Iron-sulfur cluster biogenesis

GO annotation review of 15 human genes of the mitochondrial ISC and cytosolic CIA machinery

AI Gene Review · projects/IRON_SULFUR_CLUSTER_BIOGENESIS · IN_PROGRESS · 2026

Bottom line

  • All 15 genes in the project table are reviewed (the page's status list still says only HSCB).
  • 638 GOA rows: 366 ACCEPT, 92 non-core, 92 over-annotated, 42 MODIFY, 24 REMOVE, 19 NEW.
  • Main corrections: protein binding removed on HSCB and GLRX5, heme transport removed from ABCB7, NEW Fe-S-specific chaperone and [4Fe-4S] assembly terms.

The pathway

Why this system

  • Fe-S clusters are essential cofactors for respiration, DNA metabolism and lipoate synthesis; defects cause Friedreich's ataxia (FXN), sideroblastic anemia (GLRX5, ABCB7) and multiple mitochondrial dysfunction syndromes (NFU1, BOLA3, IBA57).
  • The machinery is a relay: sulfur donor → scaffold → chaperones → carriers → targeting. Generic terms like iron-sulfur cluster assembly hide who does which step.
  • GO has step-specific terms (iron-sulfur cluster chaperone activity, [4Fe-4S] cluster assembly) that were missing from several genes.

Results by action

What a review looks like

HSCB: an IBA [2Fe-2S] cluster assembly row is modified, because HSCB transfers clusters from ISCU rather than building them.

Key changes

Gene Change
HSCB 8 protein binding rows REMOVE; NEW enzyme-substrate adaptor activity, Hsp70 protein binding, iron-sulfur cluster transfer complex
GLRX5 5 protein binding rows REMOVE; NEW iron-sulfur cluster chaperone activity (GO:0140132)
ISCA1 NEW GO:0140132, [4Fe-4S] cluster assembly (GO:0044572), 4Fe-4S binding; IBA cytoplasm REMOVE
IBA57 NEW GO:0044572 and mitochondrial [4Fe-4S] assembly complex; heme biosynthesis (IEA) REMOVE
ABCB7 heme transporter activity and heme transport REMOVE (3 rows)
MMS19 TFIIH holo complex and signaling-receptor adaptor (NAS) REMOVE

Status and next steps

  • ✅ 15/15 genes in the project table reviewed.
  • ⬜ Review FDXR, FDX2, CIAO2A, CIAO2B, CIAO3 (listed in the pathway, not in the table).
  • ⬜ Build an Fe-S biogenesis module (ISC core → transfer → [4Fe-4S] → export → CIA).
  • ⬜ Update the stale status list on the project page.

Read more: projects/IRON_SULFUR_CLUSTER_BIOGENESIS.md · genes/human/HSCB/ · genes/human/GLRX5/