MELATONIN synthesis pathway in the body

Pineal and retinal SEROTONIN (5-HT) synthesis is up-regulated at night controlled by ß-adrenergic signaling. Sympathetic nerves from the superior cervical ganglion (SCG) innervate the pineal gland via NOREPINEPHRINE (NE)-stimulation of adenergic receptors (ARs). Increased SEROTONIN synthesis is due to increased protein expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme of SEROTONIN synthesis.

Circadian 5-HT pineal production regulated by adrenergic signaling. Pineal 5-HT production displays a tri-phasic diurnal pattern, continuing in constant darkness and influenced by light intrusion at night. SEROTONIN content in the pineal gland is higher than in any other part of the body.

(i) During the day - Pineal 5-HT levels constant and high

(ii) Early in the night (just after the lights are off) - Sharp rise in pineal 5-HT synthesis and release (controlled by α-adrenergic signaling by NE) precede nocturnal rise in MELATONIN synthesis.

(iii) Late in the night - 5-HT levels are low, as 5-HT is used to make MELATONIN . However, in the absence of MELATONIN release, pineal 5-HTcan reach twice daily levels.

Diurnal variation in MELATONIN synthesis is brought about by NOREPINEPHRINE (NE). Secreted by the postganglionic sympathetic nerves (the superior cervical ganglion/SCG) that innervate the pineal gland. NE interacts with ß1-adrenoreceptors on the surface of the pinealocytes (pineal cells) to increase pineal cAMP, which in turn activate the N-acetyltransferase (NAT) required for MELATONIN synthesis in the biosynthesis pathway, converting tryptophan to MELATONIN.

MELATONIN is synthesized from dietary tryptophan via 4 enzymes
	Enzyme	Converts to:
1	TPH (tryptophan hydroxylase) (vitamin B3-dependent enzyme**)	Tryptophan→ 5-HTP
2	AADC (aromatic amino acid decarboxylase) (Aka 5-HTP decarboxylase) (vitamin B6-dependent enzyme)	5-HTP→ SEROTONIN (5-HT / 5-hydroxytryptamine)
3	NAT (Serotonin N-acetyl transferase)	SEROTONIN → NAS (N-acetylSEROTONIN)
4	HIOMT (hydroxyindole-O methyltransferase) + SAMe (Donatesmethyl group CH₃ to HIOMT ) (methionine, vitamins B6, B12, folate dependent) SAMe -And Other Methyl Donor Molecules	NAS → MELATONIN

** The body often uses Tryptophan to make vitamin B3, at a very high cost of 60mg L-Tryptophan to make just 1 mg B3.

SAMe (a methyl donor molecule made from the amino acid methionine and ATP) is essential for MELATONIN and SEROTONIN production

- SAMe is the daytime equivalent of MELATONIN - and like MELATONIN, it is produced under control of the master biological clock;

- Natural synthesis of MELATONIN (and SEROTONIN) depends on adequate SAMe synthesis during the day - SAMe donates a methyl group molecule (CH₃) to the enzyme HIOMT that converts the acetylated form of SEROTONIN (NAS) to MELATONIN;

- Vitamins B6, B12 and folate (folic acid) are essential cofactors of SAMe production

- At night MELATONIN ▲ ▲ ▲ / SAMe ▼ ▼ ▼ and in the day SAMe ▲ ▲ ▲ / MELATONIN▼ ▼ ▼ - SEROTONIN is also produced at night.

SAMe -And Other Methyl Donor Molecules

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