Affinage

NFS1

Cysteine desulfurase · UniProt Q9Y697

Length
457 aa
Mass
50.2 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NFS1 is a pyridoxal-phosphate-dependent homodimeric cysteine desulfurase that mobilizes sulfur from L-cysteine to drive the biosynthesis of iron-sulfur cofactors and other sulfur-containing biomolecules (PMID:8464885, PMID:8161529). Catalysis proceeds through nucleophilic attack of an active-site cysteine (Cys325/Cys328) on a PLP-bound substrate to generate L-alanine and an enzyme-bound cysteinyl persulfide intermediate; this catalytic cysteine sits on a flexible surface loop that must undergo a large conformational change to reach the PLP cofactor and to deliver sulfane sulfur to diverse acceptors (PMID:8161529, PMID:12860127, PMID:20404999). In mitochondria, NFS1 nucleates the core Fe-S cluster assembly machinery: ISD11 binds NFS1 to prevent its aggregation and stabilize the active enzyme, while NFS1 transfers persulfide sulfur directly to the scaffold protein ISCU, on which transient Fe-S clusters are built and later released for transfer (PMID:10639125, PMID:11577100, PMID:16341090, PMID:23940031). Frataxin associates with the preassembled NFS1-ISD11-ISCU complex and accelerates persulfide sulfur transfer onto ISCU, competing with ferredoxin for a shared, evolutionarily conserved surface on NFS1 (PMID:21298097, PMID:25597503, PMID:35026224). NFS1 must reside inside mitochondria to support maturation of both mitochondrial and cytosolic Fe-S proteins, and its depletion collapses respiratory-chain, aconitase, and other Fe-S enzyme activities while activating the iron-starvation response (PMID:16847322, PMID:16787928, PMID:29168506). Alternative in-frame AUG utilization generates cytosolic/nuclear NFS1 isoforms that additionally donate sulfur to MOCS3 for molybdenum cofactor biosynthesis and to ThiI/MnmA-type pathways for tRNA thiolation (PMID:9885568, PMID:18650437, PMID:23593335, PMID:10753862, PMID:12549933). By sustaining Fe-S cofactors under oxidative stress, NFS1 protects cells from ferroptosis, and its expression and activity are modulated in cancer and cardiac disease through transcriptional control (YAP/YY1, MYC) and post-translational regulation (S293 phosphorylation), making it a target of ferroptosis-inducing agents (PMID:29168506, PMID:35221331, PMID:36103522, PMID:40107016). Loss-of-function mutation of NFS1 causes infantile mitochondrial complex II/III deficiency in humans (PMID:24498631).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 High

    Establishing how a cysteine desulfurase chemically mobilizes sulfur defined the enzymatic basis for all downstream Fe-S and sulfur-transfer biology.

    Evidence In vitro enzyme assays with PLP cofactor identification, thiol-alkylation, and site-directed mutagenesis of the catalytic Cys in the NifS ortholog

    PMID:8161529 PMID:8464885

    Open questions at the time
    • Defined in a bacterial ortholog; human NFS1 catalytic residues inferred
    • Did not address partner-dependent sulfur delivery
  2. 2000 High

    Identifying direct sulfur transfer from the desulfurase to a scaffold protein revealed how persulfide sulfur is committed to Fe-S cluster assembly.

    Evidence In vitro Fe-S assembly with spectroscopy, 35S sulfur-transfer assays, binding measurements, and C-terminal deletion mutagenesis of IscS

    PMID:10639125 PMID:11577100

    Open questions at the time
    • Bacterial system; mammalian scaffold transfer kinetics characterized later
    • Mechanism of cluster release from scaffold not defined here
  3. 2000 High

    Demonstrating that the same desulfurase feeds tRNA thiolation, thiamine, and molybdenum cofactor pathways established NFS1 as a central sulfur hub beyond Fe-S clusters.

    Evidence iscS deletion/complementation, in vitro reconstitution of ThiS/ThiI/MnmA sulfur relays, HPLC nucleoside analysis

    PMID:10600118 PMID:10753862 PMID:10781607 PMID:12549933

    Open questions at the time
    • Defined in E. coli; human pathway partners only partly mapped
    • Compartment-specific isoform contribution not addressed
  4. 1998 Medium

    Discovering alternative AUG-driven isoform targeting explained how a single gene supplies sulfur to both mitochondrial and cytosolic/nuclear pathways.

    Evidence cDNA cloning, subcellular fractionation, alternative AUG mapping, and pH manipulation; in yeast, retrograde translocation and Icp55 processing

    PMID:19720832 PMID:9885568

    Open questions at the time
    • Physiological trigger for pH-dependent redistribution unconfirmed in vivo
    • Yeast dual-targeting mechanism may differ from human
  5. 2006 High

    Loss-of-function in mammalian cells showed NFS1 is required, from within mitochondria, for maturation of Fe-S proteins across compartments.

    Evidence siRNA depletion in HeLa and fibroblasts with multiple Fe-S enzyme readouts, IRP-1 switching, and presequence-deletion complementation

    PMID:16787928 PMID:16847322

    Open questions at the time
    • Mechanism linking mitochondrial NFS1 to cytosolic Fe-S maturation not resolved here
    • Did not address the molybdenum cofactor role of cytosolic NFS1
  6. 2008 High

    Identifying NFS1-MOCS3 sulfur transfer assigned a direct cytosolic function to NFS1 in molybdenum cofactor biosynthesis.

