Mitochondrial and cytosolic iron-sulfur cluster assembly in Drosophila melanogaster

Iron-sulfur (Fe-S) clusters are cofactors of respiratory complexes, the TCA cycle, DNA replication and repair enzymes and many other proteins. In eukaryotes all clusters depend on the mitochondrial iron-sulfur cluster (ISC) machinery. In the matrix, the cysteine desulfurase Nfs1, stabilised by Isd11 (bcn92) and acyl-ND-ACP, supplies sulfur and frataxin (fh) stimulates assembly of a [2Fe-2S] cluster on the scaffold IscU, with electrons from ferredoxin (Fdx1) and ferredoxin reductase (dare). The Hsc20-Hsc70-5 chaperone pair with glutaredoxin 5 transfers the cluster to client proteins, and the ISA proteins (MagR, CG13623) with IBA57 (CG8043) convert [2Fe-2S] into [4Fe-4S] clusters for mitochondrial targets. A sulfur-containing compound made by the ISC machinery is exported by the ABC transporter Abcb7 and used by the cytosolic iron-sulfur protein assembly (CIA) system: the diflavin reductase CG13667 and anamorsin (Ciapin1) supply electrons, the Nubp1-Nubp2 scaffold builds [4Fe-4S] clusters, and the CIA targeting complex (Ciao1, CG17683, galla2 and Mms19) inserts them into cytosolic and nuclear apoproteins.

MODULE:dmel_iron_sulfur_cluster_assemblyDRAFTCONCRETEBiological Processmodules/dmel_iron_sulfur_cluster_assembly.yaml
iron-sulfur cluster assemblyGO:0016226
FB:FBgg0001989
FlyBase gene group NIAUF: Mitochondrial 2fe-2s assembly complex
FlyBase release FB2026_03 groups 5 D. melanogaster genes as mitochondrial 2fe-2s assembly complex (NIAUF); this module models that group.
FB:FBgg0002072
FlyBase gene group ISA: Mitochondrial 4fe-4s assembly complex
FlyBase release FB2026_03 groups 2 D. melanogaster genes as mitochondrial 4fe-4s assembly complex (ISA); this module models that group.
FB:FBgg0002074
FlyBase gene group CIA-SCAF: Cytosolic 4fe-4s assembly scaffold complex
FlyBase release FB2026_03 groups 2 D. melanogaster genes as cytosolic 4fe-4s assembly scaffold complex (CIA-SCAF); this module models that group.
FB:FBgg0002075
FlyBase gene group CTC: Cytosolic 4fe-4s assembly targeting complex
FlyBase release FB2026_03 groups 4 D. melanogaster genes as cytosolic 4fe-4s assembly targeting complex (CTC); this module models that group.
FB:FBgg0002125
FlyBase gene group FESCA: Iron-sulfur cluster assembly
FlyBase release FB2026_03 groups 20 D. melanogaster genes as iron-sulfur cluster assembly (FESCA); this module models that group.
GO:0016226
iron-sulfur cluster assembly
GO term grounding the module as iron-sulfur cluster assembly.

Boundary. The module joins five FlyBase groups: the general Fe-S cluster assembly group (FESCA) and the four complex groups NIAUF (core ISC complex), ISA, CIA-SCAF and CTC. Every FESCA member is placed in one step. Fly subunit roles follow orthology to the human and yeast ISC and CIA proteins (for example bcn92 = Isd11/LYRM4, CG8043 = IBA57, CG13667 = NDOR1, CG17683 = CIAO3/NARFL, galla2 = CIAO2B); most have not been studied directly in flies. Molecular functions are given only to Nfs1, Fdx1, dare and Abcb7, whose activities are well conserved; the scaffold and carrier proteins have no clean catalytic activity. ND-ACP is also part of mitochondrial fatty acid synthesis (dmel_mitochondrial_fatty_acid_synthesis) and of respiratory complex I. The exact sulfur-containing compound exported by Abcb7 is not known. MagR has also been proposed as a magnetoreceptor; that proposal is not modelled. FlyBase groups realized by this module: NIAUF (FBgg0001989), ISA (FBgg0002072), CIA-SCAF (FBgg0002074), CTC (FBgg0002075), FESCA (FBgg0002125). Participants were generated from the FlyBase gene-group membership and mapped to UniProtKB by projects/FLYBASE_GENE_GROUPS/generate_modules.py from module_specs/dmel_iron_sulfur_cluster_assembly.yaml. None of the member genes has a gene review in this repository yet.

