NaturalProductMech

fumagillin

CHEBI:48635 EXACT SEEDED antibacterial

What these status tags mean

Curation status describes a workflow state. SEEDED means the record entered through the source-seeding workflow; it does not imply that no later curation occurred. PROPOSED marks an addition awaiting review; REVIEWED records curator sign-off on identity, structure, filing class and producer claims; DEPRECATED retains a superseded or out-of-scope record. These are workflow decisions, not independently verified human review. Agent-assisted contributions may appear in the record history.

Grounding describes the identifier mapping: EXACT uses an ontology identity asserted by the source; MINTED keeps a local identifier when no defensible ontology identity is available; REVIEW_NEEDED flags an exact structure whose ontology identity needs adjudication. The grounding note retains any unresolved alternatives. These tags do not establish the strength of producer or activity evidence.

A meroterpenoid resulting from the formal condensation of the hydroxy group of fumagillol with the carboxylic acid group of (all-E)-deca-2,4,6,8-tetraenedioic acid. Originally isolated from the fungus Aspergillus fumigatus, it is used for the control of Nosema infection in honey bees.

Structure

Standard InChIKey	NGGMYCMLYOUNGM-CSDLUJIJSA-N
SMILES	CC(=CC[C@@H]1[C@@](O1)(C)[C@H]2[C@@H]([C@@H](CC[C@]23CO3)OC(=O)/C=C/C=C/C=C/C=C/C(=O)O)OC)C
Stereochemistry	fully defined
Cross-references	npatlas:NPA010119

Filing pathway

Polyketides — 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 pks, terpene, 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
Aspergillus fumigatus Af293 NCBITaxon:330879	BGC_CHARACTERIZED	mibig:BGC0001067	DOI:10.1021/ja312503y

Occurrences 4

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
Aspergillus terreus NCBITaxon:33178	LOTUS	DOI:10.1021/ACS.JNATPROD.9B01190
Aspergillus fumigatus NCBITaxon:746128	LOTUS	DOI:10.1021/JA01475A029
Aspergillus fumigatus NCBITaxon:746128	LOTUS	DOI:10.1021/JA312503Y
Aspergillus fumigatus NCBITaxon:746128	LOTUS	DOI:10.1021/NP049893P

Biosynthetic gene clusters 1

Accession	Host	Locus evidence	Genome
mibig:BGC0001067	Aspergillus fumigatus Af293 NCBITaxon:330879	CLUSTER_DEMONSTRATED	genbank:CM000176.1

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.

Mechanism & Biosynthesis Overview

Causal graph — bioactivity 2 nodes, 1 edge

Fumagillin covalently binds human methionine aminopeptidase 2.

Subject	Predicate	Object	Notes	Evidence
fumagillin	binds	human methionine aminopeptidase 2	PDB 1BOA maps chain A to UniProtKB:P50579 residues 1-478 with a single I347/V347 sequence conflict and records FUG fumagillin covalently linked to His231 NE2 of chain A.	DOI:10.1126/science.282.5392.1324 DOI:10.2210/pdb1boa/pdb reference DOI:10.1126/science.282.5392.1324 evidence type PRIMARY_EXPERIMENT snippet Structure of human methionine aminopeptidase-2 complexed with fumagillin. notes Sin et al. solved PDB 1BOA, a structure of human MetAP2 in complex with FUG fumagillin and cobalt. reference DOI:10.2210/pdb1boa/pdb evidence type DATABASE_ASSERTION notes RCSB PDB identifies PDB 1BOA entity 1 as a methionine aminopeptidase mapped to UniProtKB:P50579, entity 3 as FUG fumagillin, and reports a 1.484 Angstrom covalent bond between His231 NE2 and FUG C11.

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

Causal graph — biosynthesis 5 nodes, 4 edges

Terminal conversion assay, not a complete pathway. The A1159-derived experimental enzyme remains accession-unresolved; Af293 is a separate reference example, not an asserted identical allele. Main Figure4 names BJ5464-NpgA; supplement S6-S8 specifies BY4705. The host discrepancy is retained. No producer, essentiality, cofactor-independence or purified-enzyme sufficiency claim is added.

Subject	Predicate	Object	Notes	Evidence
Fma-ABM (Af293 reference)	is_reference_example_for	Fma-ABM (A1159-derived construct)		https://www.uniprot.org/uniprotkb/Q4WAZ2/entry https://www.ncbi.nlm.nih.gov/protein/EAL85120.1 reference https://www.uniprot.org/uniprotkb/Q4WAZ2/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected same-named AFUA_8G00470 reference, not sequence identity of the assayed insert. Release2026_03 Q4WAZ2 matches the275-aa EAL85120.1 and translated spliced AAHF01000014.1 CDS exactly; coded_by coordinates, strand, complete start/stop, Af293 and taxon330879 agree. No experimental allele or A1159-to-Af293 equivalence was established. reference https://www.ncbi.nlm.nih.gov/protein/EAL85120.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned native Af293 protein reference. The linked genomic CDS is join(690371..690445,690513..691265) on AAHF01000014.1; no custom splice repair.
Fma-ABM (A1159-derived construct)	catalyzes_in_microsomal_fraction	Fma-ABM-containing yeast microsomal conversion		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure4B and supplement S6-S8: A1159 cDNA in pKW20202; microsomal preparation, not homogeneous protein. snippet Heat-inactivated Af470 was used in reaction as a negative control.
Prefumagillin (paper compound 4)	is_substrate_in	Fma-ABM-containing yeast microsomal conversion		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Supplement S7-S8: 100 uM compound4, 30 C, 14 h; no kinetic constant inferred.
Fma-ABM-containing yeast microsomal conversion	produces_detected_product	fumagillin		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure4B: LC-MS-supported compound4-to-compound1 conversion. Individual oxidative intermediates were not directly resolved by this assay.

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

Causal graph — biosynthesis 17 nodes, 17 edges

Precursor assays in fumagillin biosynthesis, not a complete or obligatorily ordered native pathway. Three Af293 references are separate from accession-unresolved experimental constructs. BJ5464-NpgA is the expression host; complete inserts and exact fungal source strains remain unverified. The combined microsomal assay is distinct from the existing Fma-ABM terminal conversion. Purified KR pairs follow Figure 8 and Results; the methods paragraph swaps the first two product numbers. No producer upgrade, native essentiality, isolated CPR sufficiency or kinetic constants are asserted.

