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Gene Review

SUMF1  -  sulfatase modifying factor 1

Homo sapiens

Synonyms: AAPA3037, C-alpha-formylglycine-generating enzyme 1, FGE, PSEC0152, Sulfatase-modifying factor 1, ...
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Disease relevance of SUMF1

  • The genomes of E. coli, S. cerevisiae and C. elegans lack SUMF1, indicating a phylogenetic gap and the existence of an alternative FGly-generating system [1].
  • Recently, the human C(alpha)-formylglycine (FGly)-generating enzyme (FGE), whose deficiency causes the autosomal-recessively transmitted lysosomal storage disease multiple sulfatase deficiency (MSD), has been identified [1].

High impact information on SUMF1

  • In higher eukaryotes, FGly is generated from a cysteine precursor by the FGly-generating enzyme (FGE) [2].
  • The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD [2].
  • The structures allow formulation of a novel oxygenase mechanism whereby FGE utilizes molecular oxygen to generate FGly via a cysteine sulfenic acid intermediate [2].
  • FGE is localized in the endoplasmic reticulum and is predicted to have a tripartite domain structure [3].
  • In patient fibroblasts, the activity of sulfatases is partially restored by transduction of FGE encoding cDNA, but not by cDNA carrying an MSD mutation [3].

Biological context of SUMF1

  • In several prokaryotic genomes, the SUMF1 gene is cotranscribed with genes encoding sulfatases which require FGly modification [1].
  • In sulfatases, FGE posttranslationally converts a cysteine residue to FGly, which is part of the catalytic site and is essential for sulfatase activity [1].
  • Several human inherited diseases are caused by the deficiency of individual sulfatases, while in patients with multiple sulfatase deficiency mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene cause a defect in the post-translational modification of a cysteine residue into C(alpha)-formylglycine (FGly) at the active site of all sulfatases [4].
  • Moreover, we demonstrate that the SUMF1-enhancing effect is also present in vivo after AAV-mediated delivery of the sulfamidase gene to the muscle of MPSIIIA mice, resulting in a more efficient rescue of the phenotype [5].
  • The previously determined FGE crystal structure revealed two crucial cysteine residues in the active site, one of which was thought to be implicated in substrate binding [6].

Anatomical context of SUMF1


Associations of SUMF1 with chemical compounds

  • Intracellular FGE contains a high mannose type N-glycan, which is processed to the complex type in secreted FGE [9].
  • The formylglycine (FGly)-generating enzyme (FGE) uses molecular oxygen to oxidize a conserved cysteine residue in all eukaryotic sulfatases to the catalytically active FGly [6].
  • Sulfatases degrade and remodel sulfate esters, and inactivity of FGE results in multiple sulfatase deficiency, a fatal disease [6].

Other interactions of SUMF1

  • SUMF2 evolved from a single exon SUMF1 gene as found in diptera prior to divergent intron acquisition [1].
  • Two (p.R345C and p.P266L) showed a high residual activity on some, but not all, of the nine sulfatases tested, suggesting that some SUMF1 mutations may have variable effects on the activity of each sulfatase [8].
  • Mutations in the SUMF1 gene cause MSD (multiple sulfatase deficiency), an autosomal recessive disease in which the activities of all sulfatases are profoundly reduced [5].

Analytical, diagnostic and therapeutic context of SUMF1

  • These results indicate that co-delivery of SUMF1 may enhance the efficacy of gene therapy in several sulfatase deficiencies [5].


  1. The human SUMF1 gene, required for posttranslational sulfatase modification, defines a new gene family which is conserved from pro- to eukaryotes. Landgrebe, J., Dierks, T., Schmidt, B., von Figura, K. Gene (2003) [Pubmed]
  2. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. Dierks, T., Dickmanns, A., Preusser-Kunze, A., Schmidt, B., Mariappan, M., von Figura, K., Ficner, R., Rudolph, M.G. Cell (2005) [Pubmed]
  3. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme. Dierks, T., Schmidt, B., Borissenko, L.V., Peng, J., Preusser, A., Mariappan, M., von Figura, K. Cell (2003) [Pubmed]
  4. Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship. Sardiello, M., Annunziata, I., Roma, G., Ballabio, A. Hum. Mol. Genet. (2005) [Pubmed]
  5. SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies. Fraldi, A., Biffi, A., Lombardi, A., Visigalli, I., Pepe, S., Settembre, C., Nusco, E., Auricchio, A., Naldini, L., Ballabio, A., Cosma, M.P. Biochem. J. (2007) [Pubmed]
  6. A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Roeser, D., Preusser-Kunze, A., Schmidt, B., Gasow, K., Wittmann, J.G., Dierks, T., von Figura, K., Rudolph, M.G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Sulphatase activities are regulated by the interaction of sulphatase-modifying factor 1 with SUMF2. Zito, E., Fraldi, A., Pepe, S., Annunziata, I., Kobinger, G., Di Natale, P., Ballabio, A., Cosma, M.P. EMBO Rep. (2005) [Pubmed]
  8. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Cosma, M.P., Pepe, S., Parenti, G., Settembre, C., Annunziata, I., Wade-Martins, R., Di Domenico, C., Di Natale, P., Mankad, A., Cox, B., Uziel, G., Mancini, G.M., Zammarchi, E., Donati, M.A., Kleijer, W.J., Filocamo, M., Carrozzo, R., Carella, M., Ballabio, A. Hum. Mutat. (2004) [Pubmed]
  9. Molecular characterization of the human Calpha-formylglycine-generating enzyme. Preusser-Kunze, A., Mariappan, M., Schmidt, B., Gande, S.L., Mutenda, K., Wenzel, D., von Figura, K., Dierks, T. J. Biol. Chem. (2005) [Pubmed]
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