Tryptophan is the obligatory precursor for both serotonin (5-HT) and melatonin. Tryptophan hydroxylase (TPH) is rate-limiting and exists as TPH1 (peripheral, enterochromaffin cells; ~90% of body 5-HT pool is gut) and TPH2 (CNS-restricted; brain 5-HT pool). AADC then converts 5-HTP to serotonin. In pineal gland, serotonin is N-acetylated (AANAT, the circadian-gated enzyme) and O-methylated (HIOMT/ASMT) to melatonin — concentrations rise sharply at dusk under SCN drive.
Organ Systems
nervous
endocrine
Pathway Steps
tryptophan → 5-htp — via tryptophan hydroxylase (TPH1 peripheral / TPH2 central) — rate-limiting; requires BH4 cofactor. Tryptophan hydroxylase is rate-limiting for serotonin: TPH1 (peripheral — gut enterochromaffin cells make ~90% of body serotonin) and TPH2 (central neurons). It shares the BH4 cofactor with tyrosine hydroxylase, and CNS synthesis is substrate-limited by tryptophan transport across the blood–brain barrier, where it competes with other large neutral amino acids.
5-htp → serotonin — via aromatic L-amino acid decarboxylase (AADC / DDC) — same enzyme as in catecholamine synthesis. The same AADC enzyme decarboxylates 5-HTP (→ serotonin) and L-DOPA (→ dopamine). Supplemental 5-HTP bypasses the rate-limiting TPH step and crosses the blood–brain barrier without transporter competition — its supplementation rationale — though peripheral AADC also converts it to serotonin outside the CNS.
serotonin → melatonin — via AANAT (rate-limiting in pineal; circadian-gated) → HIOMT/ASMT N-acetylserotonin O-methylation. Two-step.. Melatonin synthesis takes two steps: AANAT acetylates serotonin to N-acetylserotonin, then ASMT (HIOMT) O-methylates it using SAMe. AANAT is the rate-limiting, circadian-gated step — driven high at night by the SCN and acutely suppressed by light — so melatonin output tracks the dark phase.
Known Modulators
5 htp (substrate) — AADC step. Supplemental 5-HTP bypasses the rate-limiting TPH step and raises 5-HT pool acutely.
tryptophan (substrate) — TPH step. Tryptophan loading raises substrate but doesn't override TPH saturation in most users.
melatonin (substrate) — endpoint. Exogenous melatonin bypasses the entire endogenous synthesis — used as sleep-onset signal.