11Nodes
10Parts
0Variant Sets
0Variants
13Annotons
7Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:dmel_iron_sulfur_cluster_assembly 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.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • isc_core_complex → cluster_transfer [NOT_CHECKED]
  • cluster_transfer → mito_4fe4s_assembly [NOT_CHECKED]
  • isc_core_complex → isc_export [NOT_CHECKED]
  • cia_scaffold → cia_targeting_complex [NOT_CHECKED]

Function consistency and core coverage

0 gene-function check(s) reflected in core functions · 0 conflict(s) · 4 evidence or coverage gap(s) (4 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
isc_core_complex_complex/nfs1 Nfs1
UniProtKB:Q9VKD3
Complex Unit 		cysteine desulfurase activity
GO:0031071 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
isc_electron_supply_fdx1 Fdx1
UniProtKB:P37193
Gene 		electron transfer activity
GO:0009055 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
isc_electron_supply_dare dare
UniProtKB:Q9V3T9
Gene 		ferredoxin-NADP+ reductase activity
GO:0004324 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
isc_export_abcb7 Abcb7
UniProtKB:Q9W0C5
Gene 		ABC-type iron-sulfur cluster transporter activity
GO:0140481 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.

Gene-review completeness (0/22 grounded genes reviewed)

0 complete review(s) · 0 with deep research · 22 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
Hsc20 A8JNT7 ✗ — —
bcn92 O46098 ✗ — —
Hsc70-5 P29845 ✗ — —
Fdx1 P37193 ✗ — —
Ciao1 Q7K1Y4 ✗ — —
Grx5 Q7KV08 ✗ — —
CG17683 Q8SYS7 ✗ — —
MagR Q8T3X9 ✗ — —
ND-ACP Q94519 ✗ — —
Mms19 Q95U54 ✗ — —
dare Q9V3T9 ✗ — —
Ciapin1 Q9V3Y2 ✗ — —
CG13623 Q9VC65 ✗ — —
IscU Q9VHK6 ✗ — —
CG8043 Q9VHN4 ✗ — —
Nubp1 Q9VJI9 ✗ — —
Nfs1 Q9VKD3 ✗ — —
Nubp2 Q9VPD2 ✗ — —
CG13667 Q9VSJ5 ✗ — —
galla2 Q9VTC4 ✗ — —
Abcb7 Q9W0C5 ✗ — —
fh Q9W385 ✗ — —

Details

Context
Drosophila melanogasterNCBITaxon:7227
Iron-sulfur cluster assemblyBiological Processdmel_iron_sulfur_cluster_assembly

Mitochondrial ISC and cytosolic CIA machineries that build [2Fe-2S] and [4Fe-4S] clusters and deliver them to mitochondrial, cytosolic and nuclear proteins.

iron-sulfur cluster assemblyGO:0016226
Context
Drosophila melanogasterNCBITaxon:7227

Connections

isc_electron_supply -> isc_core_complex Provides Input For
Reduced Fdx1 provides electrons for [2Fe-2S] cluster synthesis.
The cluster built on IscU is released by Hsc20-Hsc70-5 and passed to Grx5.
[2Fe-2S] clusters are converted to [4Fe-4S] clusters by the ISA proteins and IBA57.
A sulfur compound made by the ISC machinery is exported by Abcb7.
isc_export -> cia_scaffold Provides Input For
The exported compound is required for cluster assembly on the Nubp1-Nubp2 scaffold.
cia_electron_supply -> cia_scaffold Provides Input For
CG13667 and anamorsin supply electrons for [4Fe-4S] assembly on the scaffold.
The CIA targeting complex transfers scaffold-built clusters to apoproteins.
Part 1: de novo [2Fe-2S] cluster synthesis on IscU
Mitochondrial core ISC complexProtein Complexisc_core_complex

Annotons

Mitochondrial core ISC complex
isc_core_complex_complex
Participant: Protein Complex: Mitochondrial core ISC complex
Protein Complex:
Mitochondrial core ISC complexGO:1990229
Active units:
IscU
Participant: Gene Product: IscU
Gene Product:
IscUUniProtKB:Q9VHK6
Role: scaffold on which the [2Fe-2S] cluster is assembled
ND-ACP
Participant: Gene Product: ND-ACP
Gene Product:
ND-ACPUniProtKB:Q94519
Role: acyl carrier protein that binds Isd11
Nfs1
Participant: Gene Product: Nfs1
Gene Product:
Nfs1UniProtKB:Q9VKD3
Role: cysteine desulfurase that supplies sulfur
Function:
cysteine desulfurase activityGO:0031071
bcn92
Participant: Gene Product: bcn92
Gene Product:
bcn92UniProtKB:O46098
Role: Isd11 (LYRM4) stabiliser of Nfs1
fh
Participant: Gene Product: fh
Gene Product:
fhUniProtKB:Q9W385
Role: frataxin, allosteric activator of sulfur transfer

Processes

[2Fe-2S] cluster assemblyGO:0044571
Part 2: electron supply for cluster synthesis
Mitochondrial ferredoxin electron supplyModuleisc_electron_supply

Annotons

Fdx1 Mitochondrial ferredoxin electron supply
isc_electron_supply_fdx1
Participant: Gene Product: Fdx1
Gene Product:
Fdx1UniProtKB:P37193

