Formylglycine-generating enzyme explained

Symbol:FGE-sulfatase
Formylglycine-generating enzyme
Pfam:PF03781
Interpro:IPR005532

Formylglycine-generating enzyme (FGE), located at 3p26.1 in humans, is the name for an enzyme present in the endoplasmic reticulum that catalyzes the conversion of cysteine to formylglycine (fGly).[1] There are two main classes of FGE, aerobic and anaerobic. FGE activates sulfatases, which are essential for the degradation of sulfate esters. The catalytic activity of sulfatases is dependent upon a formylglycine (sometimes called oxoalanine) residue in the active site.[2]

Aerobic

The aerobic enzyme has a structure homologous to the complex alpha/beta topology found in the gene product of human sulfatase-modifying factor 1 (SUMF1). Aerobic FGE converts a cysteine residue in the highly conserved consensus sequence CXPXR to fGly. To do so, FGE "activates" its target by utilizing mononuclear copper.[3] The substrate first binds to copper,[4] increasing reactivity of the substrate-copper complex with oxygen.[5] Activation is then accomplished through oxidation of a cysteine residue in the substrate-copper complex. Due to the nature of this reaction, FGE is termed a "copper-dependent metalloenzyme.

Anaerobic

The most well-studied anaerobic FGE is the bacterial AtsB, an iron-sulfur cluster containing enzyme present in Klebsiella pneumoniae, that is able to convert either cysteine or serine to fGly with a distinctly different mechanism than the aerobic form. While AtsB can convert either, its activity increases four fold when in the presence of cysteine over serine.[6] AtsB is 48% similar to an enzyme present in Clostridium perfringens.[7] Both enzymes possess the Cx3Cx2C motif unique to the radical S-adenosyl methionine superfamily and are able to use a reduction reaction to cleave S-adenosyl methionine. These two enzymes fall into a larger group called the anaerobic Sulfatase Maturing Enzymes, which are able to convert cysteine into fGly without the use of oxygen.

Protein domain

In molecular biology, "formylglycine-generating enzyme" (sometimes annotated as formylglycine-generating sulfatase enzyme) is the name of the FGE protein domain, whether or not the protein is catalytically active. Both prokaryotic and eukaryotic homologs of FGE possess highly conserved active sites — including the catalytic cysteine residues required for enzymatic function.[8] Activation of molecular oxygen is thought to be carried out by conserved residues close to the FGE catalytic site in aerobic organisms. The catalytic cysteine residues are involved in a thiol-cysteine exchange leading to the ultimate production of fGly.[9]

Disease states

In humans, mutations in SUMF1 result in defects in FGE, which in turn causes the impairment of sulfatases. The result is a disease called multiple sulfatase deficiency (MSD), in which the accumulation of glycosaminoglycans or sulfolipids can cause early infant death.[10] [11] [12] This disease can be further differentiated into neonatal, late infantile, and juvenile, with neonatal being the most severe.[13] Common symptoms include ichthyosis, hypotonia, skeletal abnormalities, and overall cognitive decline.[14] [15] In 2017 Weidner et al., found an association with SUMF1 expression and chronic obstructive pulmonary disease (COPD) development.[16] As of January 2020, there were more than 100 reported cases worldwide of MSD.[17] Known substrates for SUMF1 are: N-acetylgalactosamine-6-sulfate sulfatase (GALNS), arylsulfatase A (ARSA), steroid sulfatase (STS) and arylsulfatase L (ARSL); all molecules that contain cysteine. FGE converts this cysteine group into C--formylglycine.[18] SUMF1 occurs in the endoplasmic reticulum or its lumen.

