Reviewed, UniProtKB/Swiss-Prot Q8NBK3 (SUMF1_HUMAN)

Names and origin

Protein names

Recommended name:
    Sulfatase-modifying factor 1
    EC=1.8.99.-
Alternative name(s):
    C-alpha-formylglycine-generating enzyme 1

Gene names

Name:	SUMF1
Synonyms:	FGE
ORF Names:	PSEC0152, UNQ3037/PRO9852

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	374 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Using molecular oxygen and an unidentified reducing agent, oxidizes a cysteine residue in the substrate sulfatase to an active site 3-oxoalanine residue, which is also called C(alpha)-formylglycine. Known substrates include GALNS, ARSA, STS and ARSE.
Catalytic activity	[sulfatase]-cysteine + acceptor = [sulfatase]-3-oxoalanine + reduced acceptor.
Pathway	Protein modification; sulfatase oxidation.
Subunit structure	Monomer, homodimer and heterodimer with SUMF2.
Subcellular location	Endoplasmic reticulum lumen.
Tissue specificity	Ubiquitous. Highly expressed in kidney, pancreas and liver. Detected at lower levels in leukocytes, lung, placenta, small intestine, skeletal muscle and heart.
Post-translational modification	N-glycosylated. Contains high-mannose-type oligosaccharides.
Involvement in disease	Defects in SUMF1 are the cause of multiple sulfatase deficiency (MSD) [MIM:272200]. MSD is a clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. Inheritance is autosomal recessive.
Miscellaneous	The resulting 3-oxoalanine in the substrate protein is called C(alpha)-formylglycine by many authors. It should not be confused with N-formylglycine.
Sequence similarities	Belongs to the sulfatase-modifying factor family.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Ichthyosis Metachromatic leukodystrophy Mucopolysaccharidosis
Domain	Redox-active center Signal
Ligand	Calcium Metal-binding
Molecular function	Oxidoreductase
PTM	Glycoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Cellular component	endoplasmic reticulum lumen Inferred from electronic annotation. Source: UniProtKB-SubCell
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q8NBK3-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q8NBK3-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-90: Missing.

Notes: No experimental confirmation available.

Isoform 3 (identifier: Q8NBK3-3)

The sequence of this isoform differs from the canonical sequence as follows:
     340-374: YCYRYRCAARSQNTPDSSASNLGFRCAADRLPTMD → QEYYDPYFQD...QHGPRLHCVD

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Signal peptide

1 – 33

33

Chain

34 – 374

341

Sulfatase-modifying factor 1

Regions

Region

341 – 360

20

Interaction with sulfatases

Sites

Active site

333

1

Proton acceptor Probable

Metal binding

130

1

Calcium 2

Metal binding

259

1

Calcium 1

Metal binding

260

1

Calcium 1; via carbonyl oxygen

Metal binding

273

1

Calcium 1

Metal binding

275

1

Calcium 1; via carbonyl oxygen

Metal binding

293

1

Calcium 2; via carbonyl oxygen

Metal binding

296

1

Calcium 2; via carbonyl oxygen

Metal binding

298

1

Calcium 2; via carbonyl oxygen

Metal binding

300

1

Calcium 2

Amino acid modifications

Glycosylation

141

1

N-linked (GlcNAc...)

Disulfide bond

50 ↔ 52

Disulfide bond

218 ↔ 365

Disulfide bond

235 ↔ 346

Disulfide bond

336 ↔ 341

Redox-active

Natural variations

Alternative sequence

1 – 90

90

Missing in isoform 2.

Alternative sequence

340 – 374

35

YCYRY…LPTMD → QEYYDPYFQDVASEMLRRHT ASRWKAFSSLEPCCSIRRHQ QYAAIERLTCGKFELRCASL RKIDCLNTNIACSYSMRQHG PRLHCVD in isoform 3.

Natural variant

20

1

L → F in MSD; loss of activity.

Natural variant

63

1

S → N: dbSNP rs2819590.

Natural variant

155

1

S → P in MSD; loss of activity.

Natural variant

177

1

A → P in MSD; loss of activity; decreases its specific enzyme activity to less than 1%; does not affect localization of the protein in the endoplasmic reticulum of MSD fibroblasts; protein stability is almost comparable to wild-type.

Natural variant

179

1

W → S in MSD; decreases its specific enzyme activity to less than 3%; does not affect localization of the protein in the endoplasmic reticulum of MSD fibroblasts; protein stability is almost comparable to wild-type.

Natural variant

218

1

C → Y in MSD; loss of activity.

Natural variant

224

1

R → W in MSD; loss of activity.

Natural variant

259

1

N → I in MSD; loss of activity.

Natural variant

266

1

P → L in MSD; retains some activity.

Natural variant

279

1

A → V in MSD; loss of activity; decreases its specific enzyme activity to about 23%; does not affect localization of the protein in the endoplasmic reticulum of MSD fibroblasts; protein stability is decreased.

Natural variant

336

1

C → R in MSD; loss of activity.

Natural variant

345

1

R → C in MSD; retains some activity.

Natural variant

348

1

A → P in MSD; loss of activity.

Natural variant

349

1

R → Q in MSD; loss of activity.

Natural variant

349

1

R → W in MSD; loss of activity; decreases its specific enzyme activity to less than 1%; does not affect localization of the protein in the endoplasmic reticulum of MSD fibroblasts; protein stability is severely decreased.

