Affinage

SUMF1

Formylglycine-generating enzyme · UniProt Q8NBK3

Length
374 aa
Mass
40.6 kDa
Annotated
2026-06-10
43 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SUMF1 encodes the formylglycine-generating enzyme (FGE), a post-translational modifier that converts a conserved active-site cysteine to Cα-formylglycine (FGly) in all cellular sulfatases, a modification essential for sulfatase catalytic activity, and which defines a gene family conserved from prokaryotes to eukaryotes (PMID:14563551). Co-expression of SUMF1 strongly enhances sulfatase activity across diverse sulfatase-deficiency contexts, and co-delivery of SUMF1 with individual sulfatases synergistically boosts enzyme activity and corrects disease phenotypes in cell and mouse models, including in the CNS (PMID:15146462, PMID:17206939, PMID:17725987). FGE acts as a copper-dependent enzyme that installs an FGly aldehyde at a sulfatase consensus motif (PMID:31161504). Although it lacks canonical ER retention signals, FGE is largely retained in the ER where it activates nascent sulfatases, with localization and trafficking controlled by sequential physical interactions: PDI couples ER retention to activation, ERGIC-53 promotes ER export (its loss triggers proteasomal degradation of FGE), and ERp44 retrieves secreted FGE to the ER; a fraction of FGE is secreted and taken up paracrinally by distant cells (PMID:18508857). Loss of FGE function causes multiple sulfatase deficiency (MSD): hypomorphic SUMF1 mutations produce ER-localized FGE with variable residual activity, and the combination of residual enzymatic activity and mutant protein stability determines clinical severity, ranging from severe neonatal to milder forms (PMID:17657823, PMID:18157819, PMID:21224894). Beyond its conserved enzymatic role, sumf1 acts as a developmental timer of convergence-extension morphogenesis in zebrafish through the extracellular heparan-sulfate sulfatase Sulf1 [PMID:bio_10.1101_2025.10.09.681375].

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 High

    Established the molecular identity and enzymatic function of SUMF1, answering what gene product is responsible for the universal FGly modification required for sulfatase activity.

    Evidence Gene family bioinformatic analysis combined with biochemistry of FGly modification and MSD disease gene identification

    PMID:14563551

    Open questions at the time
    • Catalytic mechanism and cofactor requirement not yet defined
    • Subcellular site of modification not yet established
  2. 2004 High

    Demonstrated that SUMF1 enhances sulfatase activity in cells and that disease-associated missense mutations differentially impair this enhancing function, linking specific residues to enzyme competence.

    Evidence Expression of 11 SUMF1 missense mutants in COS-7 cells with sulfatase activity assays across 20 patients

    PMID:15146462

    Open questions at the time
    • Did not distinguish loss of stability from loss of catalysis
    • No structural basis for mutation effects
  3. 2007 High

    Showed that SUMF1 co-delivery synergistically enhances multiple distinct sulfatases in patient cells and rescues lysosomal storage phenotypes in vivo, including the CNS, establishing therapeutic relevance of co-expression.

    Evidence AAV/lentiviral co-delivery of SUMF1 with sulfatases in patient cells and MPS-IIIA mouse muscle and brain; GAG/sulfolipid clearance and activity assays

    PMID:17206939 PMID:17725987

    Open questions at the time
    • Mechanism of synergy at the molecular level not dissected
    • Optimal stoichiometry of FGE to sulfatase undefined
  4. 2007 High

    Defined MSD as a hypomorphic disorder by showing disease mutants retain correct ER localization and partial activity, reframing severity as a function of residual function rather than complete loss.

    Evidence Viral overexpression of four SUMF1 mutants in Sumf1-/- MEFs with stability, localization, and rescue assays

    PMID:17657823

    Open questions at the time
    • Did not separate contributions of stability versus intrinsic catalytic defect for all mutants
  5. 2008 High

    Resolved how FGE is retained in the ER despite lacking canonical signals, identifying a tripartite interactome (PDI, ERGIC-53, ERp44) that couples retention, export, retrieval, and paracrine secretion.

    Evidence Reciprocal Co-IP, RNAi silencing, secretion and proteasome inhibition assays, subcellular fractionation

    PMID:18508857

    Open questions at the time
    • Functional consequence of paracrine FGE uptake for sulfatase activation in recipient cells not quantified
    • Sequence determinants of each interaction not mapped
  6. 2008 High

    Established that MSD clinical phenotype reflects both residual enzymatic activity and protein stability, by showing localization-competent mutants vary independently in activity and stability.