    Evidence Protein interaction studies with MOCS3-RLD, in vitro persulfide-mediated sulfur transfer, and cytosolic colocalization plus molybdoenzyme reconstitution

    PMID:18650437 PMID:23593335

    Open questions at the time
    • Quantitative contribution of cytosolic vs mitochondrial NFS1 to Moco in vivo unclear
  7. 2006 High

    Characterizing ISD11 as an obligate NFS1 partner explained how the desulfurase is stabilized in mitochondria.

    Evidence Yeast Isd11 depletion, co-IP, NFS1 aggregation/stability assays, ISD11 mutagenesis, and a COXPD19-associated R68L variant

    PMID:16341090 PMID:26342079 PMID:28271877

    Open questions at the time
    • How ISD11/LYR-motif binding mechanistically promotes catalysis not fully resolved
    • Disease variant effects shown in cells, not whole organisms
  8. 2015 High

    Resolving frataxin's role redefined it as an enhancer of sulfur transfer within the NFS1-ISD11-ISCU complex rather than purely an iron donor.

    Evidence Co-IP showing frataxin binds the preformed core complex; persulfide intermediate trapping by mass spectrometry and sulfur-transfer kinetics

    PMID:12947415 PMID:21298097 PMID:23940031 PMID:25597503

    Open questions at the time
    • Whether frataxin also contributes iron in vivo not excluded
    • Regulation of frataxin engagement under iron status incompletely defined
  9. 2010 High

    Structural and competition studies revealed how a flexible active-site loop and a shared NFS1 surface coordinate sulfur delivery to multiple acceptors.

    Evidence Crystal structures of IscS-IscU and IscS-TusA with surface mutagenesis; mutually exclusive binding of acceptors, Jac1/Nfs1 competition, and ferredoxin/frataxin competition for a conserved site

    PMID:12860127 PMID:20404999 PMID:23839945 PMID:23946486 PMID:35026224

    Open questions at the time
    • High-resolution structure of the full mammalian core complex not described here
    • Order of acceptor engagement in vivo not directly observed
  10. 2015 Medium

    Defining the ferredoxin electron-transfer input and ISCU conformational/zinc regulation clarified additional control layers on cluster assembly.

    Evidence In vitro Fe-S assembly with NADPH/FNR/Fdx; NMR of ISCU conformational states; zinc-depletion desulfurase assays and ISCU Met140 variant analysis

    PMID:25688831 PMID:26342079 PMID:30031876

    Open questions at the time
    • In vivo electron-supply stoichiometry not established
    • Physiological role of ISCU zinc occupancy unresolved
  11. 2013 Medium

    A causative human mutation linked NFS1 desulfurase loss directly to mitochondrial respiratory chain disease.

    Evidence Autozygosity mapping, exome sequencing, and functional tests identifying p.Arg72Gln in infantile complex II/III deficiency

    PMID:24498631

    Open questions at the time
    • Single family/study
    • Direct enzymatic deficit of the variant not biochemically quantified here
  12. 2017 High

    Connecting NFS1 to ferroptosis established its protective role in maintaining Fe-S cofactors under oxidative stress and its relevance to cancer.

    Evidence RNAi loss-of-function screens, in vivo lung adenocarcinoma tumor growth, iron-starvation response readouts, and genetic cooperation with cysteine/glutathione limitation

    PMID:29168506

    Open questions at the time
    • Which specific Fe-S clients gate ferroptosis sensitivity not fully resolved
  13. 2025 Medium

    Mapping transcriptional and post-translational control of NFS1 explained how its ferroptosis-protective output is tuned in cardiac and cancer disease.

    Evidence CRISPR screen with S293 phosphosite mutagenesis (oxaliplatin/PANoptosis), OPA3 co-IP and ubiquitination assays, and YAP/YY1 promoter binding with AAV9-NFS1 rescue in mouse DCM models