Subject	Predicate	Object	Notes	Evidence
Fma-P450 (Af293 reference)	is_reference_example_for	Fma-P450 (experimental construct)		https://www.uniprot.org/uniprotkb/Q4WAZ6/entry https://www.ncbi.nlm.nih.gov/protein/EAL85116.1 reference https://www.uniprot.org/uniprotkb/Q4WAZ6/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected AFUA_8G00510 native Af293 reference, not sequence identity of the experimental insert. UniProt release 2026_03, complete spliced genomic CDS and EAL85116.1 agree exactly (536 aa; taxon 330879). Full experimental allele and source-strain equivalence remain unverified. reference https://www.ncbi.nlm.nih.gov/protein/EAL85116.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned Af293 sequence; coded_by join(AAHF01000014.1:681143..681672, AAHF01000014.1:681727..682807). Coordinates, strand and complete CDS translation verified without splice repair.
Fma-KR (Af293 reference)	is_reference_example_for	Fma-KR (experimental construct)		https://www.uniprot.org/uniprotkb/Q4WAZ4/entry https://www.ncbi.nlm.nih.gov/protein/EAL85118.1 reference https://www.uniprot.org/uniprotkb/Q4WAZ4/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected AFUA_8G00490 native Af293 reference, not sequence identity of the experimental insert. UniProt release 2026_03, complete spliced genomic CDS and EAL85118.1 agree exactly (1017 aa; taxon 330879). Full experimental allele and source-strain equivalence remain unverified. reference https://www.ncbi.nlm.nih.gov/protein/EAL85118.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned Af293 sequence; coded_by complement(join(AAHF01000014.1:685490..685801, AAHF01000014.1:685856..686210, AAHF01000014.1:686258..688644)). Coordinates, strand and complete CDS translation verified without splice repair.
AfCPR (Af293 reference)	is_reference_example_for	AfCPR (experimental construct)		https://www.uniprot.org/uniprotkb/Q4WM67/entry https://www.ncbi.nlm.nih.gov/protein/EAL88947.1 reference https://www.uniprot.org/uniprotkb/Q4WM67/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected AFUA_6G10990 native Af293 reference, not sequence identity of the experimental insert. UniProt release 2026_03, complete spliced genomic CDS and EAL88947.1 agree exactly (695 aa; taxon 330879). Full experimental allele and source-strain equivalence remain unverified. reference https://www.ncbi.nlm.nih.gov/protein/EAL88947.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned Af293 sequence; coded_by complement(join(AAHF01000006.1:1387496..1387792 ,AAHF01000006.1:1387850..1389640)). Coordinates, strand and complete CDS translation verified without splice repair.
Fma-P450 (experimental construct)	catalyzes_in_microsomal_fraction	P450/CPR microsomes plus purified KR assay		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8E and supplement S9-S10: pHCfmaP450 and pHCfmaCPR coexpression in yeast; P450 remains in microsomes. S9 describes an N-terminal His6 tag. Not purified-P450 sufficiency.
AfCPR (experimental construct)	is_coexpressed_redox_partner_in	P450/CPR microsomes plus purified KR assay		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8E; supplement S5/S9-S10 identifies AFUA_6G10990 and pHCfmaCPR. AfCPR is present in the microsomal preparation; no isolated CPR omission/rescue experiment or necessity/sufficiency claim.
Fma-KR (experimental construct)	is_added_purified_enzyme_in	P450/CPR microsomes plus purified KR assay		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8E and supplement S8-S10: pHCfmaKR expression in BJ5464-NpgA, His6-tagged soluble protein purified by Ni-NTA. Assay contains 10 uM Fma-KR, 10 mg/mL wet microsomes and NADPH regeneration.
5R-hydroxy-beta-trans-bergamotene (paper compound 8)	is_substrate_in	P450/CPR microsomes plus purified KR assay		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8E and supplement S10: 1 mM compound 8, 2 mM NADPH, 100 mM PBS pH 7.4, 100 uL total. The overnight endpoint is not a kinetic constant. snippet The reaction was incubated at room temperature overnight
P450/CPR microsomes plus purified KR assay	produces_detected_product	6-demethoxyfumagillol (paper compound 6)		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8E and Results: LC-MS detects 6 among the products; not an exclusive-product or quantitative-yield claim. Fma-KR shifts the profile toward the natural 5R-hydroxy isomer. Microscopic step order is not established by this combined assay.
Fma-KR (experimental construct)	catalyzes	Fma-KR reduction of compound 21		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8A and Results: purified recombinant Fma-KR gives the 5R-hydroxy product. A control with NADPH and substrate but without Fma-KR is shown. No native essentiality or obligatory pathway order inferred.
5-keto-cordycol (paper compound 21)	is_substrate_in	Fma-KR reduction of compound 21		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Experimental Section, Fma-KR assays: 10 uM enzyme, 1 mM substrate, 2 mM NADPH, 100 mM PBS pH 7.4, room temperature overnight. These ketone substrates were prepared by PCC oxidation; do not assert their isolation as native intermediates.
Fma-KR reduction of compound 21	produces_detected_product	cordycol (paper compound 9)		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8A and Results explicitly support 21 to 9. The Fma-KR methods paragraph transposes product numbers 6 and 9 for substrates 21 and 22; the plotted assays and Results agree on 21 to 9 and 22 to 6. This graph retains that source discrepancy.
Fma-KR (experimental construct)	catalyzes	Fma-KR reduction of compound 22		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8B and Results: purified recombinant Fma-KR gives the 5R-hydroxy product. A control with NADPH and substrate but without Fma-KR is shown. No native essentiality or obligatory pathway order inferred.
5-keto-demethoxyfumagillol (paper compound 22)	is_substrate_in	Fma-KR reduction of compound 22		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Experimental Section, Fma-KR assays: 10 uM enzyme, 1 mM substrate, 2 mM NADPH, 100 mM PBS pH 7.4, room temperature overnight. These ketone substrates were prepared by PCC oxidation; do not assert their isolation as native intermediates.
Fma-KR reduction of compound 22	produces_detected_product	6-demethoxyfumagillol (paper compound 6)		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8B and Results explicitly support 22 to 6. The Fma-KR methods paragraph transposes product numbers 6 and 9 for substrates 21 and 22; the plotted assays and Results agree on 21 to 9 and 22 to 6. This graph retains that source discrepancy.
Fma-KR (experimental construct)	catalyzes	Fma-KR reduction of compound 23		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8C and Results: purified recombinant Fma-KR gives the 5R-hydroxy product. A control with NADPH and substrate but without Fma-KR is shown. No native essentiality or obligatory pathway order inferred.
5-keto-fumagillol (paper compound 23)	is_substrate_in	Fma-KR reduction of compound 23		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Experimental Section, Fma-KR assays: 10 uM enzyme, 1 mM substrate, 2 mM NADPH, 100 mM PBS pH 7.4, room temperature overnight. These ketone substrates were prepared by PCC oxidation; do not assert their isolation as native intermediates.
Fma-KR reduction of compound 23	produces_detected_product	fumagillol (paper compound 2)		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 8C and Results explicitly support 23 to 2. The Fma-KR methods paragraph transposes product numbers 6 and 9 for substrates 21 and 22; the plotted assays and Results agree on 21 to 9 and 22 to 6. This graph retains that source discrepancy.

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

Causal graph — biosynthesis 9 nodes, 9 edges

C6H-only 6-to-7 and paired C6H/MT 6-to-2 assays. Two reference sequences are separate from accession-unresolved experimental constructs. C6H primers match reference aa39-309; MT has an explicitly partial 5-prime transcript boundary. Full inserts and fungal source strains remain unverified. Figure 4C/Results/assay recipe take precedence over conflicting Chemical Analysis numbering. No isolated MT sufficiency, sole-product yield, essentiality or complete native pathway is asserted.

