Tyrosine-melanin

PKU is an inherited disorder of amino acid metabohsm, with an incidence of 1 in 11000 Uve births in the UK, and thus is relatively common. It is caused by a deficiency of the enzyme phenylhydroxylase, which is the first step of phenylalanine degradation (and also the route for synthesis of tyrosine, melanin, dopamine, etc). If unrecognized, and untreated, the absence of the enzyme phenylalanine in the blood, which in turn causes damage to the developing brain in babies and young children. Clinical features of untreated PKU indue mental retardation, seizures, hyperactivity, and hypopigmentation of the eyes and hair. 

CgHiiNO. M.p. 282 C (decomp.). The naturally occurring substance is laevorotatory. It is an amino-acid isolated from various plant sources, but not found in the animal body. It is formed from tyrosine as the first stage in the oxidation of tyrosine to melanin. It is used in the treatment of Parkinson s disease. 

Neural cells convert tyrosine to epinephrine and norepinephrine (Figure 31—5). While dopa is also an intermediate in the formation of melanin, different enzymes hydroxylate tyrosine in melanocytes. Dopa decarboxylase, a pyridoxai phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation by dopamine P-oxidase then forms norepinephrine. In the adrenal medulla, phenylethanolamine-A -methyltransferase uti-hzes S-adenosyhnethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure 31-5). Tyrosine is also a precursor of triiodothyronine and thyroxine (Chapter 42). 

Phenoxazines — The two main types of phenoxazines are the ommochromes and the microbial phenoxazines. The biosynthesis of ommochromes occurs via the kynurenine pathway. The tryptophan amino acid is converted to formylkynurenine and then to kynurenine and 3-hydroxykynurenine. Not all the steps of ommochrome synthesis are completely elucidated yet. Ommatins are dimers and ommins are oligomers of 3-hydroxykynurenine. - The papiliochromes are derived from tyrosine as well as from the tryptophan pathway. The key intermediate in the formation of papiliochromes is N-beta-alanyldopamine (NBAD). Papiliochromes are synthesized in special wing scale cells, before melanins. " "... 

Eumelanins — These melanins are considered polymers derived from tyrosine derivatives, mainly 5,6-dihydroxyindole-2-carboxylic acid (DHCIA) and dihidrox-yindole (DHl), with high degrees of cross-linking. In vivo eumelanins are associated with proteins and with metals, most frequently copper, zinc, or iron. 

Melanin biosynthesis in animals is a complex process starting with the L-tyrosine amino acid. In the first step, L-tyrosine is converted first into DOPA and then into dopaquinone, a process catalyzed by tyrosinase. In the biosynthesis of eumelanins, dopaquinone undergoes a cyclization to form dopachrome and subsequently a tau-tomerization into 5,6-dihydroxyindole-2-carboxylic acid (DHICA). DHICA is further oxidized to indole-5,6-quinone2-carboxylic acid, the precnrsor of DHICA eumelanins. Tyrosinase-related proteins TRP-2 and TRP-1, respectively, are responsible for the last two steps, and they are under the control of the tyrosinase promoter. 

The pathway of melanin synthesis starts from the amino acid tyrosine (Fig. 1). The first two reactions are catalyzed by the copper-containing enzyme tyrosinase (EC 1.14.18.1). Tyrosine is hydroxylated to 3,4-dihy-... 

Figure 1. The biosynthetic pathway from tyrosine to melanin (according to Hearing and Tsukamoto, 1991 Tsukamoto et al., 1992). Tyrosinase catalyzes three different reactions in this pathway (1, 2, 3). The reaction catalyzed by the product of TRP-2, DOPAchrome tautomerase, is indicated by 4. DOPA = 3,4-dihydroxyphenylalanine DHICA = 5,6-dihydroxyin-dole-2-carboxylic acid DHI = 5,6-dihydroxyindole.

Melanin is a complicated mixture of optically absorbing materials. chromophores), of which melanin is the most important. Melanin is a complicated mixture of optically absorbing materials, formed as an end product during the photo-assisted metabolism of the amino acid tyrosine. Both are bound covalently to the surrounding proteins within the skin, and other pigmented regions of the body. 

Melanin is formed by a photochemical reaction, so the concentration of melanin within the human epidermis (the outer layer of the skin) increases following exposure to photochemical reactions with tyrosine in the skin. This increase is seen readily by the formation of a suntan. This increase in the concentration of melanin following exposure to the sun is more obvious for fair-skinned people, although darker people usually tan more quickly because melanin is produced more efficiently in their skins. 