    PMID:35221331 PMID:36103522 PMID:36924813 PMID:40107016

    Open questions at the time
    • Mechanistic link between S293 phosphorylation and desulfurase activity not defined
    • Single-lab models for each regulatory axis; cross-context generality untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the conformational cycle of the catalytic loop is choreographed in the assembled mammalian NFS1-ISD11-ISCU-frataxin-ferredoxin machinery to hand off sulfur and release clusters in vivo remains unresolved.
  • No high-resolution structure of the complete mammalian core complex in the corpus
  • Temporal coordination of acceptor exchange in living cells not directly observed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0016829 lyase activity 2
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 4 GO:0005634 nucleus 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1643685 Disease 3
Partners
FERREDOXINFXNISCUISD11MNMAMOCS3OPA3THII
Complex memberships
NFS1-ISD11-ISCU core Fe-S assembly complexNFS1-ISD11-ISCU-frataxin quaternary complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 NifS (NFS1 ortholog) is a pyridoxal phosphate-containing homodimer that catalyzes the formation of L-alanine and elemental sulfur from L-cysteine; activity is abolished by thiol-specific alkylating reagents, implicating an active-site cysteinyl thiolate; proposed to supply inorganic sulfide for nitrogenase metallocluster (Fe-S cluster) biosynthesis. In vitro enzyme assay, chemical modification with thiol-specific alkylating reagents, pyridoxal phosphate cofactor identification Proceedings of the National Academy of Sciences of the United States of America High 8464885
1994 The catalytic mechanism of NifS (NFS1 ortholog) involves: (1) nucleophilic attack by active-site Cys325 on a PLP-bound cysteine substrate, (2) formation of an enzyme-bound cysteinyl persulfide intermediate, and (3) generation of an enamine intermediate yielding L-alanine; Cys325 identified as the essential catalytic residue by site-directed mutagenesis and specific alkylation. Substrate analog inhibition (L-allylglycine, vinylglycine), site-directed mutagenesis of Cys325, in vitro enzyme assays, identification of persulfide intermediate Biochemistry High 8161529
1998 Human NFS1 is synthesized from a single transcript as different isoforms that localize either to mitochondria or to the cytosol/nucleus through initiation at alternative in-frame AUGs; isoform selection varies with cytosolic pH, providing a mechanism for redistribution of NFS1 between compartments in response to metabolic changes. cDNA cloning, subcellular fractionation, alternative AUG mapping, pH manipulation experiments Molecular cell High 9885568
2000 NifS directs assembly of a transient [2Fe-2S] cluster on the scaffold protein NifU in vitro when incubated with ferric ion and L-cysteine; NifU interacts physically with NifS; the transient cluster is labile and rapidly released upon reduction, supporting a model where NifS-assembled clusters on NifU are transferred to nitrogenase component proteins. In vitro Fe-S cluster assembly assay, UV-vis and EPR spectroscopy, protein interaction studies Proceedings of the National Academy of Sciences of the United States of America High 10639125
2001 E. coli IscS (NFS1 ortholog) directly transfers persulfide sulfur to the scaffold protein IscU via a high-affinity protein-protein interaction (Kd ~2 µM); transfer requires cysteinyl residues of IscU and is inhibited by iodoacetamide treatment of IscU; the C-terminal region of IscS (residues 376-413) is important for IscU binding and efficient sulfur transfer. 35S-cysteine radiotracer sulfur transfer assay, surface plasmon resonance, isothermal titration calorimetry, IscS C-terminal deletion mutagenesis The Journal of biological chemistry High 11577100
1999 IscS is required for the biosynthesis of 4-thiouridine (s4U) in tRNA, thiamine (specifically the thiazole moiety), and NAD in E. coli; IscS mobilizes sulfur for transfer to ThiS (the direct sulfur donor in thiazole biosynthesis), with ThiI stimulating the IscS-to-ThiS sulfur transfer ~7-fold; neither of the other two nifS-like E. coli genes can complement iscS deletion. iscS deletion mutant phenotypic analysis, in vitro reconstitution of ThiS thiocarboxylate synthesis, genetic complementation The Journal of biological chemistry High 10781607
1999 IscS acts as a tRNA sulfurtransferase for 4-thiouridine biosynthesis; purified IscS catalyzes sulfur transfer from cysteine to tRNA in vitro; among E. coli proteins with cysteine desulfurase activity, only IscS can mobilize sulfur for tRNA thiolation. Protein purification, in vitro tRNA thiolation assay, HPLC nucleoside analysis, N-terminal sequencing Biochemistry High 10600118
2000 IscS transfers sulfane sulfur (persulfide) sequentially to ThiI, which then transfers it to tRNA during 4-thiouridine biosynthesis; ThiI contains a reactive cysteine required for catalysis/binding protected by ATP and tRNA; IscS-generated persulfide is the direct sulfur source for ThiI. Fluorescent alkylating agent inhibition of ThiI, gel shift and protease protection assays, in vitro sulfur transfer reconstitution The Journal of biological chemistry High 10753862
2003 Crystal structure of E. coli IscS (NFS1 ortholog) solved at 2.1 Å; the catalytic Cys328 resides on a flexible surface loop >17 Å from the PLP cofactor, requiring a large conformational change for catalysis; structural modeling suggests loop rotation brings Cys328 to ~3 Å of PLP cofactor. X-ray crystallography at 2.1 Å resolution Journal of molecular biology High 12860127
2003 Frataxin ortholog Yfh1 specifically binds to the core ISC assembly complex composed of scaffold protein Isu1 and cysteine desulfurase Nfs1; binding is markedly increased by ferrous iron; Yfh1 is involved in de novo Fe-S cluster synthesis on Isu1, suggesting frataxin provides iron to the Isu scaffold. Co-immunoprecipitation, in vivo functional analysis of ISC synthesis on Isu1, iron-dependence assays EMBO reports High 12947415
2003 MnmA and IscS are both required for in vitro 2-thiouridine (s2U) biosynthesis in E. coli tRNA; IscS-generated persulfide can provide sulfur for s2U synthesis in the absence of free cysteine; MnmA binds tRNA substrates with low micromolar affinity and requires ATP. In vitro s2U biosynthesis reconstitution with purified components, 35S radiotracer, HPLC analysis, gel mobility shift Biochemistry High 12549933