Subject	Predicate	Object	Notes	Evidence
Fma-C6H (Af293 reference, 309 aa)	is_reference_example_for	Fma-C6H (pKW20172 experimental construct)		https://www.uniprot.org/uniprotkb/Q4WAZ3/entry https://www.ncbi.nlm.nih.gov/protein/EAL85119.2 DOI:10.1021/ja500881e reference https://www.uniprot.org/uniprotkb/Q4WAZ3/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected reference, not an identical experimental allele. AFUA_8G00480 native Af293 CDS, GenPept and UniProt agree exactly at 309 aa. Supplement Table S2 primer-compatible reference interval is aa39-309 (271 aa; coding nt115-927), not the entire native protein. This boundary match is not proof of the full insert, intervening sequence, source strain or tag residues. reference https://www.ncbi.nlm.nih.gov/protein/EAL85119.2 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned reference sequence independently compared with nucleotide CDS translation and UniProt2026_03. Complete reverse-strand native CDS on AAHF01000014.1:689045..689974. reference DOI:10.1021/ja500881e evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Supplement Table S2 primer alignment only; full insert equivalence remains unresolved. AFUA_8G00480 native Af293 CDS, GenPept and UniProt agree exactly at 309 aa. Supplement Table S2 primer-compatible reference interval is aa39-309 (271 aa; coding nt115-927), not the entire native protein. This boundary match is not proof of the full insert, intervening sequence, source strain or tag residues.
Fma-MT (Af293 submitted reference, partial 5-prime CDS)	is_reference_example_for	Fma-MT (pKW20174 experimental construct)		https://www.uniprot.org/uniprotkb/A0A067Z9B6/entry https://www.ncbi.nlm.nih.gov/protein/AHL19974.1 DOI:10.1021/ja500881e reference https://www.uniprot.org/uniprotkb/A0A067Z9B6/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected reference, not an identical experimental allele. The 400-aa submitted reference matches KJ187001.1 and GenPept exactly. Both source records name Af293 at species taxon746128, while UniProt uses strain taxon330879. KJ187001.1:<1..1203 is explicitly partial at the 5-prime boundary. Table S2 primers bracket the 400-aa submitted segment but do not establish the complete native N terminus, full experimental insert or fungal source strain. reference https://www.ncbi.nlm.nih.gov/protein/AHL19974.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned reference sequence independently compared with nucleotide CDS translation and UniProt2026_03. Partial KJ187001.1:<1..1203 boundary is retained, not repaired. reference DOI:10.1021/ja500881e evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Supplement Table S2 primer alignment only; full insert equivalence remains unresolved. The 400-aa submitted reference matches KJ187001.1 and GenPept exactly. Both source records name Af293 at species taxon746128, while UniProt uses strain taxon330879. KJ187001.1:<1..1203 is explicitly partial at the 5-prime boundary. Table S2 primers bracket the 400-aa submitted segment but do not establish the complete native N terminus, full experimental insert or fungal source strain.
Fma-C6H (pKW20172 experimental construct)	catalyzes	Purified C6H assay with compound 6		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 4C and Results: pKW20172 C-terminal His6 enzyme expressed in E. coli BL21(DE3) and purified by nickel affinity. Boiled-enzyme control retains substrate 6.
6-demethoxyfumagillol (paper compound 6)	is_substrate_in	Purified C6H assay with compound 6		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Dedicated C6H/MT assay methods: 10 uM C6H, 20 uM compound 6, 1 mM sodium ascorbate, 1 mM alpha-ketoglutarate, 100 mM NaCl, 100 mM Tris-HCl pH7.4, 1 h. Temperature and an iron-addition dose are not specified here; no cofactor independence inferred.
Purified C6H assay with compound 6	produces_detected_product	6-hydroxylfumagillol (paper compound 7)		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 4C and Results agree on this pair. Chemical Analysis instead labels C6H conversion 7 to 8 and paired conversion 7 to 2; these inconsistent numbers are not adopted. No sole-product yield, kinetic constant or obligatory native order is asserted.
Fma-C6H (pKW20172 experimental construct)	is_added_purified_enzyme_in	Purified C6H plus MT co-incubation with compound 6		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 4C: co-incubation includes the same recombinant C6H plus MT; this is distinct from the C6H-only assay.
Fma-MT (pKW20174 experimental construct)	is_added_purified_enzyme_in	Purified C6H plus MT co-incubation with compound 6		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 4C and methods: 10 uM pKW20174 C-terminal His6 MT from E. coli BL21(DE3), nickel-affinity purified, added with 1 mM SAM. A combined assay, not an independently demonstrated isolated MT conversion of 7 to 2.
6-demethoxyfumagillol (paper compound 6)	is_substrate_in	Purified C6H plus MT co-incubation with compound 6		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Dedicated C6H/MT assay methods: 10 uM C6H, 20 uM compound 6, 1 mM sodium ascorbate, 1 mM alpha-ketoglutarate, 100 mM NaCl, 100 mM Tris-HCl pH7.4, 1 h. Temperature and an iron-addition dose are not specified here; no cofactor independence inferred. The paired assay additionally contains 10 uM MT and 1 mM SAM.
Purified C6H plus MT co-incubation with compound 6	produces_detected_product	fumagillol (paper compound 2)		DOI:10.1021/ja500881e reference DOI:10.1021/ja500881e evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 4C and Results agree on this pair. Chemical Analysis instead labels C6H conversion 7 to 8 and paired conversion 7 to 2; these inconsistent numbers are not adopted. No sole-product yield, kinetic constant or obligatory native order is asserted. Residual compound 7 is visible in the paired-assay trace.

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

Causal graph — biosynthesis 13 nodes, 11 edges

Database-annotated precursor assembly by Fma-PKS, Fma-TC and Fma-AT. All catalytic edges cite inspected UniProt annotations, not newly inspected experiments from the inaccessible 2013 discovery article. Corrected PKS/TC mRNA references replace erroneous genomic models. PKS-bound donor labels follow FUNCTION dodecapentaenoyl wording while retaining the CATALYTIC ACTIVITY dodecapentaneoyl spelling discrepancy. Chemical and reaction IDs are not assigned. This partial graph does not connect uninspected intermediate steps or establish a complete native pathway.