Since the oxidative polymerization of phenols is the industrial process used to produce poly(phenyleneoxide)s (Scheme 4), the application of polymer catalysts may well be of interest. Furthermore, enzymic, oxidative polymerization of phenols is an important pathway in biosynthesis. For example, black pigment of animal kingdom "melanin" is the polymeric product of 2,6-dihydroxyindole which is the oxidative product of tyrosine, catalyzed by copper enzyme "tyrosinase". In plants "lignin" is the natural polymer of phenols, such as coniferyl alcohol 2 and sinapyl alcohol 3. Tyrosinase contains four Cu ions in cataly-tically active site which are considered to act cooperatively. These Cu ions are presumed to be surrounded by the non-polar apoprotein, and their reactivities in substitution and redox reactions are controlled by the environmental protein. 

Oxidative polymerization of phenol derivatives is also important pathway in vivo, and one example is the formation of melanin from tyrosine catalyzed by the Cu enzyme, tyrosinase. The pathway from tyrosine to melanin is described by Raper (7) and Mason (8) as Scheme 8 the oxygenation of tyrosine to 4-(3,4-dihydro-xyphenyl)-L-alanin (dopa), its subsequent oxidation to dopaqui-none, its oxidative cyclization to dopachrome and succeeding decarboxylation to 5,6-dihydroxyindole, and the oxidative coupling of the products leads to the melanin polymer. The oxidation of dopa to melanin was attempted here by using Cu as the catalyst. 

In addition to their well known role in protein structure, amino acids also act as precursors to a number of other important biological molecules. For example, the synthesis of haem (see also Section 5.3.1), which occurs in, among other tissues, the liver begins with glycine and succinyl-CoA. The amino acid tyrosine which maybe produced in the liver from metabolism of phenylalanine is the precursor of thyroid hormones, melanin, adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The biosynthesis of some of these signalling molecules is described in Section 4.4. 

Tyrosine (Tyr or Y) (4-hydroxyphenylalanine ((5)-2-amino-3-(4-hydroxyphenyl)-propanoic acid)) is a polar, neutral, aromatic amino acid with the formula H00CCH(NH2)CH2C6H50H and is the precursor of thyroxin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and the pigment melanin. Being the precursor amino acid for the thyroid gland hormone thyroxin, a defect in this may result in hypothyroidism. Tyr is extremely soluble in water, a property that has proven useful in isolating this amino acid from protein hydrolysates. The occurrence of tyrosine- 0-sulfate as a constituent of human urine and fibrinogen has been reported. ... 

Answer E. The child has PKU aspartame contains phenylalanine. These children may be blond, blue eyed, and pale complected because of deficient melanin production from tyrosine. 

Tyrosine is structurally related to and derived from phenylalanine. It is the metabolic precursor to dopamine, an important neurotransmitter. Tyrosine is also the precursor to the hormones epinephrine and norepinephrine and to melanin, the pigment of skin. 

Tyrosine is a precursor of thyroid hormones as well as L-dopa. Both thyroxine and L-dopa are employed in clinical medicine thyroxine to treat hypothyroid patients and L-dopa to treat patients with Parkinsonism. L-dopa is also the precursor to the pigment of the skin known as melanin. The enzyme that catalyzes the transformation of tyrosine into L-dopa, tyrosine hydroxylase, also catalyzes the transformation of L-dopa into melanin. Albinism is a genetic disease in which a mutation in the gene encoding tyrosine hydroxylase results in an inactive enzyme. People with albinism have no pigment in their skin, hair, or retina. 

Enzymatic browning. Phenol-oxidizing enzymes (such as tyrosinase and peroxidase) oxidize tyrosine residues into reactive quinone derivatives, which will condense into colored polymers (melanins). Melanins are rich in carboxyl groups and therefore have high affinity for divalent metal ions such as calcium. 

Tyrosine Adrenaline Noradrenaline Dopamine Melanin, thyroxine... 

