Adrenaline, Noradrenaline, and Their Biogenesis

The assumption of early workers that adrenaline is derived from phenylalanine and tyrosine was conclusively proved by the demonstration (328, cf. also 888) that phenylalanine labeled in the a-position of the side chain with C gave adrenaline labeled in the corresponding position. It is reasonable to assume that tyrosine is an intermediate in this conversion. The further conversion of tyrosine to adrenaline involves four changes (1) introduction of a further phenolic group, decarboxylation, (3) introduction of the side chain hydroxyl, and (4) A-methylation. A great deal about the biosynthesis of adrenaline remains obscure, but it is nevertheless possible to advance a tentative hypothesis concerning the order in which these changes occur. 

The conversion of tyrosine to 3,4-dihydroxyphenylalanine occurs both in vivo in man (590) and in vitro by the action of tissue tyrosinase (205, 688). Mammals can decarboxylate both tyrosine (402,407) and dihydroxyphenyl-alanine (406), tyrosine decarboxylase and dihydroxyphenylalanine (dopa) decarboxylases being quite distinct and separable (405), though both are dependent on pyridoxal phosphate (73, 758, and review 72). In mammals dihydroxyphenylalanine is the most readily decarboxylated of all amino acids, and it is therefore not unreasonable to assume that this is the substrate normally decarboxylated in adrenaline biosynthesis cf. 74, 75). Support for this concept derives from the fact that both the substrate and the product of the reaction (3,4-dihydroxyphenylethylamine diagram 11) can or do occur in the adrenal (298, 299, 802), and the amine is moreover, like adrenaline and noradrenaline, a normal urinary excretion product (245, 404). 

If the above are accepted as the first two steps in adrenaline biogenesis it becomes possible to predict that the remaining two steps occur in the order shown in diagram 11. 

Diagram 11. The pathway considered most probable for the biogenesis of adrenaline from tyrosine. 

The widespread co-occurrence of noradrenaline and adrenaline in itself suggests that noradrenaline is the immediate adrenaline precursor. This had been considered probable even before the natural occurrence of noradrenaline was known (70, 71), and the methylation of noradrenaline has since been shown both in vitro in adrenal preparations (110) and in vivo on perfusing the surviving adrenal (111). The methyl group can arise from methionine, probably formed from choline, in which the adrenal is extremely rich. A large proportion of the activity of administered (methyl-C ) methionine appears in the adrenal (460, 569). 

---