    Evidence Localization, FGE-specific activity, and stability assays of four mutants in MSD patient fibroblasts

    PMID:18157819 PMID:21224894

    Open questions at the time
    • Quantitative genotype-phenotype prediction model not derived
  7. 2019 Medium

    Confirmed FGE is a copper-dependent enzyme and that the FGly aldehyde it generates can be exploited as a bioconjugation handle, extending mechanistic understanding to cofactor dependence and reactive chemistry.

    Evidence Site-specific labeling assay in mammalian expression systems for antibody-drug conjugate production

    PMID:31161504

    Open questions at the time
    • Role of copper in cellular FGE activation not addressed in vivo
    • Methods-focused, not a mechanistic structural study
  8. 2020 Medium

    Extended the activity-stability model with additional variants, including a highly unstable, catalytically dead mutant producing the most severe neonatal phenotype and a partly-retained variant with reduced activity.

    Evidence Cell-culture expression, localization, stability, and activity assays of FGE-E113K and A348V variants

    PMID:28566233 PMID:32048457

    Open questions at the time
    • Single-lab variant characterizations without in vivo confirmation
    • Structural rationale only partially modeled
  9. 2022 Medium

    Validated the residual-function model in vivo by generating patient-variant knock-in mice that show partial reduction of sulfatase activities, confirming hypomorphic behavior of specific alleles.

    Evidence Knock-in mouse lines with biochemical sulfatase activity measurement and histopathology

    PMID:36433920

    Open questions at the time
    • Tissue-specific differences in residual activity not fully mapped
    • Genotype-phenotype correlation across alleles incomplete
  10. 2025 Medium

    Revealed a developmental role beyond housekeeping sulfatase activation, with sumf1/sumf2 acting as opposing temporal regulators of convergence-extension morphogenesis via the extracellular sulfatase Sulf1.

    Evidence Zebrafish explants, mRNA overexpression, loss-of-function, and HSPG sulfation manipulation (preprint)

    PMID:bio_10.1101_2025.10.09.681375

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Whether this developmental timing role is conserved in mammals unknown
    • Molecular basis of sumf1/sumf2 expression inversion not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural and catalytic determinants linking specific copper-coordination and FGE-substrate recognition to graded residual activity in MSD remain incompletely defined.
  • No high-resolution mechanism connecting cofactor handling to mutant activity loss
  • Predictive activity-stability-to-severity framework not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016491 oxidoreductase activity 1
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2
Partners
ERGIC-53ERP44PDI