Subject	Predicate	Object	Notes	Evidence
Fma-PKS (Af293 reference)	is_annotated_to_catalyze	Annotated PKS chain assembly		https://www.uniprot.org/uniprotkb/Q4WAY3/entry https://www.ncbi.nlm.nih.gov/protein/AGI05041.1 reference https://www.uniprot.org/uniprotkb/Q4WAY3/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. Sequence identity: AGI05041.1, KC407775.1 CDS and UniProt agree exactly (2435 aa). Reference identity, not an assayed construct. Corrected mRNA KC407775.1 is used; old genomic EAL85129.1 (2462 aa) is an erroneous model, not the 2435-aa reference. reference https://www.ncbi.nlm.nih.gov/protein/AGI05041.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned reference identity; coded_by KC407775.1:1..7308. No experimental insert identity claim.
Fma-TC (Af293 reference)	is_annotated_to_catalyze	Annotated terpene cyclization		https://www.uniprot.org/uniprotkb/M4VQY9/entry https://www.ncbi.nlm.nih.gov/protein/AGI05042.1 reference https://www.uniprot.org/uniprotkb/M4VQY9/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. Sequence identity: AGI05042.1, KC407776.1 CDS and UniProt agree exactly (289 aa). Reference identity, not an assayed construct. Corrected mRNA KC407776.1 is used; old genomic EAL85115.1 (173 aa) is an erroneous model, not the 289-aa reference. snippet converts farnesyl pyrophosphate (FPP) to beta-trans-bergamotene reference https://www.ncbi.nlm.nih.gov/protein/AGI05042.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned reference identity; coded_by KC407776.1:1..870. No experimental insert identity claim.
Fma-AT (Af293 reference)	is_annotated_to_catalyze	Annotated polyketide transfer		https://www.uniprot.org/uniprotkb/Q4WAY4/entry https://www.ncbi.nlm.nih.gov/protein/EAL85128.1 reference https://www.uniprot.org/uniprotkb/Q4WAY4/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. Sequence identity: EAL85128.1, AAHF01000014.1 CDS and UniProt agree exactly (292 aa). Reference identity, not an assayed construct. Native AFUA_8G00380 CDS and EAL85128.1 are 292 aa; genomic strand, coordinates and translation agree. reference https://www.ncbi.nlm.nih.gov/protein/EAL85128.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned reference identity; coded_by complement(join(AAHF01000014.1:705444..706217, AAHF01000014.1:706265..706369)). No experimental insert identity claim.
Acetyl-CoA starter	is_annotated_starter_in	Annotated PKS chain assembly		https://www.uniprot.org/uniprotkb/Q4WAY3/entry reference https://www.uniprot.org/uniprotkb/Q4WAY3/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. FUNCTION assigns one acetyl-CoA starter and five malonyl-CoA extender units; no balanced reaction or coproduct accounting is added.
Malonyl-CoA extender	is_annotated_extender_in	Annotated PKS chain assembly		https://www.uniprot.org/uniprotkb/Q4WAY3/entry reference https://www.uniprot.org/uniprotkb/Q4WAY3/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. FUNCTION assigns five malonyl-CoA extender units per chain.
Annotated PKS chain assembly	is_annotated_to_form	PKS-bound dodecapentaenoyl moiety		https://www.uniprot.org/uniprotkb/Q4WAY3/entry reference https://www.uniprot.org/uniprotkb/Q4WAY3/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. FUNCTION names the dodecapentaenoyl moiety; CATALYTIC ACTIVITY represents a PKS-bound donor but spells it dodecapentaneoyl. The discrepancy is retained; no free-acid product, chemical CURIE or reaction identifier is inferred.
Farnesyl pyrophosphate (FPP)	is_annotated_substrate_in	Annotated terpene cyclization		https://www.uniprot.org/uniprotkb/M4VQY9/entry reference https://www.uniprot.org/uniprotkb/M4VQY9/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. FUNCTION assigns FPP cyclization by af520; this is a database-backed precursor transformation, not a newly inspected primary assay.
Annotated terpene cyclization	is_annotated_to_form	beta-trans-bergamotene		https://www.uniprot.org/uniprotkb/M4VQY9/entry reference https://www.uniprot.org/uniprotkb/M4VQY9/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. FUNCTION names beta-trans-bergamotene. Chemical stereochemical identifiers are not independently grounded here.
PKS-bound dodecapentaenoyl moiety	is_annotated_acyl_donor_in	Annotated polyketide transfer		https://www.uniprot.org/uniprotkb/Q4WAY4/entry reference https://www.uniprot.org/uniprotkb/Q4WAY4/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. FUNCTION assigns transfer of the af370-derived dodecapentaenoyl group. CATALYTIC ACTIVITY identifies a PKS-bound donor but spells it dodecapentaneoyl; spelling conflict retained without chemical/Rhea grounding.
Fumagillol	is_annotated_acceptor_in	Annotated polyketide transfer		https://www.uniprot.org/uniprotkb/Q4WAY4/entry reference https://www.uniprot.org/uniprotkb/Q4WAY4/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. CATALYTIC ACTIVITY names fumagillol as acceptor; FUNCTION describes a 5R-hydroxy-seco-sesquiterpene. No complete pathway order is inferred.
Annotated polyketide transfer	is_annotated_to_form	Prefumagillin		https://www.uniprot.org/uniprotkb/Q4WAY4/entry reference https://www.uniprot.org/uniprotkb/Q4WAY4/entry evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes UniProt release 2026_03. FUNCTION and CATALYTIC ACTIVITY assign prefumagillin formation. No transfer yield, native essentiality, domain-level PKS mechanism or reconstituted pathway claim.

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Causal graph — biosynthesis 18 nodes, 20 edges

Partial fumagillin genetic-regulation graph from DOI10.1371/journal.pone.0077147. Separate perturbation components retain the measured outcomes; unproven mediation links between them are intentionally omitted. Separate Af293 protein references, accession-unresolved experimental proteins, genes, perturbations and measured outcomes. CEA10 controls the VeA series; TSD51.1 controls CEA17ku80-derived fumR/laeA deletions. Both veA deletion and overexpression decrease expression and product signal. FumR deletion lowers the nine assayed cluster transcripts and makes fumagillin undetectable at the tested times. LaeA edges concern transcripts only. No direct promoter binding, protein-abundance measurement, velvet-complex assembly, universal essentiality, complete pathway or exact experimental-allele mapping is asserted.

