Protein O-GlcNAcase

Last updated
OGA
OGA crystal structure dimer.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases OGA , MEA5, NCOAT, meningioma expressed antigen 5 (hyaluronidase), MGEA5, O-GlcNAcase
External IDs OMIM: 604039 MGI: 1932139 HomoloGene: 8154 GeneCards: OGA
Orthologs
SpeciesHumanMouse
Entrez

10724

76055

Ensembl

ENSG00000198408

ENSMUSG00000025220

UniProt

O60502

Q9EQQ9

RefSeq (mRNA)

NM_001142434
NM_012215

NM_023799

RefSeq (protein)

NP_001135906
NP_036347

NP_076288

Location (UCSC) Chr 10: 101.78 – 101.82 Mb Chr 19: 45.74 – 45.77 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] [7] [8] [9] OGA is encoded by the OGA gene. This enzyme catalyses the removal of the O-GlcNAc post-translational modification in the following chemical reaction:

Contents

  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 no. 3.2.1.169
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Search
PMC articles
PubMed articles
NCBI proteins

Other names include:

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. [10] Another isoform, resulting from proteolytic cleavage of L-OGA, has also been described. All three isoforms exhibit glycoside hydrolase activity. [11]

Homologs

Protein O-GlcNAcases belong to glycoside hydrolase family 84 of the carbohydrate active enzyme classification. [12] 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. [13]

Reaction

Protein O-GlcNAcylation

Metabolic pathway for OGA Metabolic pathway for OGA.jpg
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. [14]

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. [15] [16]

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. [17]

Mechanism and inhibition

a. Inhibitors for OGA b. Cross section of active site F3 Inhibitor.jpg
a. Inhibitors for OGA b. Cross section of active site

OGA catalyzes O-GlcNAc hydrolysis via an oxazoline reaction intermediate. [18] 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. [19]

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. [20]

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. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Post-translational modification</span> Biological processes

Post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes translating mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

<i>N</i>-Acetylglucosamine Biological molecule

N-Acetylglucosamine (GlcNAc) is an amide derivative of the monosaccharide glucose. It is a secondary amide between glucosamine and acetic acid. It is significant in several biological systems.

<span class="mw-page-title-main">Hexosaminidase</span> Class of enzymes

Hexosaminidase is an enzyme involved in the hydrolysis of terminal N-acetyl-D-hexosamine residues in N-acetyl-β-D-hexosaminides.

The enzyme mannosyl-glycoprotein endo-β-N-acetylglucosaminidase (endoglycosidase H) (EC 3.2.1.96) has systematic name glycopeptide-D-mannosyl-N4-(N-acetyl-D-glucosaminyl)2-asparagine 1,4-N-acetyl-β-glucosaminohydrolase. It is a highly specific endoglycosidase which cleaves asparagine-linked mannose rich oligosaccharides, but not highly processed complex oligosaccharides from glycoproteins. It is used for research purposes to deglycosylate glycoproteins and to monitor intracellular protein trafficking through the secretory pathway.

<span class="mw-page-title-main">UDP-glucose 4-epimerase</span> Class of enzymes

The enzyme UDP-glucose 4-epimerase, also known as UDP-galactose 4-epimerase or GALE, is a homodimeric epimerase found in bacterial, fungal, plant, and mammalian cells. This enzyme performs the final step in the Leloir pathway of galactose metabolism, catalyzing the reversible conversion of UDP-galactose to UDP-glucose. GALE tightly binds nicotinamide adenine dinucleotide (NAD+), a co-factor required for catalytic activity.

In enzymology, a [Skp1-protein]-hydroxyproline N-acetylglucosaminyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">GALNT1</span> Protein-coding gene in the species Homo sapiens

Polypeptide N-acetylgalactosaminyltransferase 1 is an enzyme that in humans is encoded by the GALNT1 gene.

<span class="mw-page-title-main">GALNT2</span> Protein-coding gene in the species Homo sapiens

Polypeptide N-acetylgalactosaminyltransferase 2 is an enzyme that in humans is encoded by the GALNT2 gene.

<span class="mw-page-title-main">STK16</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase 16 is an enzyme that in humans is encoded by the STK16 gene.

<span class="mw-page-title-main">NAGPA</span> Protein-coding gene in the species Homo sapiens

N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase is an enzyme that in humans is encoded by the NAGPA gene.

<span class="mw-page-title-main">GALNT13</span> Protein-coding gene in the species Homo sapiens

Polypeptide N-acetylgalactosaminyltransferase 13 is an enzyme that in humans is encoded by the GALNT13 gene.