2005 Isd11 forms a stable complex with Nfs1 in mitochondria; in the absence of Isd11, Nfs1 is prone to aggregation; Isd11 depletion causes strong reduction in Fe-S protein activities (aconitase, succinate dehydrogenase, Rieske protein); Isd11 acts with Nfs1 in an early step of Fe-S cluster biogenesis. Yeast genetics (Isd11 depletion), enzyme activity assays, co-immunoprecipitation, protein stability assessment The EMBO journal High 16341090
2006 Human Nfs1 (huNfs1) is located predominantly in mitochondria with small amounts in cytosol/nucleus; siRNA depletion of huNfs1 in HeLa cells strongly impairs both mitochondrial and cytosolic Fe-S protein activities and causes growth retardation and mitochondrial morphology changes; Nfs1 must be inside mitochondria to support Fe-S protein maturation—cytosolic Nfs1 lacking the mitochondrial presequence cannot complement. siRNA knockdown, enzyme activity assays for mitochondrial and cytosolic Fe-S proteins, subcellular fractionation, complementation with presequence-deleted Nfs1 Molecular and cellular biology High 16847322
2006 Depletion of mammalian m-Nfs1 by siRNA in cultured fibroblasts significantly inhibits activities of mitochondrial respiratory chain complexes I and II, mitochondrial aconitase, cytosolic xanthine oxidase (a [2Fe-2S] enzyme), and converts IRP-1 from its [4Fe-4S] aconitase form to its RNA-binding form; cytosolic Fe-S activities are affected earlier than mitochondrial activities. siRNA gene silencing, enzyme activity assays, IRP-1 RNA-binding assay, ferritin mRNA regulation The Journal of biological chemistry High 16787928
2008 Human NFS1 (purified with Isd11) interacts specifically with the rhodanese-like domain (RLD) of MOCS3, a cytosolic protein involved in molybdenum cofactor biosynthesis; sulfur is transferred from L-cysteine to MOCS3-RLD via an NFS1-bound persulfide intermediate; cytosolic NFS1 acts as sulfur donor for Moco biosynthesis. Protein-protein interaction studies, in vitro sulfur transfer assay, kinetic parameter determination The Journal of biological chemistry High 18650437
2009 Yeast Nfs1 undergoes dual targeting to mitochondria and nucleus from a single translation product; the minor nuclear/cytosolic subpopulation arises via partial mitochondrial entry followed by retrograde translocation; mitochondrial processing peptidase cleaves Nfs1, and the novel processing enzyme Icp55 subsequently removes three additional N-terminal amino acids. Alpha-complementation assay, subcellular fractionation, Edman degradation of N-terminal sequence, discovery of Icp55 protease The Journal of biological chemistry Medium 19720832
2009 Bacterial frataxin CyaY acts as an iron-dependent inhibitor of Fe-S cluster formation by binding to the desulfurase IscS; the interaction involves the iron-binding surface of CyaY; CyaY acts as an iron sensor/regulator that fine-tunes Fe-S cluster formation. Biochemical and biophysical interaction studies, in vitro Fe-S cluster assembly assays Nature structural & molecular biology High 19305405
2010 Crystal structures of IscS-IscU and IscS-TusA complexes reveal that IscS interacts with multiple partner proteins through an extensive surface area centered on catalytic Cys328; partner proteins approach Cys328 from different directions; the conformational plasticity of the active-site loop containing Cys328 is essential for sulfur transfer to multiple acceptors; sulfur acceptors (IscU, TusA) bind IscS one at a time (mutually exclusive), while frataxin/CyaY and IscX can form ternary complexes with IscU and IscS. X-ray crystallography of IscS-IscU and IscS-TusA complexes, exhaustive IscS surface mutagenesis, biochemical binding and activity assays PLoS biology High 20404999
2011 Mammalian frataxin interacts with the preformed ISCU/NFS1/ISD11 core Fe-S assembly complex (not individual components); the quaternary complex has a molecular mass of ~190 kDa; the mature FXN(81-210) form is the essential functional form in vivo. Co-immunoprecipitation from mammalian cells, heterologous expression system, molecular mass determination, in vivo complementation PloS one High 21298097
2013 Human NFS1 (cysteine desulfurase) binds preferentially to the disordered (D-state) conformation of ISCU scaffold protein; ISD11 does not interact directly with ISCU but the NFS1-ISD11 complex also binds the D-state of ISCU; in vitro Fe-S cluster assembly on ISCU is catalyzed by NFS1 alone and at higher rate by the NFS1-ISD11 complex. NMR spectroscopy, ISCU conformational state variants (D39V, N90A, D39A, H105A), in vitro Fe-S cluster assembly assay The Journal of biological chemistry High 23940031
2013 Binding of Jac1 (J-protein co-chaperone) and Nfs1 to the scaffold protein Isu is mutually exclusive; both proteins require the same hydrophobic patch on Isu surface; Jac1 and Nfs1 compete for Isu binding in vitro; competition between Jac1 and Nfs1 for Isu is proposed to transition the machinery from cluster assembly to Hsp70-mediated cluster transfer. In vitro binding assays with purified proteins, competition assays, Isu hydrophobic patch mutagenesis, in vivo functional validation The Journal of biological chemistry High 23946486
2013 NFS1 physical interaction (not enzymatic activity) with Isu protects Isu from degradation by the Pim1/Lon protease; when Fe-S cluster biogenesis is disrupted, increased Isu stability depends on its interaction with Nfs1. Yeast genetics, Pim1 protease identification, protein stability assays under various conditions including Nfs1 enzymatic mutants Proceedings of the National Academy of Sciences of the United States of America Medium 22689995
2013 Cytosolic NFS1 colocalizes and interacts with MOCS3 in the cytosol of human cells; NFS1 localization in cytosol confirmed by FRET, split-EGFP, immunodetection of fractionated cells, and confocal microscopy; purified NFS1 can reconstitute molybdoenzyme activity in Neurospora crassa nit-1 mutant. FRET, split-EGFP, immunofluorescence/confocal microscopy, cell fractionation, in vitro molybdoenzyme reconstitution PloS one High 23593335
