Biology:Formylglycine-generating enzyme

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Formylglycine-generating enzyme
Identifiers
EC number1.8.99
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Formylglycine-generating enzyme
PDB 2aik EBI.jpg
formylglycine generating enzyme c336s mutant covalently bound to substrate peptide lctpsra
Identifiers
SymbolFGE-sulfatase
PfamPF03781
InterProIPR005532

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.

A brief overview of formylglycine-generating enzyme activity in aerobes (top only) and anaerobes (top and bottom).

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-𝛼-formylglycine.[18] SUMF1 occurs in the endoplasmic reticulum or its lumen.

References

  1. ↑ Reference, Genetics Home. "SUMF1 gene" (in en). https://ghr.nlm.nih.gov/gene/SUMF1. 
  2. ↑ "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. doi:10.1107/S0907444905013831. PMID 16041070. 
  3. ↑ "Copper is a Cofactor of the Formylglycine-Generating Enzyme". ChemBioChem 18 (2): 161–165. January 2017. doi:10.1002/cbic.201600359. PMID 27862795. 
  4. ↑ "2 activation". Proceedings of the National Academy of Sciences of the United States of America 116 (12): 5370–5375. March 2019. doi:10.1073/pnas.1818274116. PMID 30824597. 
  5. ↑ "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. doi:10.1039/C9SC01723B. PMID 31588272. 
  6. ↑ "Formylglycine, a post-translationally generated residue with unique catalytic capabilities and biotechnology applications". ACS Chemical Biology 10 (1): 72–84. January 2015. doi:10.1021/cb500897w. PMID 25514000. 
  7. ↑ "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. doi:10.1021/ja067175e. PMID 17335281. 
  8. ↑ "Function and structure of a prokaryotic formylglycine-generating enzyme". The Journal of Biological Chemistry 283 (29): 20117–25. July 2008. doi:10.1074/jbc.M800217200. PMID 18390551. 
  9. ↑ "Formylglycine, a post-translationally generated residue with unique catalytic capabilities and biotechnology applications". ACS Chemical Biology 10 (1): 72–84. January 2015. doi:10.1021/cb500897w. PMID 25514000. 
  10. ↑ "SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies". The Biochemical Journal 403 (2): 305–12. April 2007. doi:10.1042/BJ20061783. PMID 17206939. 
  11. ↑ "Sulfatases and human disease". Annual Review of Genomics and Human Genetics 6: 355–79. 2005. doi:10.1146/annurev.genom.6.080604.162334. PMID 16124866. 
  12. ↑ "Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship". Human Molecular Genetics 14 (21): 3203–17. November 2005. doi:10.1093/hmg/ddi351. PMID 16174644. 
  13. ↑ "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. doi:10.1038/ejhg.2010.219. PMID 21224894. 
  14. ↑ Reference, Genetics Home. "SUMF1 gene" (in en). https://ghr.nlm.nih.gov/gene/SUMF1. 
  15. ↑ "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. doi:10.1002/mgg3.1167. PMID 32048457. 
  16. ↑ "Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease". Respiratory Research 18 (1): 77. May 2017. doi:10.1186/s12931-017-0562-5. PMID 28464818. 
  17. ↑ "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. doi:10.1002/mgg3.1167. PMID 32048457. 
  18. ↑ Reference, Genetics Home. "SUMF1 gene" (in en). https://ghr.nlm.nih.gov/gene/SUMF1. 
This article incorporates text from the public domain Pfam and InterPro: IPR005532



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