Notes and References

  1. Web site: SUMF1 gene. Reference. Genetics Home. Genetics Home Reference. en. 2020-03-27.
  2. Roeser D, Dickmanns A, Gasow K, Rudolph MG . De novo calcium/sulfur SAD phasing of the human formylglycine-generating enzyme using in-house data . Acta Crystallographica. Section D, Biological Crystallography . 61 . Pt 8 . 1057–66 . August 2005 . 16041070 . 10.1107/S0907444905013831 .
  3. Knop M, Dang TQ, Jeschke G, Seebeck FP . Copper is a Cofactor of the Formylglycine-Generating Enzyme . ChemBioChem . 18 . 2 . 161–165 . January 2017 . 27862795 . 5324649 . 10.1002/cbic.201600359 .
  4. Appel MJ, Meier KK, Lafrance-Vanasse J, Lim H, Tsai CL, Hedman B, Hodgson KO, Tainer JA, Solomon EI, Bertozzi CR . 6 . 2 activation . Proceedings of the National Academy of Sciences of the United States of America . 116 . 12 . 5370–5375 . March 2019 . 30824597 . 6431200 . 10.1073/pnas.1818274116 . free .
  5. Miarzlou DA, Leisinger F, Joss D, Häussinger D, Seebeck FP . Structure of formylglycine-generating enzyme in complex with copper and a substrate reveals an acidic pocket for binding and activation of molecular oxygen . Chemical Science . 10 . 29 . 7049–7058 . August 2019 . 31588272 . 6676471 . 10.1039/C9SC01723B .
  6. Appel MJ, Bertozzi CR . Formylglycine, a post-translationally generated residue with unique catalytic capabilities and biotechnology applications . ACS Chemical Biology . 10 . 1 . 72–84 . January 2015 . 25514000 . 4492166 . 10.1021/cb500897w .
  7. Benjdia A, Leprince J, Guillot A, Vaudry H, Rabot S, Berteau O . Anaerobic sulfatase-maturating enzymes: radical SAM enzymes able to catalyze in vitro sulfatase post-translational modification . Journal of the American Chemical Society . 129 . 12 . 3462–3 . March 2007 . 17335281 . 10.1021/ja067175e .
  8. Carlson BL, Ballister ER, Skordalakes E, King DS, Breidenbach MA, Gilmore SA, Berger JM, Bertozzi CR . 6 . Function and structure of a prokaryotic formylglycine-generating enzyme . The Journal of Biological Chemistry . 283 . 29 . 20117–25 . July 2008 . 18390551 . 2459300 . 10.1074/jbc.M800217200 . free .
  9. Appel MJ, Bertozzi CR . Formylglycine, a post-translationally generated residue with unique catalytic capabilities and biotechnology applications . ACS Chemical Biology . 10 . 1 . 72–84 . January 2015 . 25514000 . 4492166 . 10.1021/cb500897w .
  10. Fraldi A, Biffi A, Lombardi A, Visigalli I, Pepe S, Settembre C, Nusco E, Auricchio A, Naldini L, Ballabio A, Cosma MP . 6 . SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies . The Biochemical Journal . 403 . 2 . 305–12 . April 2007 . 17206939 . 1874239 . 10.1042/BJ20061783 .
  11. Diez-Roux G, Ballabio A . Sulfatases and human disease . Annual Review of Genomics and Human Genetics . 6 . 355–79 . 2005 . 16124866 . 10.1146/annurev.genom.6.080604.162334 .
  12. Sardiello M, Annunziata I, Roma G, Ballabio A . Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship . Human Molecular Genetics . 14 . 21 . 3203–17 . November 2005 . 16174644 . 10.1093/hmg/ddi351 . free .
  13. Schlotawa L, Ennemann EC, Radhakrishnan K, Schmidt B, Chakrapani A, Christen HJ, Moser H, Steinmann B, Dierks T, Gärtner J . 6 . SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency . European Journal of Human Genetics . 19 . 3 . 253–61 . March 2011 . 21224894 . 3062010 . 10.1038/ejhg.2010.219 .
  14. Web site: SUMF1 gene. Reference. Genetics Home. Genetics Home Reference. en. 2020-03-27.
  15. Staretz-Chacham O, Schlotawa L, Wormser O, Golan-Tripto I, Birk OS, Ferreira CR, Dierks T, Radhakrishnan K . 6 . A homozygous missense variant of SUMF1 in the Bedouin population extends the clinical spectrum in ultrarare neonatal multiple sulfatase deficiency . Molecular Genetics & Genomic Medicine . 8 . 9 . e1167 . September 2020 . 32048457 . 10.1002/mgg3.1167 . 7507568 . free .
  16. Weidner J, Jarenbäck L, de Jong K, Vonk JM, van den Berge M, Brandsma CA, Boezen HM, Sin D, Bossé Y, Nickle D, Ankerst J, Bjermer L, Postma DS, Faiz A, Tufvesson E . 6 . Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease . Respiratory Research . 18 . 1 . 77 . May 2017 . 28464818 . 5414362 . 10.1186/s12931-017-0562-5 . free .
  17. Staretz-Chacham O, Schlotawa L, Wormser O, Golan-Tripto I, Birk OS, Ferreira CR, Dierks T, Radhakrishnan K . 6 . A homozygous missense variant of SUMF1 in the Bedouin population extends the clinical spectrum in ultrarare neonatal multiple sulfatase deficiency . Molecular Genetics & Genomic Medicine . 8 . 9 . e1167 . September 2020 . 32048457 . 10.1002/mgg3.1167 . 7507568 . free .
  18. Web site: SUMF1 gene. Reference. Genetics Home. Genetics Home Reference. en. 2020-03-27.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Formylglycine-generating enzyme".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.