2015 Mammalian frataxin directly enhances the rate of sulfur transfer from NFS1 persulfide to both ISCU (accumulating a persulfide on ISCU Cys104) and to small free thiols (DTT, L-cysteine, GSH); frataxin acts as an enhancer of sulfur transfer within the NFS1-ISD11-ISCU complex rather than primarily as an iron donor. Maleimide-peptide trapping of cysteine-persulfide intermediates combined with mass spectrometry, in vitro sulfur transfer kinetics Nature communications High 25597503
2017 NFS1 activity is critical for maintaining Fe-S cofactors in multiple cell-essential proteins under high oxygen conditions; NFS1 suppression activates the iron-starvation response and, in combination with inhibition of glutathione biosynthesis, triggers ferroptosis; NFS1 is amplified in lung adenocarcinoma and protects against ferroptosis under high-oxygen tension. RNA interference loss-of-function screening, in vivo tumor growth experiments, genetic cooperation assays (NFS1 suppression + cysteine transport inhibition), iron-starvation response measurements Nature High 29168506
2013 Ferredoxin (Fdx) competes with frataxin CyaY for binding to the desulfurase IscS; Fdx binds in a cavity close to the enzyme active site overlapping the CyaY binding site; in vivo mutagenesis confirms importance of this interaction surface for Fe-S cluster formation. Biophysical characterization (SAXS, NMR, other), mutagenesis, in vivo complementation The Journal of biological chemistry Medium 23839945
2015 Ferredoxin (Fdx), together with NADPH and ferredoxin-NADP reductase, transfers electrons to the IscS/IscU complex to promote Fe-S cluster assembly; this electron transfer trio is sufficient to sustain in vitro Fe-S cluster assembly; Fdx does not interfere with CyaY inhibitory activity despite overlapping binding sites on IscS. In vitro Fe-S cluster assembly assay using physiological electron transfer chain (NADPH/FNR/Fdx), comparison with DTT-mediated assembly Biochimica et biophysica acta Medium 25688831
2022 During FeS cluster biogenesis in yeast, ferredoxin (Yah1) and frataxin (Yfh1) share an evolutionarily conserved interaction site on Nfs1; Yah1 and Yfh1 can each displace the other from Nfs1, demonstrating mutually exclusive binding; this binding mode mirrors bacterial CyaY/Fdx competition at IscS. In vitro competition assays with purified WT and variant Nfs1/Yah1/Yfh1 proteins, biochemical binding assays The Journal of biological chemistry Medium 35026224
2013 NFS1 deficiency (c.215G>A, p.Arg72Gln mutation) identified as causative for infantile mitochondrial complex II/III deficiency, establishing that loss of NFS1 cysteine desulfurase activity impairs respiratory chain function in humans. Autozygosity mapping, exome sequencing, in silico analyses, population studies, functional tests Molecular genetics & genomic medicine Medium 24498631
2015 ISD11 residues in helix 1 (Phe-40), helix 3 (Leu-63, Arg-68, Gln-69, Ile-72, Tyr-76), and C-terminal segment (Leu-81, Glu-84) are critical for interaction with NFS1; mutation of these residues compromises ISD11-NFS1 complex stability, causing NFS1 aggregation and reduced Fe-S cluster biosynthesis; the COXPD19-associated ISD11 R68L mutation reduces affinity for NFS1 and causes mitochondrial dysfunction. Site-directed mutagenesis of ISD11, co-immunoprecipitation, enzyme activity assays (ETC complexes), mitochondrial iron/ROS measurements The Journal of biological chemistry Medium 26342079
2017 The first 10 N-terminal amino acids of ISD11, including the conserved 'LYR' motif, are indispensable for NFS1 activity and formation of a stable, active NFS1-ISD11 complex; the N-terminus of ISD11 also contains its mitochondrial targeting sequence. In vitro purified protein interaction studies, in vivo cellular complementation, mutagenesis of ISD11 N-terminus Biochemistry Medium 28271877
2022 Oxaliplatin-induced oxidative stress enhances phosphorylation of NFS1 at serine residue S293; phosphorylation at S293 prevents PANoptosis (apoptosis, necroptosis, pyroptosis, ferroptosis) in colorectal cancer cells; NFS1 transcription is regulated by MYC; NFS1 deficiency combined with oxaliplatin triggers PANoptosis by increasing intracellular ROS. CRISPR-Cas9 metabolic enzyme screen in vivo, site-directed mutagenesis of S293, in vitro and in vivo functional assays, ROS measurement, phosphorylation site identification Signal transduction and targeted therapy Medium 35221331
2022 Eprenetapopt (APR-246) inhibits the cysteine desulfurase activity of NFS1, limiting Fe-S cluster biogenesis and potentiating ferroptosis; this effect is independent of its reported mutant-p53 reactivation activity. Unbiased genetic screen, glutathione turnover assays, NFS1 cysteine desulfurase activity assay, ferroptosis cell death assays Science advances Medium 36103522
2023 OPA3 (mitochondrial membrane protein) interacts with NFS1 and regulates ferroptosis; DOX promotes OPA3 ubiquitination and downregulates NFS1; H2S antagonizes OPA3 ubiquitination via S-sulfhydration, restoring NFS1 expression and inhibiting ferroptosis; NFS1 deficiency increases cardiomyocyte susceptibility to ferroptosis. Co-immunoprecipitation (OPA3-NFS1 interaction), overexpression/knockdown in cardiomyocytes, in vivo DOX cardiotoxicity model, ubiquitination and S-sulfhydration assays Cellular signalling Medium 36924813
2025 Nuclear YAP and YY1 interact and bind to the NFS1 promoter, mediating transcriptional downregulation of NFS1 upon Hippo pathway activation; NFS1 downregulation causes insufficient Fe-S cluster biosynthesis leading to cardiomyocyte ferroptosis and dilated cardiomyopathy; AAV9-mediated restoration of NFS1 expression alleviates ferroptosis and DCM phenotype in mice. Transcriptome analysis, ChIP/promoter binding assays, AAV9-Nfs1 rescue in Mst1-TG mice, ferroptosis assays, Mst1/dnMst1 transgenic mouse models Redox biology Medium 40107016
2018 Zinc(II)-bound ISCU inhibits NFS1-ISD11-ACP-ISCU (SDAU) desulfurase activity; removal of zinc from ISCU causes a moderate but significant increase in NFS1 desulfurase activity; frataxin can activate both zinc-depleted and zinc-bound forms of ISCU complexed to NFS1-ISD11-ACP. Human ISCU Met140 variants (M140I, M140L, M140V) do not show FXN-bypass effect on NFS1 desulfurase activity in vitro. In vitro desulfurase activity assays with zinc-depleted vs zinc-bound ISCU, mutagenesis of ISCU Met140, biochemical/biophysical characterization Biochimie Medium 30031876

