aetokthonotoxin

CHEBI:167886 EXACT SEEDED

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A bromoindole that is 2,3,5-tribromo-1H-indole which is substituted by a 5,7-dibromo-3-cyano-1H-indol-2-yl group at position 1. It is a biindole alkaloid isolated from the cyanobacterium Aetokthonos hydrillicola and causes vacuolar myelinopathy in bald eagles.

Structure

Standard InChIKey	JXJDQKCOJBAPQM-UHFFFAOYSA-N
SMILES	N#CC1=C(N2C(Br)=C(Br)C3=C2C=CC(Br)=C3)NC4=C(Br)C=C(Br)C=C41
Stereochemistry	fully defined
Cross-references	cyanometdb:CyanoMetDB_2448

Filing pathway

Alkaloids — computed by NPClassifier npclassifier.gnps2.org@2026-09-07, which is why it is pinned rather than recomputed. The gene cluster's asserted class is other, from MIBiG.

Producer organisms 1

A claim that this taxon makes the compound. The basis says what the evidence addressed — a knockout and a database assertion are not the same claim.

Taxon	Basis	Cluster	Evidence
Aetokthonos hydrillicola Thurmond2011 NCBITaxon:2712845	SOURCE_ASSERTION	mibig:BGC0002643	PMID:33766860

Occurrences 3

Somebody found the compound in this organism and cited it. That is not a claim that the organism makes it, and nothing here promotes one to the other.

Taxon	Source	Reference
Aetokthonos hydrillicola NCBITaxon:1550245	LOTUS	DOI:10.1126/SCIENCE.AAX9050
Aetokthonos hydrillicola NCBITaxon:1550245	CYANOMETDB	DOI:10.1126/science.aax9050
Aetokthonos hydrillicola NCBITaxon:1550245	CHEBI	PMID:33766860

Biosynthetic gene clusters 1

Accession	Host	Locus evidence	Genome
mibig:BGC0002643	Aetokthonos hydrillicola Thurmond2011 NCBITaxon:2712845	CLUSTER_DEMONSTRATED	genbank:MT225528.1

A locus claim and a taxon claim are different questions. Heterologous expression settles the first and leaves the second where the isolation report left it.

Biosynthesis curated

Written by a curator with claim-level evidence on each step; not derived from a source. This is what the rest of the record exists to support.

Step	Enzyme	Reaction	Substrate → product	Evidence
1	AetF tryptophan 5/7-brominase UniProtKB:A0A861B9Z9	RHEA:82463	CHEBI:16828 → CHEBI:232362	DOI:10.1021/jacs.1c12778
2	AetF tryptophan 5/7-brominase UniProtKB:A0A861B9Z9	RHEA:82467	CHEBI:232362 → CHEBI:231978	DOI:10.1021/jacs.1c12778
3	AetE 5-bromo-tryptophanase UniProtKB:A0A861BA10	RHEA:82523	CHEBI:232362 → CHEBI:232364	DOI:10.1021/jacs.1c12778
4	AetA 5-bromoindole 2,3-dibrominase UniProtKB:A0AAP5I1G4	RHEA:82527	CHEBI:232364 → CHEBI:232365	DOI:10.1021/jacs.1c12778
5	AetA 5-bromoindole 2,3-dibrominase UniProtKB:A0AAP5I1G4	RHEA:82531	CHEBI:232365 → CHEBI:232363	DOI:10.1021/jacs.1c12778
6	AetD iron-dependent nitrile synthase UniProtKB:A0A861B387	RHEA:81787	CHEBI:231978 → CHEBI:231979	DOI:10.1021/jacs.1c12778
7	AetB aetokthonotoxin synthase UniProtKB:A0A861B5L6	RHEA:82519	CHEBI:231979 + CHEBI:232363 → CHEBI:167886	DOI:10.1021/jacs.1c12778

Step 1: AetF carries the first brominated tryptophan branch point in the convergent AETX pathway and converts L-tryptophan to 5-bromo-L-tryptophan.

Step 2: AetF performs the second tryptophan bromination to form the 5,7-dibromo-L-tryptophan substrate for AetD.

Step 3: AetE diverts 5-bromo-L-tryptophan into the tribromoindole arm by cleaving it to 5-bromoindole.

