Serotonin and melatonin biosynthesis (Trp -> 5-HTP -> serotonin -> N-acetylserotonin -> melatonin)

Serotonin (5-hydroxytryptamine) and the pineal hormone melatonin are the indoleamine products of a four-step pathway from the essential amino acid L-tryptophan. Tryptophan hydroxylase - the neuronal isoform TPH2 in brainstem raphe serotonergic neurons, the peripheral isoform TPH1 in gut enterochromaffin cells, pineal gland and skin - catalyses the rate-limiting hydroxylation of L-tryptophan to 5-hydroxy-L-tryptophan (5-HTP) using tetrahydrobiopterin (BH4), O2 and a non-heme Fe(II) centre. The shared aromatic-L-amino-acid decarboxylase (DDC/AADC, curated with the catecholamine pathway) decarboxylates 5-HTP to serotonin. In the pineal gland (and retina) serotonin is then converted to melatonin in two further steps that are gated by the circadian clock: serotonin N-acetyltransferase (AANAT, the "timezyme") N-acetylates serotonin to N-acetylserotonin using acetyl-CoA - the sharply night-elevated, cAMP/14-3-3-regulated rate-controlling step - and acetylserotonin O-methyltransferase (ASMT/HIOMT) O-methylates N-acetylserotonin to melatonin using S-adenosyl-L-methionine. Serotonin acts as a central and enteric neurotransmitter and platelet mediator, while melatonin signals darkness/photoperiod. Variants across the pathway are studied in mood, autism- spectrum and sleep phenotypes.

MODULE:serotonin_melatonin_biosynthesisDRAFTMetabolic Pathwaymodules/serotonin_melatonin_biosynthesis.yaml
serotonin biosynthetic processGO:0042427 melatonin biosynthetic processGO:0030187 indolalkylamine biosynthetic processGO:0046219
GO:0042427
serotonin biosynthetic process
TPH1/TPH2 + DDC synthesise serotonin from tryptophan (GO:0042427).
GO:0030187
melatonin biosynthetic process
AANAT + ASMT convert serotonin to melatonin (GO:0030187).
file:human/TPH1/TPH1-ai-review.yaml
TPH1 gene review (human)
Tryptophan 5-hydroxylase 1 (peripheral) (UniProtKB:P17752, GO:0004510) matches the completed human TPH1 review.
file:human/TPH2/TPH2-ai-review.yaml
TPH2 gene review (human)
Tryptophan 5-hydroxylase 2 (neuronal) (UniProtKB:Q8IWU9, GO:0004510) matches the completed human TPH2 review.
file:human/DDC/DDC-ai-review.yaml
DDC gene review (human)
Aromatic-L-amino-acid decarboxylase, 5-HTP branch (UniProtKB:P20711, GO:0036467) matches the completed human DDC review.
file:human/AANAT/AANAT-ai-review.yaml
AANAT gene review (human)
Serotonin N-acetyltransferase (UniProtKB:Q16613, GO:0004059) matches the completed human AANAT review.
file:human/ASMT/ASMT-ai-review.yaml
ASMT gene review (human)
Acetylserotonin O-methyltransferase (UniProtKB:P46597, GO:0017096) matches the completed human ASMT review.
5Nodes
4Parts
0Variant Sets
0Variants
4Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:serotonin_melatonin_biosynthesis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

5 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (9 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
tph_activity TPH2 (human; neuronal)
UniProtKB:Q8IWU9
Family Representative 		tryptophan 5-monooxygenase activity
GO:0004510 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tph_activity TPH1 (human; peripheral/pineal)
UniProtKB:P17752
Family Representative 		tryptophan 5-monooxygenase activity
GO:0004510 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ddc_serotonin DDC (human)
UniProtKB:P20711
Family Representative 		5-hydroxy-L-tryptophan decarboxylase activity
GO:0036467 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aanat_activity AANAT (human)
UniProtKB:Q16613
Family Representative 		aralkylamine N-acetyltransferase activity
GO:0004059 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
asmt_activity ASMT (human)
UniProtKB:P46597
Family Representative 		acetylserotonin O-methyltransferase activity
GO:0017096 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tph_activity TPH / aromatic amino acid hydroxylase (biopterin-dependent) family
PANTHER:PTHR11473
Family 		tryptophan 5-monooxygenase activity
GO:0004510 		Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:0004510.
ddc_serotonin DDC / group II PLP decarboxylase family
PANTHER:PTHR11999
Family 		5-hydroxy-L-tryptophan decarboxylase activity
GO:0036467 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11999.
aanat_activity AANAT / GNAT arylalkylamine N-acetyltransferase family
PANTHER:PTHR10908
Family 		aralkylamine N-acetyltransferase activity
GO:0004059 		Family Supported
Family review supports GO:0004059 FAMILY_WIDE. Asserted by serotonin_melatonin_biosynthesis; accepted by AANAT and kept as non-core by PAA1.
asmt_activity ASMT / SAM-dependent O-methyltransferase family
Family 		acetylserotonin O-methyltransferase activity
GO:0017096 		Family Id Missing
The family has no identifier linking it to a curated family review.