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 623 29168506
1993 Cysteine desulfurase activity indicates a role for NIFS in metallocluster biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 489 8464885
1994 Mechanism for the desulfurization of L-cysteine catalyzed by the nifS gene product. Biochemistry 330 8161529
2018 Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell death and differentiation 319 29459771
2003 An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. EMBO reports 283 12947415
2022 Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis. Signal transduction and targeted therapy 282 35221331
2000 NifS-directed assembly of a transient [2Fe-2S] cluster within the NifU protein. Proceedings of the National Academy of Sciences of the United States of America 267 10639125
2001 Transfer of sulfur from IscS to IscU during Fe/S cluster assembly. The Journal of biological chemistry 231 11577100
1999 Functional assignment of the ORF2-iscS-iscU-iscA-hscB-hscA-fdx-ORF3 gene cluster involved in the assembly of Fe-S clusters in Escherichia coli. Journal of biochemistry 228 10544286
2010 Structural basis for Fe-S cluster assembly and tRNA thiolation mediated by IscS protein-protein interactions. PLoS biology 217 20404999
2009 Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS. Nature structural & molecular biology 207 19305405
2011 Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PloS one 190 21298097
2005 The Nfs1 interacting protein Isd11 has an essential role in Fe/S cluster biogenesis in mitochondria. The EMBO journal 190 16341090
1999 Hyperproduction of recombinant ferredoxins in escherichia coli by coexpression of the ORF1-ORF2-iscS-iscU-iscA-hscB-hs cA-fdx-ORF3 gene cluster. Journal of biochemistry 173 10393315
1996 Escherichia coli contains a protein that is homologous in function and N-terminal sequence to the protein encoded by the nifS gene of Azotobacter vinelandii and that can participate in the synthesis of the Fe-S cluster of dihydroxy-acid dehydratase. The Journal of biological chemistry 170 8663056
2000 The iscS gene in Escherichia coli is required for the biosynthesis of 4-thiouridine, thiamin, and NAD. The Journal of biological chemistry 168 10781607
1998 Targeting of a human iron-sulfur cluster assembly enzyme, nifs, to different subcellular compartments is regulated through alternative AUG utilization. Molecular cell 160 9885568
2003 Crystal structure of IscS, a cysteine desulfurase from Escherichia coli. Journal of molecular biology 147 12860127
2015 Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols. Nature communications 146 25597503
1997 Cysteine sulfinate desulfinase, a NIFS-like protein of Escherichia coli with selenocysteine lyase and cysteine desulfurase activities. Gene cloning, purification, and characterization of a novel pyridoxal enzyme. The Journal of biological chemistry 141 9278392
2006 Role of human mitochondrial Nfs1 in cytosolic iron-sulfur protein biogenesis and iron regulation. Molecular and cellular biology 140 16847322
2003 MnmA and IscS are required for in vitro 2-thiouridine biosynthesis in Escherichia coli. Biochemistry 134 12549933
2001 Mitochondrial type iron-sulfur cluster assembly in the amitochondriate eukaryotes Trichomonas vaginalis and Giardia intestinalis, as indicated by the phylogeny of IscS. Molecular biology and evolution 131 11557797
1999 SufS is a NifS-like protein, and SufD is necessary for stability of the [2Fe-2S] FhuF protein in Escherichia coli. Journal of bacteriology 129 10322040
2007 Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Human molecular genetics 125 17331979
2000 Crystal structure of a NifS-like protein from Thermotoga maritima: implications for iron sulphur cluster assembly. Journal of molecular biology 121 10715213
2000 Evidence for the transfer of sulfane sulfur from IscS to ThiI during the in vitro biosynthesis of 4-thiouridine in Escherichia coli tRNA. The Journal of biological chemistry 120 10753862
2000 Kinetic and mutational studies of three NifS homologs from Escherichia coli: mechanistic difference between L-cysteine desulfurase and L-selenocysteine lyase reactions. Journal of biochemistry 119 10739946
2005 NifS-mediated assembly of [4Fe-4S] clusters in the N- and C-terminal domains of the NifU scaffold protein. Biochemistry 115 16185064
2021 Genome-wide synthetic lethal screen unveils novel CAIX-NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors. Science advances 108 34452919
2008 A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis. The Journal of biological chemistry 101 18650437
1999 A nifS-like gene, csdB, encodes an Escherichia coli counterpart of mammalian selenocysteine lyase. Gene cloning, purification, characterization and preliminary x-ray crystallographic studies. The Journal of biological chemistry 101 10329673
1999 IscS is a sulfurtransferase for the in vitro biosynthesis of 4-thiouridine in Escherichia coli tRNA. Biochemistry 101 10600118
1989 Nitrogen fixation (nif) genes of the cyanobacterium Anabaena species strain PCC 7120. The nifB-fdxN-nifS-nifU operon. The Journal of biological chemistry 101 2553733
2000 Characterization of the NifU and NifS Fe-S cluster formation proteins essential for viability in Helicobacter pylori. Biochemistry 97 11123951