Peroxynitrite (ONOO ) is a cytoxic species that is considered to form nitric oxide (NO) and superoxide (Oj ) in biological systems (Beckman et al. 1990). The toxicity of this compound is attributed to its ability to oxidize, nitrate, and hydroxylate biomolecules. Tyrosine is nitrated to form 3-nitrotyrosine (Ramazanian et al. 1996). Phenylalanine is hydroxylated to yield o-, m-, and p-tyrosines. Cysteine is oxidized to give cystine (Radi et al. 1991a). Glutathione is converted to S-nitro- or S-nitroso derivatives (Balazy et al. 1998). Catecholamines are oxidatively polymerized to melanin (Daveu et al. 1997). Lipids are also oxidized (Radi 1991b) and DNA can be scissored by peroxynitrite (Szabo and Ohshima 1997). 

Only a few important representatives of the non-proteinogenic amino acids are mentioned here. The basic amino acid ornithine is an analogue of lysine with a shortened side chain. Transfer of a carbamoyl residue to ornithine yields citrulline. Both of these amino acids are intermediates in the urea cycle (see p.l82). Dopa (an acronym of 3,4-dihydroxy-phenylalanine) is synthesized by hydroxyla-tion of tyrosine. It is an intermediate in the biosynthesis of catecholamines (see p.352) and of melanin. It is in clinical use in the treatment of Parkinson s disease. Selenocys-teine, a cysteine analogue, occurs as a component of a few proteins—e.g., in the enzyme glutathione peroxidase (see p.284). 

As the melanin structure grows, it becomes more colored giving various shades of brown color to our skin. This brown coloration acts to help protect deeper skin elements from being damaged by the UV radiation. The absence of the enzyme tyrosinase that converts tyrosine to melanin can lead to albinism. 

In a study of intermediate duration, dermal application of 0.5% p-cresol for 6 weeks produced permanent depigmentation of the skin and hair of mice (Shelley 1974). A caustic effect on the skin was noted in one strain of mouse, but not another. Neither o- nor m-cresol produced any color change in the mice. The author suggests that only p-cresol is active because it mimics the structure of tyrosine, the amino acid present in melanin, so that tyrosinase acts on it, liberating free radicals that damage melanocytes. NOAEL and LOAEL values were not derived from this study because the applied dose was not reported. 

Hydroquinone interferes with the production of the pigment melanin by epidermal melanocytes through at least two mechanisms it competitively inhibits tyrosinase, one of the principal enzymes responsible for converting tyrosine to melanin, and it selectively damages melanocytes and melanosomes (the organelles within which melanin is stored). 

C. Hydroquinone inhibits the enzyme tyrosine kinase, which converts tyrosine to melanin. It also damages melanocytes. Becaplermin (A) is a recombinant human platelet-derived growth factor that is useful in enhancing wound healing. Etanercept (B) is a recombinant fusion protein approved for treatment of psoriatic arthritis and rheumatoid arthritis. Botulinum toxin (D) is a purified form of bofu-linum foxin fype A approved for fherapy of blepharospasm and sfrabismus. 

With tyrosinase, on the contrary, a two-electron oxidation occurs, as no EPR signal was detected in the catechol oxidation at pH 5.3 Melanins are polymerization products of tyrosine, whereby tyrosinase catalyses the first steps the formation of dopa (3,4-dihydroxyphenylalanine) and of dopaquinone, leading to an indolequi-none polymer The peroxidase mechanism for the conversion of tyrosine into dopa in melanogenesis was not substantiated In natural and synthetic melanins free radicals of a semiquinone type were detected by EPR 4-10 x 10 spins g of a hydrated suspension (the material was modified on drying and the number of free spins increased). The fairly symmetrical EPR signal had a g-value of 2.004 and a line-width of 4-10 G The melanins seem to be natural radical scavengers. 

Albinism <3 Melanin synthesis from tyrosine Tyrosine 3-monooxygenase (tyrosinase) Lack of pigmentation white hair, pink skin... 

Albinism refers to a group of conditions in which a defect in tyrosine metabolism results in a deficiency in the production of melanin. These defects result in the partial or full absence of pigment from the skin, hair, and eyes. Albinism appears in different forms, and it may be inherited by one of several modes autosomal recessive, autosomal dominant, or X-linked. Complete albinism (also called tyrosinase-negative oculocutaneous albinism) results from a defi ciency of tyrosinase activity, causing a total absence of pigment from the hair, eyes, and skin (Figure 20.20). It is the most severe form of the condition. Affected people may appear to have white hair, skin, and iris color, and they may have vision defects. They also have photophobia (sunlight is painful to their eyes), they sun burn easily, and do not tan. 

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