Subject	Predicate	Object	Notes	Evidence
FumR (Af293 reference, 622 aa)	is_reference_example_for	FumR (experimental strain series; allele unresolved)		https://www.uniprot.org/uniprotkb/Q4WAY8/entry https://www.ncbi.nlm.nih.gov/protein/EAL85124.1 DOI:10.1371/journal.pone.0077147 reference https://www.uniprot.org/uniprotkb/Q4WAY8/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected reference, not an identical experimental allele. AFUA_8G00420: native Af293 CDS, EAL85124.1 and UniProt2026_03 agree exactly at 622 aa; taxon330879. reference https://www.ncbi.nlm.nih.gov/protein/EAL85124.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned reference identity. Complete spliced CDS, strand and coordinates independently verified: complement(join(AAHF01000014.1:698638..700031, AAHF01000014.1:700097..700364, AAHF01000014.1:700420..700626)). reference DOI:10.1371/journal.pone.0077147 evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Table S1 names CEA10 as control for the VeA series and CEA17ku80-derived TSD51.1 control, TSD53.1 deltafumR and TSD62.1 deltalaeA. Af293 is the transcriptome reference, not proof of assay-strain allele identity. No full experimental allele sequence was established.
fumR gene (experimental strain series)	encodes	FumR (experimental strain series; allele unresolved)		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Introduction/Results identify FumR as the product of the manipulated gene. This entity relationship is not a protein-abundance measurement or an exact-accession assignment. FumR is described as a putative C6 transcription factor; its DNA-binding motif is not direct evidence of promoter occupancy.
VeA (Af293 reference, 570 aa)	is_reference_example_for	VeA (experimental strain series; allele unresolved)		https://www.uniprot.org/uniprotkb/E9RCK4/entry https://www.ncbi.nlm.nih.gov/protein/EAL90581.1 DOI:10.1371/journal.pone.0077147 reference https://www.uniprot.org/uniprotkb/E9RCK4/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected reference, not an identical experimental allele. AFUA_1G12490: native Af293 CDS, EAL90581.1 and UniProt2026_03 agree exactly at 570 aa; taxon330879. reference https://www.ncbi.nlm.nih.gov/protein/EAL90581.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned reference identity. Complete spliced CDS, strand and coordinates independently verified: complement(join(AAHF01000004.1:1042372..1043936 ,AAHF01000004.1:1044007..1044154)). reference DOI:10.1371/journal.pone.0077147 evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Table S1 names CEA10 as control for the VeA series and CEA17ku80-derived TSD51.1 control, TSD53.1 deltafumR and TSD62.1 deltalaeA. Af293 is the transcriptome reference, not proof of assay-strain allele identity. No full experimental allele sequence was established.
veA gene (experimental strain series)	encodes	VeA (experimental strain series; allele unresolved)		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Introduction/Results identify VeA as the product of the manipulated gene. This entity relationship is not a protein-abundance measurement or an exact-accession assignment. No purified protein assay or directly demonstrated A. fumigatus VeA-LaeA interaction is asserted here.
LaeA (Af293 reference, 373 aa)	is_reference_example_for	LaeA (experimental strain series; allele unresolved)		https://www.uniprot.org/uniprotkb/Q4WRY5/entry https://www.ncbi.nlm.nih.gov/protein/EAL90797.1 DOI:10.1371/journal.pone.0077147 reference https://www.uniprot.org/uniprotkb/Q4WRY5/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected reference, not an identical experimental allele. AFUA_1G14660: native Af293 CDS, EAL90797.1 and UniProt2026_03 agree exactly at 373 aa; taxon330879. Alternative AAR01218.1 is flagged as an erroneous gene model in UniProt; it was not independently sequence-compared here. reference https://www.ncbi.nlm.nih.gov/protein/EAL90797.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned reference identity. Complete spliced CDS, strand and coordinates independently verified: join(AAHF01000004.1:1670850..1671079, AAHF01000004.1:1671225..1672116). reference DOI:10.1371/journal.pone.0077147 evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Table S1 names CEA10 as control for the VeA series and CEA17ku80-derived TSD51.1 control, TSD53.1 deltafumR and TSD62.1 deltalaeA. Af293 is the transcriptome reference, not proof of assay-strain allele identity. No full experimental allele sequence was established.
laeA gene (experimental strain series)	encodes	LaeA (experimental strain series; allele unresolved)		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Introduction/Results identify LaeA as the product of the manipulated gene. This entity relationship is not a protein-abundance measurement or an exact-accession assignment. No purified protein assay or directly demonstrated A. fumigatus VeA-LaeA interaction is asserted here.
fumR gene replacement (TSD53.1)	replaces	fumR gene (experimental strain series)		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods, Figure S2, Table S1: fumR replaced by A. parasiticus pyrG in CEA17ku80; TSD53.1. PCR screening and Southern-blot validation reported. The marker is not a fumagillin biosynthetic enzyme.
laeA gene replacement (TSD62.1)	replaces	laeA gene (experimental strain series)		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods, Figure S3, Table S1: laeA replaced by A. parasiticus pyrG in CEA17ku80; TSD62.1. Southern-blot validation reported.
veA deletion (TSD1.15)	deletes	veA gene (experimental strain series)		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Table S1: TSD1.15, pyrG1; delta-veA::pyrG A. fumigatus; CEA10 control. Genotype statement, not a direct protein-depletion measurement.
veA overexpression (TSD2.8)	overexpresses	veA gene (experimental strain series)		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Table S1: TSD2.8, pyrG1; gpdA(p)::veA::trpC(t)::pyrG A. fumigatus. No quantitative VeA protein dosage measured in the represented assays.
fumR gene replacement (TSD53.1)	results_in	Lower assayed fumagillin-cluster transcript levels		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 5/Results: TSD53.1 versus TSD51.1 at 48 h and 72 h. Czapek-Dox stationary liquid cultures. qRT-PCR, 18S reference, three replicates with standard-error bars; transcript readout, not protein abundance or direct promoter binding. Nine assayed loci: Afu8g00370, Afu8g00520, Afu8g00380, Afu8g00510, Afu8g00500, Afu8g00480, Afu8g00470, Afu8g00440 and Afu8g00430. Afu8g00470 retains appreciable residual expression; not complete silencing of every cluster gene. Figure 5 labels, Results and Table S2 support Afu8g00380 where the caption mistakenly repeats Afu8g00370.
fumR gene replacement (TSD53.1)	results_in	Fumagillin not detected in culture extract		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 6: TSD53.1 versus TSD51.1 at 72 h and 120 h. Czapek-Dox stationary liquid cultures. Chloroform-extracted supernatants analyzed by LC-MS; commercial fumagillin standard and three replicates. No detected fumagillin in the deletion strain under these conditions, not absolute zero or universal essentiality. No numerical detection limit or fumR complementation rescue is established by this experiment. snippet No fumagillin was detected
veA deletion (TSD1.15)	results_in	Lower fumR transcript level		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure S1A/Results: 72 h, CEA10 control, TSD1.15 deletion or TSD2.8 overexpression. Czapek-Dox stationary liquid cultures. qRT-PCR, 18S reference, three replicates with standard-error bars; transcript readout, not protein abundance or direct promoter binding. Authors report 12% of wild-type fumR expression. Both deletion and overexpression decrease this readout; no monotonic dosage rule is inferred.
veA deletion (TSD1.15)	results_in	Lower Afu8g00370 PKS transcript level		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure S1B/Results: 72 h, CEA10 control, TSD1.15 deletion or TSD2.8 overexpression. Czapek-Dox stationary liquid cultures. qRT-PCR, 18S reference, three replicates with standard-error bars; transcript readout, not protein abundance or direct promoter binding. Authors report 3% of wild-type Afu8g00370 expression. This is a PKS-gene transcript measurement, not a PKS catalytic assay.
veA deletion (TSD1.15)	results_in	Lower relative fumagillin LC-MS signal		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 4A: 120 h, CEA10 control, TSD1.15 deletion or TSD2.8 overexpression; TSD3.5 complementation also shown. Czapek-Dox stationary liquid cultures. Extracted-ion LC-MS signal for fumagillin, m/z459 [M+H]+, normalized to wild type; three samples and standard-error bars. Both perturbations reduce the signal. This qualitative direction does not imply complete loss, absolute yield or a quantitative protein-dosage response.
veA overexpression (TSD2.8)	results_in	Lower fumR transcript level		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure S1A/Results: 72 h, CEA10 control, TSD1.15 deletion or TSD2.8 overexpression. Czapek-Dox stationary liquid cultures. qRT-PCR, 18S reference, three replicates with standard-error bars; transcript readout, not protein abundance or direct promoter binding. Authors report 5% of wild-type fumR expression. Both deletion and overexpression decrease this readout; no monotonic dosage rule is inferred.
veA overexpression (TSD2.8)	results_in	Lower Afu8g00370 PKS transcript level		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure S1B/Results: 72 h, CEA10 control, TSD1.15 deletion or TSD2.8 overexpression. Czapek-Dox stationary liquid cultures. qRT-PCR, 18S reference, three replicates with standard-error bars; transcript readout, not protein abundance or direct promoter binding. Authors report 0.1% of wild-type Afu8g00370 expression. This is a PKS-gene transcript measurement, not a PKS catalytic assay.
veA overexpression (TSD2.8)	results_in	Lower relative fumagillin LC-MS signal		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 4A: 120 h, CEA10 control, TSD1.15 deletion or TSD2.8 overexpression; TSD3.5 complementation also shown. Czapek-Dox stationary liquid cultures. Extracted-ion LC-MS signal for fumagillin, m/z459 [M+H]+, normalized to wild type; three samples and standard-error bars. Both perturbations reduce the signal. This qualitative direction does not imply complete loss, absolute yield or a quantitative protein-dosage response.
laeA gene replacement (TSD62.1)	results_in	Lower fumR transcript level		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 7 upper panel/Results: TSD62.1 versus corresponding control TSD51.1, 48 h and 72 h respectively. Czapek-Dox stationary liquid cultures. qRT-PCR, 18S reference, three replicates with standard-error bars; transcript readout, not protein abundance or direct promoter binding. Authors report 3% and 8% of wild-type transcript levels. No LaeA-specific fumagillin production assay or mediation through FumR is asserted from these expression data alone.
laeA gene replacement (TSD62.1)	results_in	Lower Afu8g00370 PKS transcript level		DOI:10.1371/journal.pone.0077147 reference DOI:10.1371/journal.pone.0077147 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure 7 lower panel/Results: TSD62.1 versus corresponding control TSD51.1, 48 h and 72 h respectively. Czapek-Dox stationary liquid cultures. qRT-PCR, 18S reference, three replicates with standard-error bars; transcript readout, not protein abundance or direct promoter binding. Authors report 9% and 7% of wild-type transcript levels. No LaeA-specific fumagillin production assay or mediation through FumR is asserted from these expression data alone.

