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

• We present evidence that SUMF2 colocalizes with SUMF1 within the endoplasmic reticulum and that the two proteins form heterodimers [7].
• SUMF1 strongly enhances the activity of sulfatases when coexpressed with sulfatase in Cos-7 cells [8].

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].

References