Tyrosine-hydroxylas

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). 

A combination of decarboxylation and hydroxyla-tion of the ring of tyrosine produces derivatives of o-dihydroxybenzene (catechol), which play important roles as neurotransmitters and are also precursors to melanin, the black pigment of skin and hair. Catecholamines may be formed by decarboxylation of tyrosine into tyramine (step e, Fig. 25-5) and subsequent oxidation. However, the quantitatively more important route is hydroxylation by the reduced pterin-dependent tyrosine hydroxylase (Chapter 18) to 3,4-dihydroxyphenylalanine, better known as dopa. The latter is decarboxylated to dopamine.1313 Hydroxylation of dopamine by an ascorbic acid and... 

Models have been developed to accommodate the results of the hydroxyla-tion of substrates with different structures. The cytochrome P450CAM camphor hydroxylase from the bacterium Pseudomonas putida has been studied by X-ray crystallography. The importance of hydrophilic interactions with a valine (VAL-247) and a polar interaction mediated by hydrogen bonding to a tyrosine residue (TYR-96) has been noted. A model based on the hydroxylation of numerous cyclic amides by Beauveria sulfurescens (originally named Sporotrichum sulfurescens) showed that hydroxylation occurred preferentially at a methylene group about 5.5 A from an electron-rich substituent on the substrate. 

From tyrosine, a series of enzymatic reactions including ring hydroxyla-tion, deciurboxylation, deamination, and D-methylation are responsible for over 20 majof metabolites of neurochemical interest. All of the above metabolites retain at least an electroactive phent nudeus, and most provide enhanced detectability via vanillyl or catechol functional groups. Table III provides cyclic voltammctric data in 90% 0.1 M citrate (pH 4)/10% methanol for a series of these metabolites. Substituent effects are evident. Gener-aUy the catecholamines with their OKlihydroxyphenyl structures are easiest to oxidize, followed by vanillyl dmvatives such as normetanephrine and vanillylmandelic acid. Simple phenols such as tyrosine remain the most difficult to oxidize in this series. 

Although bioinformatics analysis failed to yield clues for the biosynthetic origin of 2-aza-L-tyrosine, the authors proposed that the 18-gene type II PKS locus could play a role in such a biosynthesis and envisaged 2-aza-L-phenylalanine, either free or tethered to a carrier protein, as a penultimate intermediate of the pathway. Hydroxyla-tion of 2-aza-L-phenylalanine, catalyzed by KedY, a FAD-dependent monooxygenase requiring the KedE6 flavin reductase, finally affords 2-aza-L-tyrosine [331]. 

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