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 SUMF1 encodes the Cα-formylglycine (FGly)-generating enzyme (FGE) that post-translationally converts a conserved cysteine residue to FGly in the active sites of all sulfatases, and this modification is essential for sulfatase catalytic activity. SUMF1 defines a new gene family conserved from prokaryotes to eukaryotes, with vertebrate genomes also containing a paralog SUMF2. Gene family bioinformatic analysis combined with established biochemistry of FGly modification; functional context from identification of the MSD disease gene Gene High 14563551
2004 SUMF1 strongly enhances the activity of sulfatases when co-expressed in cells. Eleven missense mutations (p.R349W, p.R224W, p.L20F, p.A348P, p.S155P, p.C218Y, p.N259I, p.A279V, p.R349Q, p.C336R, p.A177P) resulted in severely impaired sulfatase-enhancing activity, while two mutations (p.R345C, p.P266L) showed high residual activity on some but not all sulfatases tested. Expression of SUMF1 missense mutants in COS-7 cells with functional sulfatase activity assays Human mutation High 15146462
2007 SUMF1 exhibits an enhancing effect on sulfatase activity when co-expressed with sulfatases in multiple disease cell types (MLD, CDPX, MPS II, IIIA, and VI). In vivo, AAV-mediated co-delivery of SUMF1 with sulfamidase in muscle of MPS-IIIA mice resulted in more efficient rescue of the phenotype compared to sulfamidase alone. AAV and lentiviral vector co-delivery in patient-derived cells and mouse models; sulfatase activity assays; GAG/sulfolipid clearance measurements The Biochemical journal High 17206939
2007 Co-delivery of SUMF1 and SGSH via AAV2/5 to the CNS results in a synergistic increase in SGSH (sulfamidase) activity in primary neural cells and murine brain, demonstrating SUMF1's enhancing function on sulfatase activity in the central nervous system. AAV2/5-CMV-SGSH-IRES-SUMF1 vector delivery in primary neural cells and intraventricular injection in neonatal MPS-IIIA mice; SGSH activity assays; lysosomal storage and inflammatory marker analysis Human molecular genetics High 17725987
2007 MSD is caused by hypomorphic SUMF1 mutations: four FGE mutants (p.S155P, p.R224W, p.R345C, p.R349W) expressed in Sumf1 KO mouse embryonic fibroblasts produced stable proteins of appropriate molecular weight that localized correctly to the ER, and each partially rescued sulfatase activities, indicating residual enzymatic function. Viral-mediated over-expression of SUMF1 mutants in Sumf1-/- MEFs; Western blot for protein stability; ER localization; sulfatase activity assays Human mutation High 17657823
2008 SUMF1 is largely retained in the endoplasmic reticulum (ER) despite lacking canonical retention/retrieval signals, where it activates nascent sulfatases. SUMF1 physically interacts with PDI, ERp44, and ERGIC-53. PDI couples SUMF1 retention and activation in the ER; ERGIC-53 favors SUMF1 export from the ER (silencing ERGIC-53 causes proteasomal degradation of SUMF1); ERp44 retrieves SUMF1 to the ER (down-regulating ERp44 promotes SUMF1 secretion). Part of SUMF1 is secreted and paracrinally taken up by distant cells. Co-immunoprecipitation; RNAi silencing; functional secretion assays; subcellular fractionation and localization; proteasome inhibition experiments Human molecular genetics High 18508857
2008 SUMF1 missense mutations p.A177P, p.W179S, p.A279V, and p.R349W do not affect ER localization of FGE in MSD fibroblasts but differentially affect enzymatic activity (p.A177P and p.R349W: <1%; p.W179S: ~3%; p.A279V: ~23%) and protein stability. Both residual enzyme activity and protein stability of FGE mutants contribute to MSD clinical phenotype. Subcellular localization studies in MSD patient fibroblasts; FGE-specific enzymatic activity assays; Western blot for protein stability assessment Human mutation High 18157819
2011 Both residual FGE enzymatic activity and FGE protein stability are required for MSD phenotypic outcome. Nonsense mutations causing near-total loss of FGE activity and highly unstable protein produce severe neonatal phenotype; missense mutation G263V causes unstable protein but high residual FGE activity and a mild phenotype. FGE expression analysis, localization, stability (Western blot), and enzymatic activity assays in patient-derived cells from 10 MSD patients European journal of human genetics : EJHG High 21224894
2019 FGE (SUMF1-encoded protein) is a copper-dependent post-translational modifier that generates formylglycine (fGly) in the active sites of sulfatases. The fGly aldehyde can serve as a reactive handle for chemical bioconjugation when a sulfatase-consensus sequence is engineered into target proteins. Site-specific labeling assay using FGE in mammalian expression systems; antibody-drug conjugate production Methods in molecular biology (Clifton, N.J.) Medium 31161504
2017 Novel SUMF1 variant FGE-E113K correctly localizes to the ER but is retained intracellularly (unlike wild-type FGE) and exhibits only ~15% of wild-type FGE activity in cell culture assays activating steroid sulfatase. Cell culture expression of FGE-E113K; ER localization by immunofluorescence; FGE activity assay on steroid sulfatase in immortalized MSD cells; crystal structure-based structural modeling Molecular genetics and metabolism Medium 28566233
2020 Novel SUMF1 variant A348V produces a formylglycine-generating enzyme (FGE) that is highly unstable and lacks catalytic function, resulting in the most severe (neonatal) MSD phenotype. Expression of SUMF1-A348V in cell culture; protein stability and catalytic activity assays Molecular genetics & genomic medicine Medium 32048457
2022 Knock-in mice carrying patient-derived hypomorphic SUMF1 variants p.Ser153Pro and p.Ala277Val show partial reduction of sulfatase activities, confirming these variants produce residual but reduced FGE function in vivo. Genetic engineering of knock-in mouse lines; biochemical measurement of sulfatase activities; histopathological analysis Journal of inherited metabolic disease Medium 36433920
2025 In zebrafish, sumf1 and sumf2 encode positive and negative regulators of sulfatase activity respectively; their expression levels invert at gastrulation onset. Overexpressing sumf1 delays convergence and extension (C&E) onset, while loss of sumf1 function causes precocious C&E. The extracellular sulfatase Sulf1 (which modifies heparan sulfate proteoglycans) is identified as the key effector downstream of sumf1/sumf2 in timing C&E morphogenesis. Zebrafish embryonic explants; mRNA overexpression; morpholino/genetic loss-of-function; C&E timing assays; HSPG sulfation manipulation bioRxivpreprint Medium bio_10.1101_2025.10.09.681375

