Biology:Protein O-GlcNAcase

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Short description: Protein-coding gene in the species Homo sapiens


Protein O-GlcNAcase (EC 3.2.1.169, OGA, glycoside hydrolase O-GlcNAcase, O-GlcNAcase, BtGH84, O-GlcNAc hydrolase) is an enzyme with systematic name (protein)-3-O-(N-acetyl-D-glucosaminyl)-L-serine/threonine N-acetylglucosaminyl hydrolase.[1][2][3][4][5] OGA is encoded by the OGA gene. This enzyme catalyses the removal of the O-GlcNAc post-translational modification in the following chemical reaction:

  1. [protein]-3-O-(N-acetyl-β-D-glucosaminyl)-L-serine + H2O ⇌ [protein]-L-serine + N-acetyl-D-glucosamine
  2. [protein]-3-O-(N-acetyl-β-D-glucosaminyl)-L-threonine + H2O ⇌ [protein]-L-threonine + N-acetyl-D-glucosamine

Nomenclature

Protein O-GlcNAcase
Cartoon Image of OGA.jpg
Identifiers
EC number3.2.1.169
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum

Other names include:

  • Nuclear cytoplasmic O-GlcNAcase and acetyltransferase

Isoforms

The human OGA gene is capable of producing two different transcripts, each capable of encoding a different OGA isoform. The long isoform L-OGA, a bifunctional enzyme that possess a glycoside hydrolase activity and a pseudo histone-acetyl transferase domain, primarily resides in the cytoplasm and the nucleus. The short isoform S-OGA, which only exhibit the glycoside hydrolase domain, was initially described as residing within the nucleus. However, more recent work showed that S-OGA is located in mitochondria and regulates reactive oxygen production in this organelle.[6] Another isoform, resulting from proteolytic cleavage of L-OGA, has also been described. All three isoforms exhibit glycoside hydrolase activity.[7]

Homologs

Protein O-GlcNAcases belong to glycoside hydrolase family 84 of the carbohydrate active enzyme classification.[8] Homologs exist in other species as O-GlcNAcase is conserved in higher eukaryotic species. In a pairwise alignment, humans share 55% homology with Drosophila and 43% with C. elegans. Drosophila and C. elegans share 43% homology. Among mammals, the OGA sequence is even more highly conserved. The mouse and the human have 97.8% homology. However, OGA does not share significant homology with other proteins. However, short stretches of about 200 amino acids in OGA have homology with some proteins such as hyaluronidase, a putative acetyltransferase, eukaryotic translation elongation factor-1γ, and the 11-1 polypeptide.[9]

Reaction

Protein O-GlcNAcylation

Main page: Biology:O-GlcNAc
Metabolic pathway for OGA

O-GlcNAcylation is a form of glycosylation, the site-specific enzymatic addition of saccharides to proteins and lipids. This form of glycosylation is with O-linked β-N-acetylglucosamine or β-O-linked 2-acetamido-2-deoxy-D-glycopyranose (O-GlcNAc). In this form, a single sugar (β-N-acetylglucosamine) is added to serine and threonine residues of nuclear or cytoplasmic proteins. Two conserved enzymes control this glycosylation of serine and threonine: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). While OGT catalyzes the addition of O-GlcNAc to serine and threonine, OGA catalyzes the hydrolytic cleavage of O-GlcNAc from post-transitionally modified proteins.[10]

OGA is a member of the family of hexosaminidases. However, unlike lysosomal hexosaminidases, OGA activity is the highest at neutral pH (approximately 7) and it localizes mainly to the cytosol. OGA and OGT are synthesized from two conserved genes and are expressed throughout the human body with high levels in the brain and pancreas. The products of O-GlcNAc and the process itself plays a role in embryonic development, brain activity, hormone production, and a myriad of other activities.[11][12]

Over 600 proteins are targets for O-GlcNAcylation. While the functional effects of O-GlcNAc modification is not fully known, it is known that O-GlcNAc modification impacts many cellular activities such as lipid/carbohydrate metabolism and hexosamine biosynthesis. Modified proteins may modulate various downstream signaling pathways by influencing transcription and proteomic activities.[13]

Mechanism and inhibition

a. Inhibitors for OGA b. Cross section of active site

OGA catalyzes O-GlcNAc hydrolysis via an oxazoline reaction intermediate.[14] Stable compounds which mimic the reaction intermediate can act as selective enzyme inhibitors. Thiazoline derivatives of GlcNAc can be used as a reaction intermediate. An example of this includes Thiamet-G as shown on the right. A second form of inhibition can occur from the mimicry of the transition state. The GlcNAcstatin family of inhibitors exploit this mechanism in order to inhibit OGA activity. For both types of inhibitors, OGA can be selected apart from the generic lysosomal hexosaminidases by elongating the C2 substituent in their chemical structure. This takes advantage of a deep pocket in OGA's active site that allow it to bind analogs of GlcNAc.[15]