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Causal graph — biosynthesis 5 nodes, 4 edges

Partial fumagillin regulation view: AceA deletion and the reported Afu8g00430 transcript difference under copper stress. The independently verified Af293 protein is a separate reference, not the experimental allele. This paper measures RNA, not enzyme catalysis. Only the shared Figure2/Table S11 locus claim is added; broader cluster labels and other loci are not generalized. No direct promoter binding, protein-abundance measurement, product yield, universal essentiality or complete pathway is asserted. Strain and growth-time wording differences remain explicit in evidence.

Subject	Predicate	Object	Notes	Evidence
AceA (Af293 reference, 667 aa)	is_reference_example_for	AceA (experimental strain; allele unresolved)		https://www.uniprot.org/uniprotkb/Q4WN33/entry https://www.ncbi.nlm.nih.gov/protein/EAL88631.1 DOI:10.1080/21505594.2021.1958057 reference https://www.uniprot.org/uniprotkb/Q4WN33/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected reference, not an identical experimental allele. UniProt2026_03 Q4WN33, native AFUA_6G07780 spliced CDS and GenPept EAL88631.1 agree exactly at 667 aa; Af293 taxon330879. The paper uses a different strain background and does not establish its complete AceA allele sequence. reference https://www.ncbi.nlm.nih.gov/protein/EAL88631.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Complete versioned native reference; coded_by complement(join(AAHF01000006.1:457442..457708,457749..457877,458448..459805,459861..460034,460105..460180)). Genomic strand, exact coordinates, start/stop and translation independently checked. reference DOI:10.1080/21505594.2021.1958057 evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Table S1 identifies the experimental deletion as delta-akuB::PyrG1, delta-AFUB_073740::PyrG in akuBKU80, CEA17 background. Methods and this table take precedence for strain description; Results also calls WT A1163. No Af293-to-experimental sequence identity is asserted.
aceA gene (experimental AFUB_073740 locus)	encodes	AceA (experimental strain; allele unresolved)		DOI:10.1080/21505594.2021.1958057 reference DOI:10.1080/21505594.2021.1958057 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Introduction and Results identify AceA as the transcription factor encoded by aceA. This is an entity relationship, not a measurement of protein abundance, purified-protein activity or direct binding to this promoter.
aceA deletion under copper stress	replaces	aceA gene (experimental AFUB_073740 locus)		DOI:10.1080/21505594.2021.1958057 reference DOI:10.1080/21505594.2021.1958057 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Table S1, PDF page3: delta-AFUB_073740::PyrG in the akuBKU80 CEA17 background; corresponding akuBKU80 WT control. The deletion strain is attributed to Weimann2017 by the table. No newly performed complementation or full-allele sequencing is inferred.
aceA deletion under copper stress	results_in	Lower Afu8g00430 transcript under copper stress		DOI:10.1080/21505594.2021.1958057 reference DOI:10.1080/21505594.2021.1958057 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure2a/c explicitly compares WT(+Cu)/deltaaceA(+Cu); Afu8g00430 is higher in WT, also listed in the upregulated group in Table S11A. Thus the deletion strain has lower transcript abundance under this comparison. RNAseq, three samples per group, MM liquid, 37 C, 200 uM Cu for1 h. Methods specifies24 h growth plus1 h exposure; Results says25 h before exposure, a retained discrepancy. Reads mapped to A1163; the Afu locus label is retained as printed, not assigned an exact experimental protein accession. The reported2.42 ratio and category enrichment P-value are not turned into a new per-gene statistical or protein measurement. This is not whole-cluster silencing, direct AceA-promoter occupancy, FumR mediation or a fumagillin product-yield assay. snippet AceA directly or indirectly activates these genes

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Causal graph — biosynthesis 7 nodes, 6 edges

Partial fumagillin biosynthesis view: pptA genetic deletion and native-locus rescue in CEA10-derived A1160p+, with the bounded LC-MS detection phenotype. A separately sequence-verified CEA10/A1163 reference is not equated to the experimental allele. No direct PptA-to-FmaPKS priming, catalytic substrate/product step, protein-abundance measurement, universal essentiality or fumagillin-mediated virulence mechanism is asserted; the paper's recombinant activity assay uses AarA.

Subject	Predicate	Object	Notes	Evidence
PptA (CEA10/A1163 reference, 357 aa)	is_reference_example_for	PptA (A1160p+ experimental allele unresolved)		https://www.uniprot.org/uniprotkb/B0XWE4/entry https://www.ncbi.nlm.nih.gov/protein/EDP54396.1 DOI:10.1128/mbio.01504-16 reference https://www.uniprot.org/uniprotkb/B0XWE4/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected genomic reference, not a proven identical experimental allele. Unreviewed UniProt B0XWE4, AFUB_024520, taxon451804 CEA10/A1163, 357 aa. Complete native CDS translation, GenPept and UniProt sequence agree exactly. Prefer the matching AFUB locus/background over reviewed but different Af293 Q4X1W0. reference https://www.ncbi.nlm.nih.gov/protein/EDP54396.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned A1163 native reference EDP54396.1, coded_by DS499595.1:2189402..2190475. Exact start/stop, coordinates, strand and complete translation independently checked. This is not full experimental-allele or recombinant-construct sequencing. reference DOI:10.1128/mbio.01504-16 evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Methods uses CADRE pptA AFUB_024520A. Table1 and Strains identify the parent as A1160p+, derived from CEA10 with Ku80 deletion and pyrG+. Shared locus/background supports a reference example, not full allele identity.
pptA gene (experimental AFUB_024520 locus)	encodes	PptA (A1160p+ experimental allele unresolved)		DOI:10.1128/mbio.01504-16 reference DOI:10.1128/mbio.01504-16 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Results and Methods identify pptA as the gene encoding phosphopantetheinyl transferase PptA. This entity relationship is not a protein-abundance measurement or a purified FmaPKS activation assay.
pptA deletion in A1160p+	replaces	pptA gene (experimental AFUB_024520 locus)		DOI:10.1128/mbio.01504-16 reference DOI:10.1128/mbio.01504-16 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Table1, mutant-generation Methods and Figure S4A: delta-pptA is derived from A1160p+, carries the hph replacement cassette and lacks pptA. PCR and Southern blotting verify locus recombination; Table S4 lists the genetic primers.
pptA restoration at its original locus	restores	pptA gene (experimental AFUB_024520 locus)		DOI:10.1128/mbio.01504-16 reference DOI:10.1128/mbio.01504-16 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods restores pptA at its original locus using a fragment amplified with P1/P4; Table1 describes pptA rec derived from delta-pptA, hph negative. PCR and Southern blotting (Figure S4A) confirm recombination. Selection was on VMM lacking supplemental lysine and iron; that selection medium is not substituted for the metabolite-assay medium.
pptA deletion in A1160p+	results_in	Fumagillin peak not detected in 7-day SAB extract		DOI:10.1128/mbio.01504-16 reference DOI:10.1128/mbio.01504-16 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure2B and Secondary metabolite assay Methods: A1160p+ parent, delta-pptA and pptA rec; 1e7 spores in 100 mL SAB for 7 days at 30 C; equal-volume ethyl-acetate extraction of supernatants, dried and redissolved in 1 mL methanol. Fumagillin is assigned at retention time 13.50 min; identification uses retention time and exact mass against isolated standards. The displayed trace is absorbance in mAU. No numerical detection limit, biomass-normalized yield, replicate count or metabolite-specific supplementation regimen is supplied for this comparison. Results reports absence of the named peaks, including fumagillin, in delta-pptA; parent provides the positive comparison and medium-only extract the background control. This means not detected under these conditions, not absolute zero biosynthesis, all-metabolite absence or universal essentiality. snippet None of these peaks was identified
pptA restoration at its original locus	results_in	Fumagillin peak restored in 7-day SAB extract		DOI:10.1128/mbio.01504-16 reference DOI:10.1128/mbio.01504-16 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure2B and Secondary metabolite assay Methods: A1160p+ parent, delta-pptA and pptA rec; 1e7 spores in 100 mL SAB for 7 days at 30 C; equal-volume ethyl-acetate extraction of supernatants, dried and redissolved in 1 mL methanol. Fumagillin is assigned at retention time 13.50 min; identification uses retention time and exact mass against isolated standards. The displayed trace is absorbance in mAU. No numerical detection limit, biomass-normalized yield, replicate count or metabolite-specific supplementation regimen is supplied for this comparison. The reconstituted isolate restores the fumagillin-associated peak and a parental-like profile. This is qualitative genetic rescue, not a quantified fold change or equal normalized production rate. snippet consistent with that of the parental isolate