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Human gene therapy 208 24524415
2007 Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes. Human molecular genetics 104 17725987
2007 SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies. The Biochemical journal 66 17206939
2008 Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44. Human molecular genetics 59 18508857
2004 Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Human mutation 59 15146462
2003 The human SUMF1 gene, required for posttranslational sulfatase modification, defines a new gene family which is conserved from pro- to eukaryotes. Gene 59 14563551
2011 SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. European journal of human genetics : EJHG 52 21224894
2008 Molecular analysis of SUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency. Human mutation 35 18157819
2007 Multiple sulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene. Human mutation 35 17657823
2015 Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency. Orphanet journal of rare diseases 29 25885655
2008 Effect of elongation factor 1alpha promoter and SUMF1 over in vitro expression of N-acetylgalactosamine-6-sulfate sulfatase. Molecular biology reports 26 18989752
2017 Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease. Respiratory research 10 28464818
2019 Scientific Opinion on Flavouring Group Evaluation 210 Revision 3 (FGE.210Rev3): Consideration of genotoxic potential for α,β-unsaturated alicyclic ketones and precursors from chemical subgroup 2.4 of FGE.19. EFSA journal. European Food Safety Authority 9 32626305
2018 Scientific Opinion on Flavouring Group Evaluation 201 Revision 2 (FGE.201Rev2): 2-alkylated, aliphatic, acyclic alpha,beta-unsaturated aldehydes and precursors, with or without additional double-bonds, from chemical subgroup 1.1.2 of FGE.19. EFSA journal. European Food Safety Authority 9 32625708
2017 Expanding the genetic cause of multiple sulfatase deficiency: A novel SUMF1 variant in a patient displaying a severe late infantile form of the disease. Molecular genetics and metabolism 9 28566233
2018 Integrative expression analysis identifies a novel interplay between CFTR and linc-SUMF1-2 that involves CF-associated gene dysregulation. Biochemical and biophysical research communications 8 30598261
2018 Scientific Opinion on Flavouring Group Evaluation 203, Revision 2 (FGE.203Rev2): α,β-unsaturated aliphatic aldehydes and precursors from chemical subgroup 1.1.4 of FGE.19 with two or more conjugated double-bonds and with or without additional non-conjugated double-bonds. EFSA journal. European Food Safety Authority 8 32625963
2017 Scientific Opinion on Flavouring Group Evaluation 226 Revision 1 (FGE.226Rev1): consideration of genotoxicity data on one α,β-unsaturated aldehyde from chemical subgroup 1.1.1(b) of FGE.19. EFSA journal. European Food Safety Authority 7 32625501
2023 Flavouring Group Evaluation 21 Revision 6 (FGE.21Rev6): thiazoles, thiophenes, thiazoline and thienyl derivatives from chemical groups 29 and 30. EFSA journal. European Food Safety Authority 6 36794062
2022 New mouse models with hypomorphic SUMF1 variants mimic attenuated forms of multiple sulfatase deficiency. Journal of inherited metabolic disease 6 36433920
2020 Detection of 2,4-dichlorophenoxyacetic acid herbicide using a FGE-sulfatase based whole-cell Agrobacterium biosensor. Journal of microbiological methods 6 32645339
2017 Scientific Opinion of Flavouring Group Evaluation 410 (FGE.410): 4',5,7-trihydroxyflavanone from chemical group 25 (phenol derivatives containing ring-alkyl, ring-alkoxy, and side-chains with an oxygenated functional group). EFSA journal. European Food Safety Authority 6 32625330
2019 Scientific Opinion on Flavouring Group Evaluation 208 Revision 3 (FGE.208Rev3): consideration of genotoxicity data on alicyclic aldehydes with α,β-unsaturation in ring/side-chain and precursors from chemical subgroup 2.2 of FGE.19. EFSA journal. European Food Safety Authority 5 32626109
