ABSTRACT
Melatonin is synthesized from dietary tryptophan through actions of four enzymes (see Fig. 3 and ref. 2). Tryptophan hydroxylase (TPH) controls the first step of the pathway in which tryptophan is converted to 5-hydroxytryptophan (5-HTP). Aromatic amino acid decarboxylase (AADC) catalyzes the conversion of 5-HTP to 5-hydroxytryptamine (5-HT, serotonin). Melatonin formation from 5-HT requires two pineal/retina specific enzymes: serotonin N-acetyltransferase (NAT), which forms N-acetylserotonin (NAS) from serotonin, and hydroxyindole-O-methyltransferase (HIOMT), which produces melatonin from NAS. Of the four enzymes involved, NAT has long been viewed as the ‘rate-limiting’ enzyme for melatonin production, due to its diurnal pattern of activity, and has been extensively analyzed.2 In comparison, the regulation of TPH and its contribution in melatonin production is less well understood. A few decades ago, TPH, the rate-limiting enzyme for 5-HT production, was found to be diurnally regulated in the rat pineal with a two-fold increase in activity at night.3,4 Recently, we have shown that 5-HT synthesis is increased early at night, and that the increase in 5-HT production is abolished when beta-adrenergic signaling is blocked.1
