Reactome: A Curated Pathway Database

FXN:NFS1:ISD11:ISCU assembles 2Fe-2S iron-sulfur cluster

Stable Identifier
Reaction [BlackBoxEvent]
Homo sapiens
Locations in the PathwayBrowser

Iron-sulfur clusters are assembled on the scaffold, ISCU. Based on homology with bacterial IscU:IscS complexes (reviewed in Johnson et al. 2005), one molecule of ISCU is bound to each subunit of a NFS1 dimer (Marinoni et al. 2012). A single complex may thus be capable of assembling two 2Fe-2S clusters. Sulfide is provided by desulfuration of cysteine by NFS1:ISD11 (Biederbick et al. 2006, Shi et al. 2009, Tsai and Barondeau 2010). It has been proposed that ferrous iron is delivered by FXN (Gerber et al. 2003, Yoon and Cowan 2003, Schmucker et al. 2011) bound to ISCU (inferred from yeast, Wang and Craig 2008), although more recent studies suggested that FXN functions as an allosteric effector to stimulate sulfide transfer (Tsai et al. 2010). Holo-ISCU (ISCU bound to a newly synthesized 2Fe-2S cluster) transiently interacts with a dedicated HSP70 chaperone system including Mortalin (GRP75) and HSP20 and GLRX5 (GRX5). Electrons supplied by FDXL1 (FDX2) are required and may reduce the sulfur from S0 to S2-. NFU1 binds an Fe-S cluster (Tong et al. 2003, inferred from bacteria Yuvaniyama et al. 2000) and, from biochemical studies of bacterial NFU1 homologues, is proposed to be an intermediate Fe-S cluster carrier (Bandyopadhy et al. 2008). Mutations in human NFU1 affect only a subset of Fe-S proteins (Navarro-Sastre et al. 2011).

Literature References
PubMed ID Title Journal Year
15952888 Structure, function, and formation of biological iron-sulfur clusters Annu. Rev. Biochem. 2005
12947415 An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1 EMBO Rep. 2003
26016389 The Human Iron-Sulfur Assembly Complex Catalyzes the Synthesis of [2Fe-2S] Clusters on ISCU2 That Can Be Transferred to Acceptor Molecules Biochemistry 2015
22352884 Effector role reversal during evolution: the case of frataxin in Fe-S cluster biosynthesis Biochemistry 2012
22101253 Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis Biochim. Biophys. Acta 2012
18339629 A proposed role for the Azotobacter vinelandii NfuA protein as an intermediate iron-sulfur cluster carrier J. Biol. Chem. 2008
22077971 A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins Am. J. Hum. Genet. 2011
18319250 Binding of yeast frataxin to the scaffold for Fe-S cluster biogenesis, Isu J. Biol. Chem. 2008
17331979 Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones Hum Mol Genet 2007
21944046 Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes Am. J. Hum. Genet. 2011
12970193 Components involved in assembly and dislocation of iron-sulfur clusters on the scaffold protein Isu1p EMBO J. 2003
20873749 Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex Biochemistry 2010
12886008 Subcellular compartmentalization of human Nfu, an iron-sulfur cluster scaffold protein, and its ability to assemble a [4Fe-4S] cluster Proc. Natl. Acad. Sci. U.S.A. 2003
26016518 Frataxin Accelerates [2Fe-2S] Cluster Formation on the Human Fe-S Assembly Complex Biochemistry 2015
19454487 Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis Hum Mol Genet 2009
12785837 Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins J Am Chem Soc 2003
16847322 Role of human mitochondrial Nfs1 in cytosolic iron-sulfur protein biogenesis and iron regulation Mol. Cell. Biol. 2006
22306468 Interaction of J-protein co-chaperone Jac1 with Fe-S scaffold Isu is indispensable in vivo and conserved in evolution J. Mol. Biol. 2012
22511353 (IscS-IscU)2 complex structures provide insights into Fe2S2 biogenesis and transfer Angew. Chem. Int. Ed. Engl. 2012
10639125 NifS-directed assembly of a transient [2Fe-2S] cluster within the NifU protein Proc. Natl. Acad. Sci. U.S.A. 2000
Participant Of
This entity is regulated by:
Title Physical Entity Activity
cysteine desulfurase activity of 2 Iron:FXN:NFS1:ISD11:ISCU [mitochondrial matrix] 2 Iron:FXN:NFS1:ISD11:ISCU [mitochondrial matrix] cysteine desulfurase activity (0031071)
electron carrier activity of FDX1,FDX1L (red.) [mitochondrial matrix] FDX1,FDX1L (red.) [mitochondrial matrix] electron carrier activity (0009055)
Orthologous Events