1y1g

Human formylglycine generating enzyme, double sulfonic acid formHuman formylglycine generating enzyme, double sulfonic acid form

Structural highlights

1y1g is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.67Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SUMF1_HUMAN 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.^[1] ^[2] ^[3] ^[4]

Function

SUMF1_HUMAN 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.^[5] ^[6]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Sulfatases are enzymes essential for degradation and remodeling of sulfate esters. Formylglycine (FGly), the key catalytic residue in the active site, is unique to sulfatases. In higher eukaryotes, FGly is generated from a cysteine precursor by the FGly-generating enzyme (FGE). Inactivity of FGE results in multiple sulfatase deficiency (MSD), a fatal autosomal recessive syndrome. Based on the crystal structure, we report that FGE is a single-domain monomer with a surprising paucity of secondary structure and adopts a unique fold. The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD. The catalytic mechanism of FGly generation was elucidated by six high-resolution structures of FGE in different redox environments. The structures allow formulation of a novel oxygenase mechanism whereby FGE utilizes molecular oxygen to generate FGly via a cysteine sulfenic acid intermediate.

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 MG Cell. 2005 May 20;121(4):541-52. PMID:15907468^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell. 2003 May 16;113(4):445-56. PMID:12757706
↑ Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, von Figura K. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme. Cell. 2003 May 16;113(4):435-44. PMID:12757705
↑ Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R, Di Domenico C, Di Natale P, Mankad A, Cox B, Uziel G, Mancini GM, Zammarchi E, Donati MA, Kleijer WJ, Filocamo M, Carrozzo R, Carella M, Ballabio A. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mutat. 2004 Jun;23(6):576-81. PMID:15146462 doi:10.1002/humu.20040
↑ Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gartner J. Molecular analysis of SUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency. Hum Mutat. 2008 Jan;29(1):205. PMID:18157819 doi:10.1002/humu.9515
↑ Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell. 2003 May 16;113(4):445-56. PMID:12757706
↑ Preusser-Kunze A, Mariappan M, Schmidt B, Gande SL, Mutenda K, Wenzel D, von Figura K, Dierks T. Molecular characterization of the human Calpha-formylglycine-generating enzyme. J Biol Chem. 2005 Apr 15;280(15):14900-10. Epub 2005 Jan 18. PMID:15657036 doi:M413383200
↑ Dierks T, Dickmanns A, Preusser-Kunze A, Schmidt B, Mariappan M, von Figura K, Ficner R, Rudolph MG. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. Cell. 2005 May 20;121(4):541-52. PMID:15907468 doi:http://dx.doi.org/10.1016/j.cell.2005.03.001

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OCA

[1] Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell. 2003 May 16;113(4):445-56. PMID:12757706

[2] Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, von Figura K. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme. Cell. 2003 May 16;113(4):435-44. PMID:12757705

[3] Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R, Di Domenico C, Di Natale P, Mankad A, Cox B, Uziel G, Mancini GM, Zammarchi E, Donati MA, Kleijer WJ, Filocamo M, Carrozzo R, Carella M, Ballabio A. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mutat. 2004 Jun;23(6):576-81. PMID:15146462 doi:10.1002/humu.20040

[4] Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gartner J. Molecular analysis of SUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency. Hum Mutat. 2008 Jan;29(1):205. PMID:18157819 doi:10.1002/humu.9515

[5] Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell. 2003 May 16;113(4):445-56. PMID:12757706

[6] Preusser-Kunze A, Mariappan M, Schmidt B, Gande SL, Mutenda K, Wenzel D, von Figura K, Dierks T. Molecular characterization of the human Calpha-formylglycine-generating enzyme. J Biol Chem. 2005 Apr 15;280(15):14900-10. Epub 2005 Jan 18. PMID:15657036 doi:M413383200

[7] Dierks T, Dickmanns A, Preusser-Kunze A, Schmidt B, Mariappan M, von Figura K, Ficner R, Rudolph MG. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. Cell. 2005 May 20;121(4):541-52. PMID:15907468 doi:http://dx.doi.org/10.1016/j.cell.2005.03.001

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