NFS1: Cysteine Desulfurase Essential for Iron-Sulfur Cluster Biogenesis
A critical enzyme in mitochondrial and cellular iron-sulfur protein maturation, linked to metabolic and neurodegenerative disorders.
Gene Information Card
| Symbol | NFS1 |
|---|---|
| Full Name | NFS1 cysteine desulfurase |
| Gene Type | Protein-coding |
| Chromosomal Location | 20q11.22 |
| NCBI Gene ID | 9054 ncbi.nlm.nih.gov/gene/9054 |
| Ensembl ID | ENSG00000101333 |
| UniProt ID | Q9Y697 |
| OMIM ID | 603485 |
| HGNC ID | 7810 |
| Aliases | IscS, NIFS, NifS-like, HUSSY-08 |
Description
NFS1 encodes a cysteine desulfurase that catalyzes the removal of sulfur from L-cysteine to produce L-alanine and elemental sulfur. This sulfur is used for the biosynthesis of iron-sulfur (Fe-S) clusters, which are essential cofactors for numerous proteins involved in electron transport, DNA repair, and metabolic processes. NFS1 functions as a homodimer and interacts with the accessory protein ISD11 (LYRM4) and other scaffold proteins to facilitate Fe-S cluster assembly in mitochondria and the cytosol. Mutations in NFS1 are associated with mitochondrial dysfunction and multiple metabolic disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Mitochondrial complex I deficiency, nuclear type 33 (MC1DN33) | Loss-of-function mutations impair Fe-S cluster assembly, disrupting respiratory chain complex I and other Fe-S proteins. | ClinVar, OMIM #618811 |
| Multiple mitochondrial dysfunctions syndrome 6 (MMDS6) | Defective NFS1 leads to reduced Fe-S cluster biogenesis, causing lactic acidosis, encephalopathy, and early death. | OMIM #618811, PubMed 29159939 |
| Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) | Biallelic NFS1 variants cause severe developmental delay, seizures, and pancreatic insufficiency. | ClinVar, OMIM #603485 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | Medium |
| Heart | 10.8 | Medium |
| Brain | 8.2 | Low |
| Kidney | 9.1 | Low |
| Testis | 7.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 15.3 | High expression in cervical cancer cells |
| HEK293 | 12.1 | Moderate expression in embryonic kidney cells |
| K562 | 9.8 | Moderate expression in leukemia cells |
| HepG2 | 11.4 | Moderate expression in liver cancer cells |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.215G>A (p.Arg72Gln) | Missense | Rare | Reduced cysteine desulfurase activity; associated with MC1DN33 |
| c.382C>T (p.Arg128Trp) | Missense | Rare | Impaired Fe-S cluster assembly; linked to MMDS6 |
| c.1015C>T (p.Arg339Ter) | Nonsense | Rare | Premature truncation; loss of function; severe phenotype |
Mutation functional classification
Loss of Function (LOF)
Most NFS1 disease-associated mutations are loss-of-function, reducing or abolishing cysteine desulfurase activity and Fe-S cluster biogenesis.
Gain of Function (GOF)
No gain-of-function mutations reported in NFS1.
Dominant Negative (DN)
No dominant-negative mutations reported; all pathogenic variants are recessive.
View complete mutation data：
Gene Ontology (GO)
| • cysteine desulfurase activity (GO:0031071) | • iron ion binding (GO:0005506) |
| • mitochondrion (GO:0005739) | • iron-sulfur cluster assembly (GO:0016226) |
| • cytosol (GO:0005829) | • 4 iron (GO:0051539) |
Pathways
• Iron-sulfur cluster assembly (mitochondrial) - Reactome R-HSA-1369007
• Metabolism of amino acids and derivatives - Reactome R-HSA-71291
• Mitochondrial biogenesis - KEGG hsa04122
Protein Summary
NFS1 is a 457-amino acid cysteine desulfurase that localizes primarily to mitochondria. It forms a stable complex with LYRM4 (ISD11) and functions as a sulfur donor for Fe-S cluster assembly on scaffold proteins such as ISCU and NFU1. The enzyme requires pyridoxal phosphate (PLP) as a cofactor. NFS1 is essential for cellular respiration, DNA repair, and iron homeostasis. Structural studies show a homodimeric architecture with a conserved catalytic cysteine residue (Cys381) that forms a persulfide intermediate during sulfur transfer.
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