Step 4: AetA catalyzes the first pyrrole-ring bromination of 5-bromoindole to generate 3,5-dibromoindole.

Step 5: AetA carries out the second pyrrole-ring bromination, converting 3,5-dibromoindole to the AetB substrate 2,3,5-tribromoindole.

Step 6: AetD forms the 5,7-dibromo-indole-3-carbonitrile arm from 5,7-dibromo-L-tryptophan without a confirmed role for AetC.

Step 7: AetB completes AETX biosynthesis by coupling the separately assembled 5,7-dibromo-indole-3-carbonitrile and 2,3,5-tribromoindole monomers.

Mechanism & Biosynthesis Overview

Causal graph — biosynthesis 13 nodes, 15 edges

In vitro reconstituted AetF/AetE/AetA and AetF/AetD branch construction of the two indole monomers that AetB couples to form aetokthonotoxin.

Subject	Predicate	Object	Notes	Evidence
L-tryptophan	is brominated by	AetF	AetF accepts L-tryptophan to begin the AETX pathway.	DOI:10.1021/jacs.1c12778 RHEA:82463 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes Purified AetF formed brominated L-tryptophan products from L-tryptophan. reference RHEA:82463 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: bromide plus L-tryptophan plus NADPH plus oxygen form 5-bromo-L-tryptophan, NADP(+), and water.
AetF	forms	5-bromo-L-tryptophan	AetF forms the monobrominated branch-point precursor.	DOI:10.1021/jacs.1c12778 RHEA:82463 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes Purified AetF formed 5-bromo-L-tryptophan from L-tryptophan. reference RHEA:82463 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: bromide plus L-tryptophan plus NADPH plus oxygen form 5-bromo-L-tryptophan, NADP(+), and water.
5-bromo-L-tryptophan	is brominated by	AetF	AetF also accepts 5-bromo-L-tryptophan for the second bromination.	DOI:10.1021/jacs.1c12778 RHEA:82467 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes The in vitro AetF reaction formed 5,7-dibromo-L-tryptophan. reference RHEA:82467 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5-bromo-L-tryptophan plus bromide plus NADPH plus oxygen form 5,7-dibromo-L-tryptophan, NADP(+), and water.
AetF	forms	5,7-dibromo-L-tryptophan	AetF forms the dibrominated tryptophan precursor of the nitrile arm.	DOI:10.1021/jacs.1c12778 RHEA:82467 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes The in vitro AetF reaction formed 5,7-dibromo-L-tryptophan. reference RHEA:82467 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5-bromo-L-tryptophan plus bromide plus NADPH plus oxygen form 5,7-dibromo-L-tryptophan, NADP(+), and water.
5-bromo-L-tryptophan	is cleaved by	AetE	AetE consumes the monobrominated tryptophan in the tribromoindole arm.	DOI:10.1021/jacs.1c12778 RHEA:82523 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes AetE was assigned by in vitro conversion of 5-bromo-L-tryptophan to 5-bromoindole. reference RHEA:82523 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5-bromo-L-tryptophan plus water forms 5-bromoindole, pyruvate, and ammonium.
AetE	forms	5-bromoindole	AetE forms 5-bromoindole for downstream AetA brominations.	DOI:10.1021/jacs.1c12778 RHEA:82523 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes AetE was assigned by in vitro conversion of 5-bromo-L-tryptophan to 5-bromoindole. reference RHEA:82523 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5-bromo-L-tryptophan plus water forms 5-bromoindole, pyruvate, and ammonium.
5-bromoindole	is brominated by	AetA	AetA brominates the pyrrole ring of 5-bromoindole.	DOI:10.1021/jacs.1c12778 RHEA:82527 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes The reconstituted AetA reaction formed 3,5-dibromoindole from 5-bromoindole. reference RHEA:82527 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5-bromoindole plus bromide plus reduced FAD plus oxygen form 3,5-dibromoindole, FAD, and water.
AetA	forms	3,5-dibromoindole	AetA forms 3,5-dibromoindole as the intermediate before C2 bromination.	DOI:10.1021/jacs.1c12778 RHEA:82527 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes The reconstituted AetA reaction formed 3,5-dibromoindole from 5-bromoindole. reference RHEA:82527 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5-bromoindole plus bromide plus reduced FAD plus oxygen form 3,5-dibromoindole, FAD, and water.