There is potential for regulation of O-GlcNAcase for the treatment of Alzheimer's disease. When the tau protein in the brain is hyperphosphorylated, neurofibrillary tangles form, which are a pathological hallmark for neurodegenerative diseases such as Alzheimer's disease. In order to treat this condition, OGA is targeted by inhibitors such as Thiamet-G in order to prevent O-GlcNAc from being removed from tau, which assists in preventing tau from becoming phosphorylated.[16]

Structure

X-ray structures are available for a range of O-GlcNAcase proteins. The X-ray structure of human O-GlcNAcase in complex with Thiamet-G identified the structural basis of enzyme inhibition.[17]

See also

References

  1. ↑ "Dynamic O-glycosylation of nuclear and cytosolic proteins: further characterization of the nucleocytoplasmic beta-N-acetylglucosaminidase, O-GlcNAcase". The Journal of Biological Chemistry 277 (3): 1755–61. January 2002. doi:10.1074/jbc.M109656200. PMID 11788610. 
  2. ↑ "Identification of Asp174 and Asp175 as the key catalytic residues of human O-GlcNAcase by functional analysis of site-directed mutants". Biochemistry 45 (11): 3835–44. March 2006. doi:10.1021/bi052370b. PMID 16533067. http://summit.sfu.ca/item/20441. 
  3. ↑ "Structure and mechanism of a bacterial beta-glucosaminidase having O-GlcNAcase activity". Nature Structural & Molecular Biology 13 (4): 365–71. April 2006. doi:10.1038/nsmb1079. PMID 16565725. 
  4. ↑ "Enzymatic characterization of O-GlcNAcase isoforms using a fluorogenic GlcNAc substrate". Carbohydrate Research 341 (8): 971–82. June 2006. doi:10.1016/j.carres.2006.03.004. PMID 16584714. PMC 10561171. https://zenodo.org/record/1258816. 
  5. ↑ "Purification and characterization of an O-GlcNAc selective N-acetyl-beta-D-glucosaminidase from rat spleen cytosol". The Journal of Biological Chemistry 269 (30): 19321–30. July 1994. doi:10.1016/S0021-9258(17)32170-1. PMID 8034696. 
  6. ↑ "Short O-GlcNAcase is targeted to the mitochondria and regulates mitochondrial reactive oxygen species level". Cells 11 (11): 1827. June 2022. doi:10.3390/cells11111827. PMID 35681522. 
  7. ↑ "Isoforms of human O-GlcNAcase show distinct catalytic efficiencies". Biochemistry. Biokhimiia 75 (7): 938–43. July 2010. doi:10.1134/S0006297910070175. PMID 20673219. 
  8. ↑ Greig, Ian; Vocadlo, David. "Glycoside Hydrolase Family 84". https://www.cazypedia.org/index.php/Glycoside_Hydrolase_Family_84. 
  9. ↑ "Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain". The Journal of Biological Chemistry 276 (13): 9838–45. March 2001. doi:10.1074/jbc.M010420200. PMID 11148210. 
  10. ↑ "O-GlcNAcylation: a novel post-translational mechanism to alter vascular cellular signaling in health and disease: focus on hypertension". Journal of the American Society of Hypertension 3 (6): 374–87. 2009. doi:10.1016/j.jash.2009.09.004. PMID 20409980. 
  11. ↑ "Increased O-GlcNAc levels correlate with decreased O-GlcNAcase levels in Alzheimer disease brain". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1842 (9): 1333–9. September 2014. doi:10.1016/j.bbadis.2014.05.014. PMID 24859566. 
  12. ↑ "The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny". Proceedings of the National Academy of Sciences of the United States of America 97 (11): 5735–9. May 2000. doi:10.1073/pnas.100471497. PMID 10801981. Bibcode: 2000PNAS...97.5735S. 
  13. ↑ "Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity". Proceedings of the National Academy of Sciences of the United States of America 107 (16): 7413–8. April 2010. doi:10.1073/pnas.0911857107. PMID 20368426. Bibcode: 2010PNAS..107.7413L. 
  14. ↑ "Structure and mechanism of a bacterial beta-glucosaminidase having O-GlcNAcase activity". Nature Structural & Molecular Biology 13 (4): 365–71. April 2006. doi:10.1038/nsmb1079. PMID 16565725. 
  15. ↑ "O-GlcNAcase: promiscuous hexosaminidase or key regulator of O-GlcNAc signaling?". The Journal of Biological Chemistry 289 (50): 34433–9. December 2014. doi:10.1074/jbc.R114.609198. PMID 25336650. 
  16. ↑ "Monitoring of Intracellular Tau Aggregation Regulated by OGA/OGT Inhibitors". International Journal of Molecular Sciences 16 (9): 20212–24. August 2015. doi:10.3390/ijms160920212. PMID 26343633. 
  17. ↑ "Structural and functional insight into human O-GlcNAcase". Nature Chemical Biology 13 (6): 610–612. June 2017. doi:10.1038/nchembio.2358. PMID 28346405. PMC 5438047. http://eprints.whiterose.ac.uk/117506/. 

Further reading

External links



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