2019 Scientific Opinion on Flavouring Group Evaluation 204 Revision 1 (FGE.204Rev1): consideration of genotoxicity data on representatives for 17 monounsaturated, aliphatic, α,β-unsaturated ketones and precursors from chemical subgroup 1.2.1 of FGE.19. EFSA journal. European Food Safety Authority 5 32626370
2014 Molecular evaluation of a novel missense mutation & an insertional truncating mutation in SUMF1 gene. The Indian journal of medical research 5 25222778
2023 Late infantile form of multiple sulfatase deficiency with a novel missense variant in the SUMF1 gene: case report and review. BMC pediatrics 4 36959582
2019 Site-Specific Labeling of Proteins Using the Formylglycine-Generating Enzyme (FGE). Methods in molecular biology (Clifton, N.J.) 4 31161504
2024 Flavouring group evaluation 419 (FGE.419): 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one. EFSA journal. European Food Safety Authority 3 38711805
2023 Flavouring Group Evaluation 217 Revision 3 (FGE.217Rev3): consideration of genotoxic potential for α,β-unsaturated ketones and precursors from chemical subgroup 4.1 of FGE.19: lactones. EFSA journal. European Food Safety Authority 3 37089172
2022 Scientific opinion on Flavouring group evaluation 216 revision 2 (FGE.216Rev2): consideration of the genotoxicity potential of α,β-unsaturated 2-phenyl-2-alkenals from subgroup 3.3 of FGE.19. EFSA journal. European Food Safety Authority 3 35991962
2020 A homozygous missense variant of SUMF1 in the Bedouin population extends the clinical spectrum in ultrarare neonatal multiple sulfatase deficiency. Molecular genetics & genomic medicine 3 32048457
2024 Non-syndromic retinal dystrophy associated with biallelic variation of SUMF1 and reduced leukocyte sulfatase activity. Clinical genetics 2 38863195
2025 Preclinical use of a clinically-relevant scAAV9/SUMF1 vector for the treatment of multiple sulfatase deficiency. Communications medicine 1 39870870
2025 Structure of the T9SS PorKN ring complex reveals conformational plasticity based on the repurposed FGE fold. mBio 1 40772760
2024 SUMF1 overexpression promotes tumorous cell growth and migration and is correlated with the immune status of patients with glioma. Aging 1 38460946
2023 Association between SUMF1 polymorphisms and COVID-19 severity. BMC genomic data 1 37344788
2022 Scientific opinion on flavouring group evaluation 415 (FGE.415): (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide. EFSA journal. European Food Safety Authority 1 35814922
2022 Genetic analysis of a novel SUMF1 variation associated with a late infantile form of multiple sulfatase deficiency. Journal of clinical laboratory analysis 1 36441600
2025 Flavouring group evaluation 418 (FGE. 418): 3-[3-(2-isopropyl-5-methyl-cyclohexyl)-ureido]-butyric acid ethyl ester. EFSA journal. European Food Safety Authority 0 39896350
2025 SUMF1 Common Variant rs793391 Is Associated with Response to Inhaled Corticosteroids in Patients with COPD. International journal of molecular sciences 0 41155512
2021 Family-based gene-environment interaction using sequence kernel association test (FGE-SKAT) for complex quantitative traits. Scientific reports 0 33795796
2015 Scientific Opinion on Flavouring Group Evaluation 208 Revision 1 (FGE.208Rev1): Consideration of genotoxicity data on representatives for 10 alicyclic aldehydes with the α,β-unsaturation in ring / side-chain and precursors from chemical subgroup 2.2 of FGE.19. EFSA journal. European Food Safety Authority 0 42109808
2012 Scientific Opinion on Flavouring Group Evaluation 226 (FGE.226): Consideration of genotoxicity data on one α,β-unsaturated aldehyde from chemical subgroup 1.1.1(b) of FGE.19 by EFSA. EFSA journal. European Food Safety Authority 0 42016130

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