1992 The nifU, nifS and nifV gene products are required for activity of all three nitrogenases of Azotobacter vinelandii. Molecular & general genetics : MGG 89 1538703
2002 Requirement for IscS in biosynthesis of all thionucleosides in Escherichia coli. Journal of bacteriology 88 12446632
2012 The E. coli SufS-SufE sulfur transfer system is more resistant to oxidative stress than IscS-IscU. FEBS letters 86 23068614
2002 Analysis of the E. coli NifS CsdB protein at 2.0 A reveals the structural basis for perselenide and persulfide intermediate formation. Journal of molecular biology 84 11827487
2006 Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly. The Journal of biological chemistry 83 16527810
2000 Structure of a NifS homologue: X-ray structure analysis of CsdB, an Escherichia coli counterpart of mammalian selenocysteine lyase. Biochemistry 81 10684605
2001 Nifs and Sufs in malaria. Molecular microbiology 80 11555280
2002 Repair of nitric oxide-modified ferredoxin [2Fe-2S] cluster by cysteine desulfurase (IscS). The Journal of biological chemistry 79 11825893
2022 Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction. Science advances 75 36103522
2009 Dual targeting of Nfs1 and discovery of its novel processing enzyme, Icp55. The Journal of biological chemistry 72 19720832
2013 Ferredoxin competes with bacterial frataxin in binding to the desulfurase IscS. The Journal of biological chemistry 71 23839945
1993 Cloning, nucleotide sequence, and regulation of the Bacillus subtilis nadB gene and a nifS-like gene, both of which are essential for NAD biosynthesis. Journal of bacteriology 70 8444804
2007 A novel DNA modification by sulfur: DndA is a NifS-like cysteine desulfurase capable of assembling DndC as an iron-sulfur cluster protein in Streptomyces lividans. Biochemistry 67 17469805
1996 Activation of SoxR-dependent transcription in vitro by noncatalytic or NifS-mediated assembly of [2Fe-2S] clusters into apo-SoxR. The Journal of biological chemistry 67 8631739
2002 Structure of external aldimine of Escherichia coli CsdB, an IscS/NifS homolog: implications for its specificity toward selenocysteine. Journal of biochemistry 61 11983074
2002 The cysteine desulfurase IscS is required for synthesis of all five thiolated nucleosides present in tRNA from Salmonella enterica serovar typhimurium. Journal of bacteriology 61 12446633
2006 Knock-downs of iron-sulfur cluster assembly proteins IscS and IscU down-regulate the active mitochondrion of procyclic Trypanosoma brucei. The Journal of biological chemistry 59 16882667
2006 Evolution of the Isd11-IscS complex reveals a single alpha-proteobacterial endosymbiosis for all eukaryotes. Molecular biology and evolution 58 16648156
2009 IscS functions as a primary sulfur-donating enzyme by interacting specifically with MoeB and MoaD in the biosynthesis of molybdopterin in Escherichia coli. The Journal of biological chemistry 57 19946146
2000 Escherichia coli NifS-like proteins provide selenium in the pathway for the biosynthesis of selenophosphate. The Journal of biological chemistry 55 10829016
1998 The NIFS protein can function as a selenide delivery protein in the biosynthesis of selenophosphate. The Journal of biological chemistry 55 9812986
2004 The iron-sulfur cluster assembly genes iscS and iscU of Entamoeba histolytica were acquired by horizontal gene transfer. BMC evolutionary biology 53 15040816
2003 Mitochondrial-type iron-sulfur cluster biosynthesis genes (IscS and IscU) in the apicomplexan Cryptosporidium parvum. Microbiology (Reading, England) 53 14663084
2013 Binding of the chaperone Jac1 protein and cysteine desulfurase Nfs1 to the iron-sulfur cluster scaffold Isu protein is mutually exclusive. The Journal of biological chemistry 51 23946486
2013 Exome sequencing identifies NFS1 deficiency in a novel Fe-S cluster disease, infantile mitochondrial complex II/III deficiency. Molecular genetics & genomic medicine 51 24498631
1993 Homology of pyridoxal-5'-phosphate-dependent aminotransferases with the cobC (cobalamin synthesis), nifS (nitrogen fixation), pabC (p-aminobenzoate synthesis) and malY (abolishing endogenous induction of the maltose system) gene products. European journal of biochemistry 51 8425548
1998 cDNA cloning and characterization of mouse nifS-like protein, m-Nfs1: mitochondrial localization of eukaryotic NifS-like proteins. FEBS letters 49 9738949
2013 Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU). The Journal of biological chemistry 47 23940031
2007 Evidence for nifU and nifS participation in the biosynthesis of the iron-molybdenum cofactor of nitrogenase. The Journal of biological chemistry 47 17959596
2002 The iscS gene is essential for the biosynthesis of 2-selenouridine in tRNA and the selenocysteine-containing formate dehydrogenase H. Proceedings of the National Academy of Sciences of the United States of America 47 11997471
2006 RNA silencing of mitochondrial m-Nfs1 reduces Fe-S enzyme activity both in mitochondria and cytosol of mammalian cells. The Journal of biological chemistry 45 16787928
2000 Comparison of the sequences of the Aspergillus nidulans hxB and Drosophila melanogaster ma-l genes with nifS from Azotobacter vinelandii suggests a mechanism for the insertion of the terminal sulphur atom in the molybdopterin cofactor. Molecular microbiology 45 11029694