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Causal graph — biosynthesis 7 nodes, 6 edges

Partial fumagillin genetic-regulation view: ppzA deletion and complementation under iron depletion. The independently sequence-verified CEA10/A1163 reference is not equated to the experimental CEA17 allele. Preserve the unspecified Figure4 timepoint, non-specific metal chelation and qualitative LC-MS scope. No direct phosphatase substrate, complete pathway, iron-repletion reduction, universal essentiality or fumagillin-mediated virulence is asserted.

Subject	Predicate	Object	Notes	Evidence
PpzA (CEA10/A1163 reference, 540 aa)	is_reference_example_for	PpzA (CEA17 experimental allele unresolved)		https://www.uniprot.org/uniprotkb/B0XUR7/entry https://www.ncbi.nlm.nih.gov/protein/EDP54052.1 reference https://www.uniprot.org/uniprotkb/B0XUR7/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected reference, not a proven identical experimental allele. Reviewed UniProt2026_03 B0XUR7 names ppzA/AFUB_021020, CEA10/A1163 taxon451804,540 aa and cites both primary papers for function/disruption. Complete native CDS, GenPept and UniProt sequence agree exactly. reference https://www.ncbi.nlm.nih.gov/protein/EDP54052.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Versioned A1163 EDP54052.1, coded_by complement(join(DS499595.1:1057660..1057944,DS499595.1:1058020..1059357)). Exact strand, splicing, start/stop and translation checked. Native reference identity does not establish the complete CEA17 experimental allele.
ppzA gene (CEA17 experimental background)	encodes	PpzA (CEA17 experimental allele unresolved)		DOI:10.1111/cmi.12770 reference DOI:10.1111/cmi.12770 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes The paper identifies ppzA as encoding protein phosphatase Z PpzA; Methods4.2 names CEA17 pyrG+/pyrG- akuBKU80 parental backgrounds. Gene identity is not a direct measurement of protein abundance or a specific fumagillin-enzyme substrate assignment.
ppzA deletion under iron depletion	deletes	ppzA gene (CEA17 experimental background)		DOI:10.1534/g3.115.016766 reference DOI:10.1534/g3.115.016766 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes The2015 Materials and Methods, Strains and DNA manipulations sections, specify CEA17-80 ku80-/pyrG- as deletion recipient and pyrG replacement strategy. Table1 labels PpzA with reference locus Afu2g03950; this does not make the mutant an Af293 strain.
ppzA complementation under iron depletion	reintroduces	ppzA gene (CEA17 experimental background)		DOI:10.1111/cmi.12770 reference DOI:10.1111/cmi.12770 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods4.3 reports co-transformation of the ppzA ORF with about1 kb each flanking region plus pHATalpha, hygromycin selection and PCR confirmation. The integration site and copy number are not established here; do not call this proven native-locus restoration.
ppzA deletion under iron depletion	results_in	Lower fumagillin LC-MS signal under iron depletion		DOI:10.1111/cmi.12770 reference DOI:10.1111/cmi.12770 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure4a and Methods4.6: CEA17 wild type, delta-ppzA and complemented strain; 5e7 spores, MM for24 h at37 C and200 rpm, then iron-free MM with200 uM BPS and300 uM ferrozine; triplicate conditions. Methods lists2 and4 h transfers, but Figure4 does not assign a particular timepoint. Fumagillin EIC m/z459.23 [M+H]+ is a qualitative readout, not a biomass-normalized production rate or absolute yield. Results2.3 and Discussion specifically support reduced fumagillin under iron depletion. No all-condition absence, quantitative fold change or iron-repletion reduction is inferred. Growth effects and chelation of other metals are not excluded. snippet reduction in the production of fumagillin during iron starvation
ppzA complementation under iron depletion	results_in	Higher fumagillin LC-MS signal after complementation		DOI:10.1111/cmi.12770 reference DOI:10.1111/cmi.12770 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Figure4a and Methods4.6: CEA17 wild type, delta-ppzA and complemented strain; 5e7 spores, MM for24 h at37 C and200 rpm, then iron-free MM with200 uM BPS and300 uM ferrozine; triplicate conditions. Methods lists2 and4 h transfers, but Figure4 does not assign a particular timepoint. Fumagillin EIC m/z459.23 [M+H]+ is a qualitative readout, not a biomass-normalized production rate or absolute yield. Figure4a shows a higher complemented-strain fumagillin peak than deletion; Results describes increased or comparable secondary-metabolite production versus wild type. Qualitative genetic rescue is not proof of equal wild-type yield, insertion-site identity or a direct phosphatase reaction. snippet complementing strain has increased or comparable SM production

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Causal graph — biosynthesis 11 nodes, 9 edges

Partial fumagillin genetic-regulation view: SreA and HapX deletion outcomes at specified iron concentrations. Separate perturbation components intentionally omit unproven mediation links. Af293 protein references are not equated to experimental ATCC46645 alleles. HPLC-PDA peak areas are dry-weight normalized and compared with WT at each iron condition. No direct promoter binding, protein-abundance measurement, universal essentiality, complete pathway or rescue claim is asserted.

