DOPA is converted to dopaquinone by tyrosinase . Dopaquinone in subsequent couple of reactions occur spontaneously, forming leucodopachrome followed by 5,6-dihydroxy indole .

18. The oxidation of 5,6-dihydroxyindole to indole 5,6-quinone is catalyzed by tyrosinase . DOPA serves as a cofactor. This reaction, inhibited by tyrosine regulates the synthesis of melanin. Melanochromes are formed from indole quinone , which on polymerization are converted to black melanin.

19. Another pathway: Cysteine condenses with dopaquinone & in the next series of reactions results the synthesis of red melanins . Melanin-the color pigment: The skin color of the individual is determined by the relative concentrations of black & red melanins .

20. This, in turn, is dependent on many factors, both genetic & environmental. These include the activity of tyrosinase , the density of melanocytes , availability of tyrosine etc. The presence of moles on the body represents a localized severe hyperpigmentation due to hyperactivity of melanocytes .

21. Localized absence or degeneration of melanocytes results in white patches on the skin commonly known as leucoderma . Albinism is an inborn error with generalized lack of melanin synthesis.

22. Synthesis of melanin

23. Synthesis of melanin

24. B iosynthesis of thyroid hormones Thyroid hormones - T hyroxine ( tetraiodothyronine ) & triiodithyronine - are synthesized from the tyrosine residues of the protein thyroglobulin & activated iodine.

25. Iodination of tyrosine ring occurs to produce mono & diiodotyrosine from which triiodothyronine (T3) & thyroxine (T4) are synthesized. The protein thyroglobulin undergoes proteolytic breakdown to release the free hormones - T3 & T4.

26. Synthesis of thyroid hormones

27. Biosynthesis of catecholamines Catecholamines are derived from tyrosine . The name catechol refers to the dihydroxylated phenyl ring (catechol nucleus). The amine derivatives of catechol are called catecholamines .

28. Tyrosine is the precursor for the synthesis of catecholamines , namely dopamine, norepinephrine ( noradrinaline ) & epinephrine ( adrinaline ) Conversion of tyrosine to catecholamines occurs in adrenal medulla & central nervous system.

29. Tyrosine hydroxylase: Tyrosine is hydroxylated to 3,4-dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. It is a rate limiting enzyme & requires tetrahydrobiopterin as coenzyme. In contrast to this enzyme, tyrosinase present in melanocytes converts tyrosine to DOPA. Reactions

30. Two different enzyme systems exist to convert tyrosine to DOPA. DOPA-decarboxylase: DOPA undergoes PLP-dependent decarboxylation to give dopamine. Dopamine is a catecholamine. Dopamine is an inhibitor of prolactin secretion Dopamine is neurotransmitter in substantia nigra , extrapyramidal tract , & striatal tract.

31. In Parkinsonism , the dopamine content in brain is reduced. As dopamine will not enter into the brain cells, the precursor, L-DOPA is used as a drug in Parkinsonism. Alpha methyl DOPA will inhibit DOPA decarboxylase & prevent production of epinephrine ; so it is an antihypertensive drug .

32. Nor epinephrine: Dopamine is further hydroxylated to nor-epinephrine or noradrenaline The term “ nor” denotes that the molecule does not contain the "R" or methyl group. Methylation of norepinephrine by S- adenosylmethionine gives epinephrine.

33. Epinephrine: Nor-epinephrine is methylated by the enzyme N-methyl transferase to epinephrine or adrenaline. S- adenosyl methionine ( SAM) is the methyl donor. It is mainly produced by adrenal medulla & adrenergic nerve endings.

34. The difference between epinephrine & norepinephrine is only a methyl group . In adrenal medulla , synthesis of the hormones, norepinephrine & epinephrine is prominent. Norepinephrine is produced in certain areas of brain while dopamine is predominantly synthesized in substantia nigra .

35. F unctions of catecholamines They cause the increase in blood pressure. Adrenaline also increases the rate & force of myocardial contraction. Adrenaline is anti-insulin in nature , it increases glycogenolysis & stimulates lipolysis . Serve as neurotransmitters in the brain ANS.

36. The half-life of epinephrine is 2-5 minutes . Epinephrine is catabolized in tissues , by catechol-O-methyl transferase (COMT) to metanephrine . It is then acted upon by mono amine oxidase (MAO ). MAO will oxidatively deaminate metanephrine . Degradation of Adrenaline

37. The major end product is 3-hydroxy-4-methoxy mandelic acid or vanillyl mandelic acid (VMA ). Homovanillic acid (HVA) in Urine: It is also called methoxy hydroxy phenyl acetic acid. HVA is the main urinary metabolite of DOPA & dopamine.

38. C atecholamines

39. C atecholamines

40. References Textbook of Biochemistry-u Satyanarayana Textbook of Biochemistry-DM Vasudevan

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