Tyrosine, aromatic hydroxylation

Dopamine is the decarboxylation product of DOPA, dihydroxyphenylalanine, and is formed in a reaction catalysed by DOPA decarboxylase. This enzyme is sometimes referred to as aromatic amino acid decarboxylase, since it is relatively non-specific in its action and can catalyse decarboxylation of other aromatic amino acids, e.g. tryptophan and histidine. DOPA is itself derived by aromatic hydroxylation of tyrosine, using tetrahydrobiopterin (a pteridine derivative see Section 11.9.2) as cofactor. 

Dopamine is formed from tyrosine by hydroxylation with tyrosine hydroxylase and the removal of a CO2 group by aromatic amino acid decarboxylase. The catecholamine is found in high concentrations in parts of the brain—the caudate nucleus, the median eminence, the tuberculum olfactorium, and the nucleus accumbens. Dopamine appears to act as an inhibitory neurotransmitter. 

It was mentioned above that in aromatic hydroxylation an oxidant is required, and the product yields vary considerably with the oxidant used (for the reason why 02 does not serve as a typical one-electron oxidant, see Chap. 8). A typical example is the formation of tyrosines from phenylalanine (Table 3.4). Their yields are especially low in the absence of an oxidant, since dimerization usually dominates over disproportionation in these systems. The determination of the products is usually done by either HPLC or GC/MS after trimethylsilylation, and the proteins have to be hydrolyzed prior to analysis. Attention has been drawn to the fact that in vivo cytochrome P-450 enzymes hydroxylate phenylalanine to p-tyrosine (Bailey et al. 1997). 

Immobilization of enzymes. Enzymes consist of amino acids which contain reactive groups such as amino(lysine, c-terminus), thiol (cysteine), carbonyl (aspartate, glutamate and c-terminus), aromatic hydroxyl (tyrosine) and aliphatic hydroxyl (serine and threonine). Chemical, ionic or chelation reactions with such groups can enable us to attach the amino acids and hence proteins to insoluble, inert supports. Immobilization is one of the best ways of stabilizing enzymes. There is a vast literature on this subject and the reader is directed to Barker (9) and Goughian et al (10) for further reading on specific systems, techniques and applications of immobilization. 

V2. van der Vliet, A., O Neill, C. A., Halliwell, B., Cross, C. E., and Kaur, H., Aromatic hydroxylation and nitration of phenylalanine and tyrosine by peroxynitrite. Evidence for hydroxyl radical production from peroxynitrite. FEBS Lett. 339, 89—92 (1994). 

The pterin-dependent oxygenases, typified by the aryl amino acid hydroxylases, are a small family of closely related enzymes, which are essential to mammalian physiology. This class of metalloenzymes employs tetrahydrobiopterin (BH4) as a two-electron donating cofactor for the activation of O2. Members of this class include phenylalanine (PheH), tyrosine (TyrH) and tryptophan (TrpH) hydroxylases, which effect regiospecific aromatic hydroxylations of the namesake amino acids. 

Activated sulfate. Fibrinogen contains tyrosine-G-sulfate. Propose an activated form of sulfate that could react in vivo with the aromatic hydroxyl group of a tyrosine residue in a protein to form tyrosine-G-sulfate. 

A 1,2-shift of hydrogen in the course of aromatic hydroxylation in vivo leading to preferential retention of isotopic hydrogen in accord with primary isotope effects is widespread. Known as the NIH shift it is observed only with entry of the first of two adjacent aromatic hydroxy-groups (for example, [4 - H] phenylalanine is transformed into tyrosine with NIH shift of the C-4 tritium equally to C-3 and C-5 and retention of most of it at these sites in preference to hydrogen by primary isotope effect. Subsequent conversion into dopa involves hydroxylation at C-3 /C-5 and, not being accompanied by an NIH shift, loss of half of the tritium present in the tyrosine is observed). ... 

The unusual glycoside triglochinin (90) co-occurs with (i )-dhurrin in Triglochin spp and the biosynthetic routes were presumed to be related This was confirmed by feeding experiments on a monocot Triglochin spp) and a dicot (Thalictrum spp), which indicated the scheme in Figure 19 with tyrosine as parent in each example. There was some doubt whether aromatic hydroxylation preceded or followed glycosylation. ... 

Fig. 22.3. Tyrosine is hydroxylated in a rate-limiting step by tyrosine hydroxylase (TOH) to form dihydroxylphenylalanine (DOPA), which is decarboxylated by L-aromatic amino acid decarboxylase (AAD) to form dopamine (DA). Newly synthesized DA is stored in vesicles, from which release occurs into the synaptic...