Function

electron transfer activityGO:0009055
dare Mitochondrial ferredoxin electron supply
isc_electron_supply_dare
Participant: Gene Product: dare
Gene Product:
dareUniProtKB:Q9V3T9

Function

ferredoxin-NADP+ reductase activityGO:0004324
Part 3: release of [2Fe-2S] clusters from IscU and transfer to recipients
Chaperone-mediated cluster transferModulecluster_transfer

Annotons

Hsc20 Chaperone-mediated cluster transfer
cluster_transfer_hsc20
Participant: Gene Product: Hsc20
Gene Product:
Hsc20UniProtKB:A8JNT7

J-protein co-chaperone that binds IscU

Hsc70-5 Chaperone-mediated cluster transfer
cluster_transfer_hsc70_5
Participant: Gene Product: Hsc70-5
Gene Product:
Hsc70-5UniProtKB:P29845

mitochondrial Hsp70 that releases the cluster from IscU

Grx5 Chaperone-mediated cluster transfer
cluster_transfer_grx5
Participant: Gene Product: Grx5
Gene Product:
Grx5UniProtKB:Q7KV08

monothiol glutaredoxin that carries [2Fe-2S] clusters

Part 4: conversion of [2Fe-2S] to [4Fe-4S] clusters for mitochondrial proteins
Mitochondrial [4Fe-4S] cluster assemblyModulemito_4fe4s_assembly
[4Fe-4S] cluster assemblyGO:0044572
Part 1: ISCA1-ISCA2 A-type carrier pair
ISA complexProtein Complexisa_complex

Annotons

ISA complex
isa_complex_complex
Participant: Protein Complex: ISA complex
Protein Complex:
ISA complex
Active units:
CG13623
Participant: Gene Product: CG13623
Gene Product:
CG13623UniProtKB:Q9VC65
MagR
Participant: Gene Product: MagR
Gene Product:
MagRUniProtKB:Q8T3X9

Processes

[4Fe-4S] cluster assemblyGO:0044572
Part 2: partner of the ISA proteins in [4Fe-4S] assembly
IBA57Moduleiba57

Annotons

CG8043 IBA57
iba57_cg8043
Participant: Gene Product: CG8043
Gene Product:
CG8043UniProtKB:Q9VHN4

Processes

[4Fe-4S] cluster assemblyGO:0044572
Part 5: export of the ISC-derived sulfur compound
Export to the cytosolTransport Stepisc_export

Annotons

Abcb7 Export to the cytosol
isc_export_abcb7
Participant: Gene Product: Abcb7
Gene Product:
Abcb7UniProtKB:Q9W0C5

Function

ABC-type iron-sulfur cluster transporter activityGO:0140481
Part 6: NADPH-dependent electron supply to the CIA scaffold
CIA electron supplyModulecia_electron_supply

Annotons

CG13667 CIA electron supply
cia_electron_supply_cg13667
Participant: Gene Product: CG13667
Gene Product:
CG13667UniProtKB:Q9VSJ5

NDOR1 diflavin reductase

Ciapin1 CIA electron supply
cia_electron_supply_ciapin1
Participant: Gene Product: Ciapin1
Gene Product:
Ciapin1UniProtKB:Q9V3Y2

anamorsin, [2Fe-2S] protein that receives electrons from CG13667

Part 7: assembly of [4Fe-4S] clusters in the cytosol
CIA scaffold complexProtein Complexcia_scaffold

Annotons

CIA scaffold complex
cia_scaffold_complex
Participant: Protein Complex: CIA scaffold complex
Protein Complex:
CIA scaffold complex
Active units:
Nubp1
Participant: Gene Product: Nubp1
Gene Product:
Nubp1UniProtKB:Q9VJI9
Nubp2
Participant: Gene Product: Nubp2
Gene Product:
Nubp2UniProtKB:Q9VPD2

Processes

[4Fe-4S] cluster assemblyGO:0044572
Part 8: insertion of [4Fe-4S] clusters into cytosolic and nuclear apoproteins
CIA targeting complexProtein Complexcia_targeting_complex

Annotons

CIA targeting complex
cia_targeting_complex_complex
Participant: Protein Complex: CIA targeting complex
Protein Complex:
CIA targeting complexGO:0097361
Active units:
CG17683
Participant: Gene Product: CG17683
Gene Product:
CG17683UniProtKB:Q8SYS7
Role: CIAO3 (NARFL) [4Fe-4S] protein that receives clusters from the scaffold
Ciao1
Participant: Gene Product: Ciao1
Gene Product:
Ciao1UniProtKB:Q7K1Y4
Role: CIAO1 WD40 subunit
Mms19
Participant: Gene Product: Mms19
Gene Product:
Mms19UniProtKB:Q95U54
Role: MMS19 subunit that binds client apoproteins
galla2
Participant: Gene Product: galla2
Gene Product:
galla2UniProtKB:Q9VTC4
Role: CIAO2B (MIP18 family) subunit