Experimental info

Mutagenesis

333

1

S → A: Loss of activity

Mutagenesis

333

1

S → T: Reduces activity by 99%

Mutagenesis

336

1

C → S: Loss of activity

Mutagenesis

337

1

H → A: Reduces activity 5-fold

Mutagenesis

340

1

Y → F: No effect

Mutagenesis

341

1

C → S: Loss of activity

Sequence conflict

124

1

F → L in BAC11634. Ref.5

Sequence conflict

264

1

E → D in BAC11634. Ref.5

Secondary structure

1

.

.

.

.

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.

.

.

.

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.

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.

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374

Helix Strand Turn

Details...

Beta strand

91 – 94

4

Beta strand

97 – 102

6

Helix

109 – 111

3

Beta strand

117 – 121

5

Beta strand

124 – 129

6

Helix

133 – 143

11

Helix

148 – 152

5

Beta strand

154 – 158

5

Helix

159 – 161

3

Beta strand

180 – 184

5

Helix

211 – 220

10

Helix

228 – 236

9

Helix

252 – 254

3

Turn

265 – 267

3

Beta strand

293 – 305

13

Beta strand

315 – 317

3

Beta strand

325 – 331

7

Turn

338 – 340

3

Beta strand

350 – 352

3

Beta strand

366 – 369

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 29, 2005. Version 3. Checksum: E64F2DF004C8CEA3	FASTA	374	40,556
	10 20 30 40 50 60 MAAPALGLVC GRCPELGLVL LLLLLSLLCG AAGSQEAGTG AGAGSLAGSC GCGTPQRPGA 70 80 90 100 110 120 HGSSAAAHRY SREANAPGPV PGERQLAHSK MVPIPAGVFT MGTDDPQIKQ DGEAPARRVT 130 140 150 160 170 180 IDAFYMDAYE VSNTEFEKFV NSTGYLTEAE KFGDSFVFEG MLSEQVKTNI QQAVAAAPWW 190 200 210 220 230 240 LPVKGANWRH PEGPDSTILH RPDHPVLHVS WNDAVAYCTW AGKRLPTEAE WEYSCRGGLH 250 260 270 280 290 300 NRLFPWGNKL QPKGQHYANI WQGEFPVTNT GEDGFQGTAP VDAFPPNGYG LYNIVGNAWE 310 320 330 340 350 360 WTSDWWTVHH SVEETLNPKG PPSGKDRVKK GGSYMCHRSY CYRYRCAARS QNTPDSSASN 370 LGFRCAADRL PTMD
	Isoform 2 [UniParc]. Checksum: E616A28A77F81996		284	31,900
	10 20 30 40 50 60 MVPIPAGVFT MGTDDPQIKQ DGEAPARRVT IDAFYMDAYE VSNTEFEKFV NSTGYLTEAE 70 80 90 100 110 120 KFGDSFVFEG MLSEQVKTNI QQAVAAAPWW LPVKGANWRH PEGPDSTILH RPDHPVLHVS 130 140 150 160 170 180 WNDAVAYCTW AGKRLPTEAE WEYSCRGGLH NRLFPWGNKL QPKGQHYANI WQGEFPVTNT 190 200 210 220 230 240 GEDGFQGTAP VDAFPPNGYG LYNIVGNAWE WTSDWWTVHH SVEETLNPKG PPSGKDRVKK 250 260 270 280 GGSYMCHRSY CYRYRCAARS QNTPDSSASN LGFRCAADRL PTMD
	Isoform 3 [UniParc]. Checksum: 957E7E1E13D034A6		426	46,857
	10 20 30 40 50 60 MAAPALGLVC GRCPELGLVL LLLLLSLLCG AAGSQEAGTG AGAGSLAGSC GCGTPQRPGA 70 80 90 100 110 120 HGSSAAAHRY SREANAPGPV PGERQLAHSK MVPIPAGVFT MGTDDPQIKQ DGEAPARRVT 130 140 150 160 170 180 IDAFYMDAYE VSNTEFEKFV NSTGYLTEAE KFGDSFVFEG MLSEQVKTNI QQAVAAAPWW 190 200 210 220 230 240 LPVKGANWRH PEGPDSTILH RPDHPVLHVS WNDAVAYCTW AGKRLPTEAE WEYSCRGGLH 250 260 270 280 290 300 NRLFPWGNKL QPKGQHYANI WQGEFPVTNT GEDGFQGTAP VDAFPPNGYG LYNIVGNAWE 310 320 330 340 350 360 WTSDWWTVHH SVEETLNPKG PPSGKDRVKK GGSYMCHRSQ EYYDPYFQDV ASEMLRRHTA 370 380 390 400 410 420 SRWKAFSSLE PCCSIRRHQQ YAAIERLTCG KFELRCASLR KIDCLNTNIA CSYSMRQHGP RLHCVD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Multiple sulfatase deficiency is caused by mutations in the gene encoding the Homo sapiens C-alpha-formyglycine-generating enzyme." Dierks T., Schmidt B., Borissenko L.V., Peng J., Preusser A., Mariappan M., von Figura K. Cell 113:435-444(2003) [PubMed: 12757705] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS MSD VAL-279; ARG-336; GLN-349 AND TRP-349, VARIANT ASN-63.
[2]	"The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases." Cosma M.P., Pepe S., Annunziata I., Newbold R.F., Grompe M., Parenti G., Ballabio A. Cell 113:445-456(2003) [PubMed: 12757706] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS MSD PRO-155; TYR-218; ARG-336; CYS-345; PRO-348; GLN-349 AND TRP-349, FUNCTION.
[3]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed: 12975309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), VARIANT ASN-63.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A.,