Norepinephrine is biosynthesized in the neurons of both the central nervous system and the autonomio nervous system, whereas EPI is formed in the ohromaffin cells of the adrenal medulla. Both NE and EPI are derived from L-tyrosine by a series of enzyme-catalyzed reactions (Fig. 44.4 depicts the overall pathway). L-Tyrosine hydroxylase hydroxylates the meta position of L-tyrosine, producing L-dihydroxyphenylalanine (L-DOPA) and is the rate-limiting step. The L-DOPA is then decarboxylated by L-aromatic amino acid decarboxylase to form dopamine, which is converted to NE by the action of dopamine p-hydroxylase. Dopamine p-hydroxylase occurs in storage vesicles of the nerve ending, and the NE formed is stored there until it is released into the synaptic cleft. In the chromaffin cells, the formed NE is converted to EPI by N-methylation catalyzed by phenylethanolamine N-methyltransferase. 

DA is involved in movement disorders, as well as in schizophrenia and substance abuse. The neurotransmitter is synthesized from a precursor amino add tyrosine. L-tyrosine is hydroxylated to L-dopa by the action of the enzyme, tyrosine hydroxylase. L-dopa is then converted to DA by the L-aromatic amino acid enzyme decarboxylase. 

A apart. Dioxygen binding results in the two-electron reduced peroxide in a side-on bound dicopper(II) structure (Fig. 1). Crystallographic information is (also) established for the reduced, as well as the oxidized met forms (3-5). Based on their spectroscopic similarities, a similar active-site structure is proposed for the monooxygenase tyrosinase (Tyr) X-ray structures are available for catechol oxidase (CO) depicting a similar active-site structure to He and Tyr (6). However, unlike the reversible binding reactivity of hemocyanin, tyrosinase catalyzes the aromatic hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (l-DOPA), and can further perform catechol oxidase activity which oxidizes the catechol to the quinone (Fig. 2) (7). 

Like the thyroid hormone thyroxine, noradrenaline and adrenaline originate as well from the amino acid tyrosine, which is formed in the liver by hydroxylation of phenylalanine. Tyrosine is hydroxylated a second time in the aromatic ring and, subsequent to decarboxylation, again in the side-chain. The JV-methylation of noradrenaline with S-adenosylmethionine in the chromaffin cells of the adrenal medulla leads finally to adrenaline. [107]... 

Industrially, diphenols such as bisphenol A are frequently used in order to increase the stiffness of polymers thanks to their aromatic backbone (Fig. 1.20). However, for biomedical applications diphenols cannot be used as monomers because they are cytotoxic. Tyrosine (2-amino-3-(4-hydroxyphenyl) propanoic acid) is the only major natural nutrient containing an aromatic hydroxyl group. Thus, tyrosine dipeptide (where the terminal amino group and terminal carboxylic group are protected) can be seen as replacing diphenols for biomedical devices. 

Finally, Section C of Fig. 17 summarizes some of the important CNS species and related compounds which definitely are not electrochemically active. Neither ACh, GABA, nor any of the amino acids (except tyrosine and glutathione, as mentioned earlier) are electroactive. Many drugs like amphetamine and / -chloroamphetamine are innocuous from the electrochemical viewpoint. As a rule of thumb, any drug having an aromatic hydroxyl, amino or sulfhydryl function, or a phenothiazine-like structure may be electro-oxidizable. However, it is always advisable to check the electrochemistry of any new drug. 

Tyrosine is the only major, natural nutrient containing an aromatic hydroxyl group. Derivatives of tyrosine dipeptide can be regarded as diphenols and may be employed as replacements for the industrially used diphenols such as Bisphenol A in the design of medical implant materials (Kigime 1). The observation that aromatic backbone structures can significantly increase the stiffness and mechanical strength of polymers prowded the rationale for the use of tyrosine dipeptides as monomers. 

Aromatic hydroxyls Phenols, halogenated phenols, R(Hal) + 1200 salicylic acid (and derivatives) bcnzofuranols, chlorophenols (and metabolites), paracetamol, hesperidin, tyrosine... 

The octahydroindole moiety in these alkaloids derives from tyrosine via tyramine, and iV-methyltyramine [149]. Phenylalanine is the source of the unusual, if not unique, mesembrine Cg unit. As with other metabolites phenylalanine is utilized by way of cinnamic acid and, in this case, mono- and di-hydroxy-derivatives may be involved too. Late-stage aromatic hydroxylation is also possible, for... 

Speculation still surrounds some of the aromatic hydroxylation processes which are believed to operate in higher plants. Griffith and Conn have thus shown, contrary perhaps to expectation, that partially purified phenolase preparation from Vicia faba do not catalyse the conversion of L-tyrosine to L-dopa and they concluded that phenolase does not appear to play a role in L-dopa synthesis. 

CVPAH and RLPAH when [4- Hl-phenylalanine and [2,3,5,6- H]phenylalanine was used as substrates. This suggests that PAH from either source probably does not directly mediate the NIH shift mechanism and that the two hydroxylating intermediates are the same. It has been proposed that the aromatic hydroxylation proceeds via an arene oxide intermediate which rearranges to tyrosine or 3-hydroxyphenylalanine via a 1,2-hydride shift and aromatizes as shown in Scheme 8 [127]. 

---