Gene-review completeness (5/5 grounded genes reviewed)

5 complete review(s) · 0 with deep research · 0 missing review · 5 reviewed but lacking deep research

Gene Review Complete Deep research
AANAT Q16613 ✓ ✓ ✗
ASMT P46597 ✓ ✓ ✗
DDC P20711 ✓ ✓ ✗
TPH1 P17752 ✓ ✓ ✗
TPH2 Q8IWU9 ✓ ✓ ✗

Details

Context
cytosolGO:0005829
Serotonin and melatonin biosynthesisMetabolic Pathwayserotonin_melatonin_biosynthesis
serotonin biosynthetic processGO:0042427 melatonin biosynthetic processGO:0030187 indolalkylamine biosynthetic processGO:0046219
Context
cytosolGO:0005829

Serotonin and melatonin biosynthesis (GO:0042427 -> GO:0030187), grounded to five completed human gene reviews (four new + the shared DDC, already merged). Route: TPH2 (Q8IWU9, neuronal) / TPH1 (P17752, peripheral/pineal) both PTHR11473 (same family as TH/PAH), GO:0004510, BH4/Fe(II), Trp -> 5-HTP (rate- limiting); DDC (P20711 PTHR11999, GO:0036467, PLP) 5-HTP -> serotonin (shared with the catecholamine module's catecholamine_biosynthesis); then the pineal melatonin steps: AANAT (Q16613 PTHR10908, GO:0004059, acetyl-CoA) serotonin -> N-acetylserotonin (the circadian "timezyme", cAMP/14-3-3-gated); ASMT/HIOMT (P46597, PTHR11746 per PANTHER 19.0; GO:0017096, SAM) N-acetylserotonin -> melatonin. All cytosolic. Precursor tryptophan and BH4 come from separate pathways; DDC and TPH share the aromatic-amino-acid-hydroxylase/decarboxylase logic with the catecholamine pathway (TPH/TH same PANTHER family; DDC the common decarboxylase). Curation: TPH1 peripheral so neuron-projection IBA over-annotated (belongs to TPH2); AANAT's GO:0006474 N-terminal- protein-acetylation IDA is a small-molecule-vs-protein misclassification (over-annotated); ASMT's S-methyltransferase TAS is wrong branch (O-, not S-methylation). GO term ids/labels verified against the local go.db; module passes structural + term-label validation.

Connections

TPH-made 5-HTP is decarboxylated by DDC to serotonin.
DDC-made serotonin is N-acetylated by AANAT (in the pineal) to N-acetylserotonin.
AANAT-made N-acetylserotonin is O-methylated by ASMT to melatonin.
Part 1: tryptophan hydroxylation (Trp -> 5-HTP)
Tryptophan hydroxylase (TPH2 neuronal / TPH1 peripheral)Reactiontryptophan_hydroxylation

Annotons

TPH1/TPH2: tryptophan 5-monooxygenase
tph_activity
Participant: Family: TPH / aromatic amino acid hydroxylase (biopterin-dependent) family
Family:
TPH / aromatic amino acid hydroxylase (biopterin-dependent) familyPANTHER:PTHR11473
Representative Members: TPH2 (human; neuronal)UniProtKB:Q8IWU9 TPH1 (human; peripheral/pineal)UniProtKB:P17752

Function

tryptophan 5-monooxygenase activityGO:0004510
Substrates: L-tryptophan tetrahydrobiopterin (BH4) O2 (non-heme Fe2+)
Products: 5-hydroxy-L-tryptophan (5-HTP) 4a-hydroxytetrahydrobiopterin

Locations

cytosolGO:0005829

Hydroxylate L-tryptophan to 5-HTP (rate-limiting step).

Part 2: 5-HTP decarboxylation (5-HTP -> serotonin)
Aromatic-L-amino-acid decarboxylase (DDC/AADC)Reactionhtp_decarboxylation

Annotons

DDC: 5-hydroxy-L-tryptophan decarboxylase
ddc_serotonin
Participant: Family: DDC / group II PLP decarboxylase family
Family:
DDC / group II PLP decarboxylase familyPANTHER:PTHR11999
Representative Members: DDC (human)UniProtKB:P20711

Function

5-hydroxy-L-tryptophan decarboxylase activityGO:0036467
Substrates: 5-hydroxy-L-tryptophan (5-HTP; PLP)
Products: serotonin (5-hydroxytryptamine) CO2

Locations

cytosolGO:0005829

Decarboxylate 5-HTP to serotonin.

Part 3: serotonin N-acetylation (serotonin -> N-acetylserotonin)
Serotonin N-acetyltransferase (AANAT, the timezyme)Reactionserotonin_acetylation

Annotons

AANAT: aralkylamine N-acetyltransferase
aanat_activity
Participant: Family: AANAT / GNAT arylalkylamine N-acetyltransferase family
Family:
AANAT / GNAT arylalkylamine N-acetyltransferase familyPANTHER:PTHR10908
Representative Members: AANAT (human)UniProtKB:Q16613

Function

aralkylamine N-acetyltransferase activityGO:0004059
Substrates: serotonin acetyl-CoA
Products: N-acetylserotonin (NAS) CoA

Locations

cytosolGO:0005829

N-acetylate serotonin to N-acetylserotonin (circadian control point).

Part 4: O-methylation (N-acetylserotonin -> melatonin)
Acetylserotonin O-methyltransferase (ASMT/HIOMT)Reactionacetylserotonin_methylation

Annotons

ASMT: acetylserotonin O-methyltransferase
asmt_activity
Participant: Family: ASMT / SAM-dependent O-methyltransferase family
Family:
ASMT / SAM-dependent O-methyltransferase family
Representative Members: ASMT (human)UniProtKB:P46597

Function

acetylserotonin O-methyltransferase activityGO:0017096
Substrates: N-acetylserotonin S-adenosyl-L-methionine (SAM)
Products: melatonin S-adenosyl-L-homocysteine

Locations

cytosolGO:0005829

O-methylate N-acetylserotonin to melatonin (final step).