Dopamine, benzylic oxidation

Analogous side-chain oxidations occur in various biosynthetic pathways. The neurotransmitter norepinephrine, for instance, is biosynthesized from dopamine by a benzylic hydroxylation reaction. The process is catalyzed by the copper-containing enzyme dopamine /3-monooxygenase and occurs by a radical mechanism. A copper-oxygen species in the enzyme first abstracts the pro-R benzylic hydrogen to give a radical, and a hydroxyl is then transferred from copper to carbon. 

These systems are also described as normal copper proteins due to their conventional ESR features. In the oxidized state, their color is light blue (almost undetectable) due to weak d-d transitions of the single Cu ion. The coordination sphere around Cu, which has either square planar or distorted tetrahedral geometry, contains four ligands with N and/or 0 donor atoms [ 12, 22]. Representative examples of proteins with this active site structure (see Fig. 1) and their respective catalytic function include galactose oxidase (1) (oxidation of primary alcohols) [23,24], phenylalanine hydroxylase (hydroxy-lation of aromatic substrates) [25,26], dopamine- 6-hydroxylase (C-Hbond activation of benzylic substrates) [27] and CuZn superoxide dismutase (disproportionation of 02 superoxide anion) [28,29]. 

In contrast to other inactivators of dopamine /3-hydroxylase, p-cresol is unusual in that it does not contain a latent electrophile (Goodhart et al., 1987). Oxidation of the benzylic carbon occurs, as evidenced by production of 4-hydroxybenzyl alcohol as well as the corresponding aldehyde. Inactivation with radiolabeled p-cresol leads to substoichiometric modification of the enzyme, with the majority of the radiolabel distributed between four tryptic peptides (DeWolf et al., 1988). Analysis of two of the peptides indicates that they are of identical sequence, each containing modified tyrosine residues which differ in the structure of the p-cresol-amino acid adduct. A second pathway for inactivation is proposed which requires radical-mediated oxidation of the enzyme without incorporation of the inactivator. 

Benzylisoquinollne alkaloids a group of alkaloids found mainly in members of the poppy family (Papaveraceae). The benzyl substituent on Cl of the isoquinoline radical can enter various secondary cycli-zations through phenol oxidation. The ring structures of the medically important Papaveraceae alkaloids (see), Erythrina alkaloids (see) and the fcisbenzyliso-quinoline Curare alkaloids (see) arise in this way. Biosynthetically, papaverine is derived from 2 molecules of dopa, one being converted to dopamine, the other to 3,4-dihydroxyphenylacetaldehyde. Mannich condensation of these two leads first to norlaudano-sine, which is dehydrated to papaverine (Fig. 1). 

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