Formylglycine generating enzyme

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Formylglycine generating enzyme
Formylglycine generating enzyme
C336S mutant
other names

FGE, sulfatase modifying factor 1, UNQ3037, AAPA3037

Existing structural data : PDB  2aik

Mass / length primary structure 374 amino acids , 40,556 Da
Identifier
External IDs
Enzyme classification
EC, category 1.8.3.7
Orthologue (human)
Entrez 285362
Ensemble ENSG00000144455
UniProt Q8NBK3
Refseq (mRNA) NM_001164674.1
Refseq (protein) NP_001158146.1
Gene locus Chr 3: 4.03 - 4.47 Mb
PubMed search 285362

Formylglycine-generating enzyme (FGE) is an enzyme from the group of oxygenases . It post-translationally changes a cysteine in sulfatases into a formylglycine . FGE can occur in both prokaryotes and eukaryotes .

structure

The active enzyme is a monomer with two protein domains . The secondary structure consists of α-helices and β-sheets , which are stabilized by calcium ions. It has three disulfide bridges . Activation takes place by splitting off a signal peptide after it has been transported into the endoplasmic reticulum .

functionality

The FGE is encoded by the SUMF1 gene . At the time of the reaction the sulfatase is not yet folded . FGE recognizes the short sequence CxPxR in the active center of sulfatases and xxxLTGR as an auxiliary sequence. The cysteine ​​in this sequence is post-translationally converted to formylglycine . This activates sulfatases. FGE is an oxygenase that has copper as a cofactor . A cysteine ​​at position 341 in the FGE, which binds to the cysteine ​​to be changed, is involved in the reaction of cysteine ​​to formylglycine. From the cysteine, the reaction to 3-oxoalanine (also called formylglycine (fGly)) on target proteins is catalyzed by oxidation with molecular oxygen and an unidentified reducing agent.

The 3-oxoalanine modification, occurs in the post-translational modification of aryl sulfatases and some alkaline phosphatases that use the hydrated form of 3-oxoalanine as the catalytic nucleophile . Substrates for FGE include N-acetylgalactosamine-6-sulfate sulfatase ( GALNS ), aryl sulfatase A (ARSA), steroid sulfatase (STS), and aryl sulfatase E (ARSE).

Occurrence

FGE occurs in the endoplasmic reticulum of eukaryotes. Prokaryotes also have FGE, with these having the additional AtsB system .

malfunction

When mutations in SUMF1 gene it comes to inactivate the FGE. As a result, sulfatases, which hydrolyze sulfate esters, can no longer be activated. There is a multiple sulfatase deficiency .

Individual evidence

  1. ↑ Thomas Dierks, Achim Dickmanns, Andrea Preusser-Kunze, Bernhard Schmidt, Malaiyalam Mariappan: Molecular Basis for Multiple Sulfatase Deficiency and Mechanism for Formylglycine Generation of the Human Formylglycine-Generating Enzyme . In: Cell . tape 121 , no. 4 , May 20, 2005, ISSN  0092-8674 , p. 541-552 , doi : 10.1016 / j.cell.2005.03.001 , PMID 15907468 .
  2. ↑ PG Holder, LC Jones, PM Drake, RM Barfield, S. Bañas, GW de Hart, J. Baker, D. Rabuka: Reconstitution of Formylglycine-generating Enzyme with Copper (II) for Aldehyde Tag Conversion. In: Journal of Biological Chemistry . Volume 290, number 25, June 2015, pp. 15730–15745, doi : 10.1074 / jbc.M115.652669 , PMID 25931126 , PMC 4505483 (free full text).
  3. ^ MP Cosma, S. Pepe, I. Annunziata, RF Newbold, M. Grompe, G. Parenti, A. Ballabio: The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. In: Cell . Volume 113, Number 4, May 2003, pp. 445-456, doi : 10.1016 / s0092-8674 (03) 00348-9 , PMID 12757706 .
  4. ^ A. Preusser-Kunze, M. Mariappan, B. Schmidt, SL Gande, K. Mutenda, D. Wenzel, K. von Figura, T. Dierks: Molecular characterization of the human Calpha-formylglycine-generating enzyme. In: Journal of Biological Chemistry . Volume 280, Number 15, April 2005, pp. 14900-14910, doi : 10.1074 / jbc.M413383200 , PMID 15657036 .
  5. ^ MP Cosma, S. Pepe, I. Annunziata, RF Newbold, M. Grompe, G. Parenti, A. Ballabio: The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. In: Cell . Volume 113, Number 4, May 2003, pp. 445-456, doi : 10.1016 / s0092-8674 (03) 00348-9 , PMID 12757706 .
  6. ^ A. Preusser-Kunze, M. Mariappan, B. Schmidt, SL Gande, K. Mutenda, D. Wenzel, K. von Figura, T. Dierks: Molecular characterization of the human Calpha-formylglycine-generating enzyme. In: Journal of Biological Chemistry . Volume 280, Number 15, April 2005, pp. 14900-14910, doi : 10.1074 / jbc.M413383200 , PMID 15657036 .
  7. ↑ Qinghua Fang, Jianhe Peng, Thomas Dierks: Post-translational Formylglycine Modification of Bacterial Sulfatases by the Radical S-Adenosylmethionine Protein AtsB . In: Journal of Biological Chemistry . tape 279 , no. 15 , April 9, 2004, ISSN  0021-9258 , p. 14570–14578 , doi : 10.1074 / jbc.M313855200 , PMID 14749327 ( jbc.org [accessed November 19, 2019]).
  8. ↑ Maria Pia Cosma, Stefano Pepe, Giancarlo Parenti, Carmine Settembre, Ida Annunziata: Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency . In: Human Mutation . tape 23 , no. 6 , 2004, ISSN  1098-1004 , p. 576-581 , doi : 10.1002 / humu.20040 .