1993 Homology of the NifS family of proteins to a new class of pyridoxal phosphate-dependent enzymes. FEBS letters 45 8482384
2012 A novel target of IscS in Escherichia coli: participating in DNA phosphorothioation. PloS one 44 23240007
2015 Ferredoxin, in conjunction with NADPH and ferredoxin-NADP reductase, transfers electrons to the IscS/IscU complex to promote iron-sulfur cluster assembly. Biochimica et biophysica acta 43 25688831
2003 Assembly of iron-sulfur clusters mediated by cysteine desulfurases, IscS, CsdB and CSD, from Escherichia coli. Biochimica et biophysica acta 42 12686149
2003 The Geobacillus stearothermophilus V iscS gene, encoding cysteine desulfurase, confers resistance to potassium tellurite in Escherichia coli K-12. Journal of bacteriology 42 13129955
2012 Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold. Proceedings of the National Academy of Sciences of the United States of America 39 22689995
2000 Role of a NifS-like protein from the cyanobacterium Synechocystis PCC 6803 in the maturation of FeS proteins. Biochemistry 39 10727236
2013 The L-cysteine desulfurase NFS1 is localized in the cytosol where it provides the sulfur for molybdenum cofactor biosynthesis in humans. PloS one 38 23593335
2005 NifU and NifS are required for the maturation of nitrogenase and cannot replace the function of isc-gene products in Azotobacter vinelandii. Biochemical Society transactions 38 15667274
2014 The cysteine desulfurase IscS of Mycobacterium tuberculosis is involved in iron-sulfur cluster biogenesis and oxidative stress defence. The Biochemical journal 37 24548275
2006 Regulation of the Helicobacter pylori Fe-S cluster synthesis protein NifS by iron, oxidative stress conditions, and fur. Journal of bacteriology 36 16816209
2004 Substitutions in an active site loop of Escherichia coli IscS result in specific defects in Fe-S cluster and thionucleoside biosynthesis in vivo. The Journal of biological chemistry 35 14978044
2023 Hydrogen sulfide alleviates mitochondrial damage and ferroptosis by regulating OPA3-NFS1 axis in doxorubicin-induced cardiotoxicity. Cellular signalling 34 36924813
2010 Of the vulnerability of orphan complex proteins: the case study of the E. coli IscU and IscS proteins. Protein expression and purification 33 20471481
2000 Contribution of cysteine desulfurase (NifS protein) to the biotin synthase reaction of Escherichia coli. Journal of bacteriology 32 10781558
1995 Characterization of nifB, nifS, and nifU genes in the cyanobacterium Anabaena variabilis: NifB is required for the vanadium-dependent nitrogenase. Journal of bacteriology 32 7883714
2023 Lactobacillus rhamnosus GG Promotes Recovery of the Colon Barrier in Septic Mice through Accelerating ISCs Regeneration. Nutrients 28 36771378
2015 Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19. The Journal of biological chemistry 26 26342079
2020 Defective mitochondrial ISCs biogenesis switches on IRP1 to fine tune selective mitophagy. Redox biology 24 32795936
2006 Structural alterations of the cysteine desulfurase IscS of Salmonella enterica serovar Typhimurium reveal substrate specificity of IscS in tRNA thiolation. Journal of bacteriology 21 16585765
2005 The cysteine-desulfurase IscS promotes the production of the rhodanese RhdA in the persulfurated form. FEBS letters 20 16310786
2017 The N-Terminus of Iron-Sulfur Cluster Assembly Factor ISD11 Is Crucial for Subcellular Targeting and Interaction with l-Cysteine Desulfurase NFS1. Biochemistry 18 28271877
2000 Gene cloning, purification, and characterization of two cyanobacterial NifS homologs driving iron-sulfur cluster formation. Bioscience, biotechnology, and biochemistry 18 11193410
2014 Reactive oxygen species regulates expression of iron-sulfur cluster assembly protein IscS of Leishmania donovani. Free radical biology & medicine 17 25062827
2023 Resveratrol drives ferroptosis of acute myeloid leukemia cells through Hsa-miR-335-5p/NFS1/ GPX4 pathway in a ROS-dependent manner. Cellular and molecular biology (Noisy-le-Grand, France) 16 37715395
2022 During FeS cluster biogenesis, ferredoxin and frataxin use overlapping binding sites on yeast cysteine desulfurase Nfs1. The Journal of biological chemistry 15 35026224
2018 Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity. Biochimie 15 30031876
2013 The effect of the adaptor protein Isd11 on the quaternary structure of the eukaryotic cysteine desulphurase Nfs1. Biochemical and biophysical research communications 15 24045011
1997 Role of NifS in maturation of glutamine phosphoribosylpyrophosphate amidotransferase. Journal of bacteriology 15 9393728
1988 Further analysis of nitrogen fixation (nif) genes in Azotobacter chroococcum: identification and expression in Klebsiella pneumoniae of nifS, nifV, nifM, and nifB genes and localization of nifE/N-, nifU-, nifA- and fixABC-like genes. Journal of general microbiology 15 3053983
2005 Sensitivity to potassium tellurite of Escherichia coli cells deficient in CSD, CsdB and IscS cysteine desulfurases. Research in microbiology 14 15862443
2025 Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1. Redox biology 13 40107016
2008 The iscS gene deficiency affects the expression of pyrimidine metabolism genes. Biochemical and biophysical research communications 13 18482579

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