3,5-dibromoindole	is brominated by	AetA	AetA performs the second pyrrole-ring bromination on 3,5-dibromoindole.	DOI:10.1021/jacs.1c12778 RHEA:82531 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes AetA directly converted 3,5-dibromoindole to 2,3,5-tribromoindole. reference RHEA:82531 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 3,5-dibromoindole plus bromide plus reduced FAD plus oxygen form 2,3,5-tribromoindole, FAD, and water.
AetA	forms	2,3,5-tribromoindole	AetA forms the tribromoindole substrate for the final AetB coupling.	DOI:10.1021/jacs.1c12778 RHEA:82531 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes AetA directly converted 3,5-dibromoindole to 2,3,5-tribromoindole. reference RHEA:82531 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 3,5-dibromoindole plus bromide plus reduced FAD plus oxygen form 2,3,5-tribromoindole, FAD, and water.
5,7-dibromo-L-tryptophan	is rearranged by	AetD	AetD converts the dibrominated tryptophan into the nitrile-arm indole.	DOI:10.1021/jacs.1c12778 RHEA:81787 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes AetD alone, stimulated by Fe(II), formed 5,7-dibromo-indole-3-carbonitrile. reference RHEA:81787 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5,7-dibromo-L-tryptophan plus oxygen form 5,7-dibromo-indole-3-carbonitrile, glycolate, water, and a proton.
AetD	forms	5,7-dibromo-indole-3-carbonitrile	AetD forms the 5,7-dibromo-indole-3-carbonitrile substrate for AetB.	DOI:10.1021/jacs.1c12778 RHEA:81787 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes AetD alone, stimulated by Fe(II), formed 5,7-dibromo-indole-3-carbonitrile. reference RHEA:81787 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5,7-dibromo-L-tryptophan plus oxygen form 5,7-dibromo-indole-3-carbonitrile, glycolate, water, and a proton.
5,7-dibromo-indole-3-carbonitrile	is coupled by	AetB	AetB couples this nitrile-arm monomer with 2,3,5-tribromoindole.	DOI:10.1021/jacs.1c12778 RHEA:82519 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes AetB coupled the two functionalized indole monomers to make AETX in vitro. reference RHEA:82519 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5,7-dibromo-indole-3-carbonitrile plus 2,3,5-tribromoindole couple with reduced ferredoxin and oxygen to form aetokthonotoxin.
2,3,5-tribromoindole	is coupled by	AetB	AetB couples this tribromoindole monomer with the nitrile-arm monomer.	DOI:10.1021/jacs.1c12778 RHEA:82519 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes AetB coupled the two functionalized indole monomers to make AETX in vitro. reference RHEA:82519 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5,7-dibromo-indole-3-carbonitrile plus 2,3,5-tribromoindole couple with reduced ferredoxin and oxygen to form aetokthonotoxin.
AetB	forms	aetokthonotoxin	AetB completes the final biaryl coupling to aetokthonotoxin.	DOI:10.1021/jacs.1c12778 RHEA:82519 reference DOI:10.1021/jacs.1c12778 evidence type PRIMARY_EXPERIMENT notes The AetB enzymatic product was confirmed as AETX by coelution with a synthetic standard. reference RHEA:82519 evidence type DATABASE_ASSERTION retrieved on 2026-09-28 notes Rhea grounds the left-to-right AETX pathway reaction: 5,7-dibromo-indole-3-carbonitrile plus 2,3,5-tribromoindole couple with reduced ferredoxin and oxygen to form aetokthonotoxin.

Every edge carries its own citation; an uncited edge is refused by the corpus tests.

Explore across X-Mech

AntibioticMech (aetokthonotoxin) ↗ MediaIngredientMech (CHEBI:167886) ↗ TaxonMech: Aetokthonos hydrillicola Thurmond2011 (NCBITaxon:2712845) ↗ PathwayMech (mibig:BGC0002643) ↗

Provenance

Source concept	Source	Version
BGC0002643	MIBIG	2
CHEBI:167886	CHEBI	3-star

This page is generated from data/natural_products/alkaloids/aetokthonotoxin.yaml, which is generated from the committed inventories. Neither is edited by hand.