Subject	Predicate	Object	Notes	Evidence
SreA (Af293 reference, 546 aa)	is_reference_example_for	SreA (ATCC46645 experimental allele unresolved)		https://www.uniprot.org/uniprotkb/Q4WV91/entry https://www.ncbi.nlm.nih.gov/protein/EAL91485.1 DOI:10.3389/fmicb.2014.00530 reference https://www.uniprot.org/uniprotkb/Q4WV91/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected Af293 reference, not an identical ATCC46645 allele. Reviewed UniProt Q4WV91, AFUA_5G11260, taxon330879, 546 aa agrees exactly with versioned GenPept and the complete native genomic CDS translation. reference https://www.ncbi.nlm.nih.gov/protein/EAL91485.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Native Af293 EAL91485.1: exact locus, strand, complete start/stop and translation checked against UniProt. The versioned protein and its linked nucleotide sequence do not establish the complete experimental allele. reference DOI:10.3389/fmicb.2014.00530 evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Methods, Strains and culture conditions, identifies ATCC46645 as the wild type for these metabolite experiments; Af293 is used in a separate RNA-seq series. This supports selecting a separate named reference example, not assigning the Af293 accession to the experimental allele. No strain equivalence is asserted.
SreA gene (ATCC46645 background)	encodes	SreA (ATCC46645 experimental allele unresolved)		DOI:10.3389/fmicb.2014.00530 reference DOI:10.3389/fmicb.2014.00530 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Introduction and Results identify SreA as the transcription factor encoded by the named gene. This entity relationship does not measure protein abundance or direct contact with a fumagillin-cluster promoter.
SreA gene deletion	deletes	SreA gene (ATCC46645 background)		DOI:10.3389/fmicb.2014.00530 reference DOI:10.3389/fmicb.2014.00530 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods, Strains and culture conditions, and Results name the delta-srea strain alongside ATCC46645 for secondary-metabolite analysis. No new construct sequence, insertion-site claim or fumagillin complementation experiment is inferred.
HapX (Af293 reference, 491 aa)	is_reference_example_for	HapX (ATCC46645 experimental allele unresolved)		https://www.uniprot.org/uniprotkb/Q4WER3/entry https://www.ncbi.nlm.nih.gov/protein/EAL85914.1 DOI:10.3389/fmicb.2014.00530 reference https://www.uniprot.org/uniprotkb/Q4WER3/entry evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Selected Af293 reference, not an identical ATCC46645 allele. Reviewed UniProt Q4WER3, AFUA_5G03920, taxon330879, 491 aa agrees exactly with versioned GenPept and the complete native genomic CDS translation. reference https://www.ncbi.nlm.nih.gov/protein/EAL85914.1 evidence type DATABASE_ASSERTION retrieved on 2026-10-12 notes Native Af293 EAL85914.1: exact locus, strand, complete start/stop and translation checked against UniProt. The versioned protein and its linked nucleotide sequence do not establish the complete experimental allele. reference DOI:10.3389/fmicb.2014.00530 evidence type CURATOR_INFERENCE retrieved on 2026-10-12 notes Methods, Strains and culture conditions, identifies ATCC46645 as the wild type for these metabolite experiments; Af293 is used in a separate RNA-seq series. This supports selecting a separate named reference example, not assigning the Af293 accession to the experimental allele. No strain equivalence is asserted.
HapX gene (ATCC46645 background)	encodes	HapX (ATCC46645 experimental allele unresolved)		DOI:10.3389/fmicb.2014.00530 reference DOI:10.3389/fmicb.2014.00530 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Introduction and Results identify HapX as the transcription factor encoded by the named gene. This entity relationship does not measure protein abundance or direct contact with a fumagillin-cluster promoter.
HapX gene deletion	deletes	HapX gene (ATCC46645 background)		DOI:10.3389/fmicb.2014.00530 reference DOI:10.3389/fmicb.2014.00530 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods, Strains and culture conditions, and Results name the delta-hapx strain alongside ATCC46645 for secondary-metabolite analysis. No new construct sequence, insertion-site claim or fumagillin complementation experiment is inferred.
SreA gene deletion	results_in	Lower relative fumagillin at 1 mM iron		DOI:10.3389/fmicb.2014.00530 reference DOI:10.3389/fmicb.2014.00530 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods and Results/Figure9 caption: ATCC46645 wild type and deletion strains; triplicate 50 mL GMM cultures, 5e6 conidia/mL, 5 days at25 C,250 rpm,ambient light. Supernatant extracts analyzed by HPLC-PDA against commercial fumagillin standard; peak areas normalized to sample dry weight, then mutant relative to WT at the same iron concentration. This differs from Figure8 normalization to30 uM within each strain. No absolute yield or fold change is assigned. Results reports reduced fumagillin in delta-sreA at high iron (1 mM). Do not generalize to all iron conditions or infer direct promoter binding. snippet was greatly reduced in
HapX gene deletion	results_in	Higher relative fumagillin with no added iron		DOI:10.3389/fmicb.2014.00530 reference DOI:10.3389/fmicb.2014.00530 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods and Results/Figure9 caption: ATCC46645 wild type and deletion strains; triplicate 50 mL GMM cultures, 5e6 conidia/mL, 5 days at25 C,250 rpm,ambient light. Supernatant extracts analyzed by HPLC-PDA against commercial fumagillin standard; peak areas normalized to sample dry weight, then mutant relative to WT at the same iron concentration. This differs from Figure8 normalization to30 uM within each strain. No absolute yield or fold change is assigned. Results reports significantly increased fumagillin in delta-hapX versus WT under no-iron conditions (0 added iron). No-added-iron medium is not a claim of chemically zero iron. snippet significantly increased in
HapX gene deletion	results_in	Higher relative fumagillin at 30 uM iron		DOI:10.3389/fmicb.2014.00530 reference DOI:10.3389/fmicb.2014.00530 evidence type PRIMARY_EXPERIMENT retrieved on 2026-10-12 notes Methods and Results/Figure9 caption: ATCC46645 wild type and deletion strains; triplicate 50 mL GMM cultures, 5e6 conidia/mL, 5 days at25 C,250 rpm,ambient light. Supernatant extracts analyzed by HPLC-PDA against commercial fumagillin standard; peak areas normalized to sample dry weight, then mutant relative to WT at the same iron concentration. This differs from Figure8 normalization to30 uM within each strain. No absolute yield or fold change is assigned. Results reports significantly increased fumagillin in delta-hapX versus WT under iron-replete conditions (30 uM). Do not extrapolate this direction to1 mM iron.

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Elsewhere in the fleet

AntibioticMech — CHEBI:48635 (same structure, same inchikey)

Explore across X-Mech

AntibioticMech (fumagillin) ↗ MediaIngredientMech (CHEBI:48635) ↗ TaxonMech: Aspergillus fumigatus Af293 (NCBITaxon:330879) ↗ PathwayMech (mibig:BGC0001067) ↗

Open questions 8

curator-fumagillin-abm-assay-identity — Which deposited insert sequence and yeast-host assignment resolve the Fma-ABM microsomal assay?

curator-fumagillin-p450-kr-assay-scope — Which deposited construct sequences resolve these reference mappings, and should the transposed Fma-KR methods product numbers be corrected?

curator-fumagillin-c6h-mt-reference-scope — Which deposited inserts and fungal strains resolve C6H/MT assay identity, and can the source numbering and donor-name discrepancies be reconciled?

curator-fumagillin-regulator-alleles — Which experimental-strain allele sequences ground FumR, VeA and LaeA, and which direct regulatory contacts mediate the fumagillin phenotype?

curator-fumagillin-acea-scope — Which experimental AceA allele and full RNAseq comparison resolve the strain, timing and broader cluster-label ambiguities?

curator-fumagillin-ppta-scope — What complete A1160p+ PptA allele and direct FmaPKS activation evidence would extend the genetic loss/rescue claim?

curator-fumagillin-ppza-scope — Which complete CEA17 PpzA allele, sampling time and direct mechanism resolve the iron-depletion fumagillin phenotype?

curator-fumagillin-iron-regulator-alleles — Which ATCC46645 allele sequences and direct regulatory mechanisms explain the SreA/HapX fumagillin phenotypes?

Provenance

Source concept	Source	Version
BGC0001067	MIBIG	5
CHEBI:48635	CHEBI	3-star

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