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It is not surprising that the metabolism of these two aromatic amino acids is closely linked because they differ only by the presence of a phenolic OH in the tyrosine molecule.
We will not study here their biosynthesis which — in organisms where it takes place, especially bacteria — starts from 2 compounds of the carbohydrate metabolism (erythrose-4-℗ and phosphocnolpyruvate) and passes through shikimic acid which is also a precursor of tryptophan.
In man, phenylalanine is an essential amino acid while tyrosine is not because, as we will see in the following, it can be easily formed from phenylalanine.
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The study of the metabolism of these two amino acids is interesting on more than one score, because among the transformations they can undergo in the organism, some lead to hormones or pigments; but more importantly, some hereditary diseases are characterized by disorders of the catabolism of these two amino acids, which will enable us to examine how, in some cases, one can determine exactly which enzyme (i.e. which gene) is affected by the lesion which causes a hereditary disease.
Normal Catabolism of Phenylalanine and Tyrosine:
As shown by figure 7-24, phenylalanine is hydroxylated to tyrosine; this reaction is not reversible which explains that the phenylalanine requirements cannot be covered by administration of tyrosine. One molecule of oxygen participates in this reaction: one atom is incorporated to the substrate, the other is reduced to H2O by FH4 which is oxidized to FH2 (it is then again reduced to FH4 by NADPH).
Tyrosine then loses its amino group by transamination and gives para-hydroxy-phenyl-pyruvic acid which is oxidized to quinol. After transposition, an oxidative decarboxylation leads to alcaptone or homogentisic acid which is normally catabolized, on one hand, to fumaric acid (which can join the Krebs cycle and give glucose by neoglucogenesis which confers on the two amino acids a glucogenic character), and on the other hand, to aceto-acetic acid (thence the ketogenic character of phenylalanine and tyrosine).
Disorders of the Catabolism of Phenylalanine and Tyrosine:
a) At the Level of Phenylalanine-Hydroxylase:
This enzyme is absent in persons suffering from phenylketonuria, a congenital disease also called phenyl-pyruvic oligophrenia because of the accompanying mental disorders. Phenylalanine cannot be converted into tyrosine and, as shown in figure 7-25, it forms phenyl-pyruvic, phenyl-lactic and phenyl acetic acids (the latter is eliminated in urine in a form conjugated to glutamine).
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This is a serious disease but if detected early (by means of micro-organisms requiring for their growth, phenylalanine, phenyl-pyruvic acid or phenyl-lactic acid), the infants can be put on a rigorous diet (without excess phenylalanine) which will prevent the appearance of pathological symptoms.
b) At the Level of Homogentisic Acid Oxidase:
In the absence of this enzyme, homogentisic acid can no longer be catabolized and passes into the urine which takes up a brown coloration after alkalinization, either spontaneous, by formation of NH3, or induced (alcaptone gets oxidized and forms brown pigments). Alcaptonuria is not a serious hereditary disease.
c) At the Level of Para-Hydroxy-Phenyl-Pyruvate-Oxidase:
In humans and animals suffering from scurvy, one observes an elimination of para-hydroxy- phenyl-pyruvic acid and para-hydroxy-phenyl lactic acid; administration of vitamin C restores a normal catabolism.
Contrary to the above two cases, here, it is not the absence of an enzyme due to a lesion of the corresponding gene, but the inactivation of the oxidase which is causing problems; ascorbic acid probably exerts a protective effect thanks to its reducing properties and prevents the inactivation of the enzyme by oxidation.
Formation of Melanines:
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They are black pigments present not only in micro-organisms and plants but also in animals and man; in the latter melanines are present especially in the skin and hairs, in varying quantities, except in some individuals called albinos, where the transformation of tyrosine into melanines is arrested (see fig. 7-26).
This block may be due to, either the absence — in the melanocytes where melanogenesis takes place — of the enzyme catalyzing the hydroxylation of tyrosine to dopa (which is called “tyrosinase”, a misnomer because it does not catalyze a hydrolysis), or a deficiency in the processes that take place after the formation of dopa, especially in the polymerization.
Formation of Nor-Adrenaline and Adrenaline:
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As shown by figure 7-27, phenylalanine and tyrosine are also the precursors of nor-adrenaline and adrenaline. This series of reactions comprise first 2 successive hydroxylations (of phenylalanine to tyrosine and tyrosine to dopa), a decarboxylation leading to dopamine, then another hydroxylation giving nor-adrenaline and finally a methylation carried out at the cost of S-adenosyl- methionine and giving adrenaline.
Formation of Thyroid Hormones:
Iodides (I–) circulating in blood are picked up by the thyroid gland where they are oxidized (to I° or I+). The H atoms which are in ortho with respect to the phenol group of tyrosyl residues of a protein specific of the gland — thyroglobulin — are then substituted by iodine and there is formation of 3- mono-iodotyrosyl and 3,5 di-iodotyrosyl residues; these condense to give 3, 5, 3′ triiodothyronine (T3) and 3, 5, 3′, 5′ tetra-iodothyronine (T4) or thyroxine (see fig. 7-28) which are liberated by the action of proteases on thyroglobulin. The 2 hormones can then be secreted and pass into the blood.
Figure 7.29 is an overall diagram of the metabolism of phenylalanine and tyrosine.