O-linked glycosylation is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or threonine (Thr) residues in a protein. O-glycosylation is a post-translational modification that occurs after the protein has been synthesised. In eukaryotes, it occurs in the endoplasmic reticulum, Golgi apparatus and occasionally in the cytoplasm; in prokaryotes, it occurs in the cytoplasm. Several different sugars can be added to the serine or threonine, and they affect the protein in different ways by changing protein stability and regulating protein activity. O-glycans, which are the sugars added to the serine or threonine, have numerous functions throughout the body, including trafficking of cells in the immune system, allowing recognition of foreign material, controlling cell metabolism and providing cartilage and tendon flexibility. Because of the many functions they have, changes in O-glycosylation are important in many diseases including cancer, diabetes and Alzheimer's. O-glycosylation occurs in all domains of life, including eukaryotes, archaea and a number of pathogenic bacteria including Burkholderia cenocepacia, Neisseria gonorrhoeae and Acinetobacter baumannii.

<span class="mw-page-title-main">GBA3</span> Protein-coding gene in the species Homo sapiens

Cytosolic beta-glucosidase, also known as cytosolic beta-glucosidase-like protein 1, is a beta-glucosidase enzyme that in humans is encoded by the GBA3 gene.

Protein <i>O</i>-GlcNAc transferase Protein-coding gene in the species Homo sapiens

Protein O-GlcNAc transferase also known as OGT or O-linked N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the OGT gene. OGT catalyzes the addition of the O-GlcNAc post-translational modification to proteins.

Endo-α-N-acetylgalactosaminidase (EC 3.2.1.97, endo-α-acetylgalactosaminidase, endo-α-N-acetyl-D-galactosaminidase, mucinaminylserine mucinaminidase, D-galactosyl-3-(N-acetyl-α-D-galactosaminyl)-L-serine mucinaminohydrolase, endo-α-GalNAc-ase, D-galactosyl-N-acetyl-α-D-galactosamine D-galactosyl-N-acetyl-galactosaminohydrolase) is an enzyme with systematic name glycopeptide-D-galactosyl-N-acetyl-α-D-galactosamine D-galactosyl-N-acetyl-galactosaminohydrolase. This enzyme catalyses the following chemical reaction

<i>O</i>-GlcNAc

O-GlcNAc is a reversible enzymatic post-translational modification that is found on serine and threonine residues of nucleocytoplasmic proteins. The modification is characterized by a β-glycosidic bond between the hydroxyl group of serine or threonine side chains and N-acetylglucosamine (GlcNAc). O-GlcNAc differs from other forms of protein glycosylation: (i) O-GlcNAc is not elongated or modified to form more complex glycan structures, (ii) O-GlcNAc is almost exclusively found on nuclear and cytoplasmic proteins rather than membrane proteins and secretory proteins, and (iii) O-GlcNAc is a highly dynamic modification that turns over more rapidly than the proteins which it modifies. O-GlcNAc is conserved across metazoans.

<span class="mw-page-title-main">PNGase F</span>

Peptide:N-glycosidase F, commonly referred to as PNGase F, is an amidase of the peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase class. PNGase F works by cleaving between the innermost GlcNAc and asparagine residues of high mannose, hybrid, and complex oligosaccharides from N-linked glycoproteins and glycopeptides. This results in a deaminated protein or peptide and a free glycan.

<span class="mw-page-title-main">Endo-beta-n-acetylglucosaminidase</span> Protein-coding gene in the species Homo sapiens

Endo-beta-N-acetylglucosaminidase is a protein that in humans is encoded by the ENGASE gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000198408 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025220 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Wells L, Gao Y, Mahoney JA, Vosseller K, Chen C, Rosen A, Hart GW (January 2002). "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. doi: 10.1074/jbc.M109656200 . PMID   11788610.
  6. ↑ Cetinbaş N, Macauley MS, Stubbs KA, Drapala R, Vocadlo DJ (March 2006). "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. doi:10.1021/bi052370b. PMID   16533067.
  7. ↑ Dennis RJ, Taylor EJ, Macauley MS, Stubbs KA, Turkenburg JP, Hart SJ, et al. (April 2006). "Structure and mechanism of a bacterial beta-glucosaminidase having O-GlcNAcase activity". Nature Structural & Molecular Biology. 13 (4): 365–71. doi:10.1038/nsmb1079. PMID   16565725. S2CID   9239755.
  8. ↑ Kim EJ, Kang DO, Love DC, Hanover JA (June 2006). "Enzymatic characterization of O-GlcNAcase isoforms using a fluorogenic GlcNAc substrate". Carbohydrate Research. 341 (8): 971–82. doi:10.1016/j.carres.2006.03.004. PMC   10561171 . PMID   16584714.
  9. ↑ Dong DL, Hart GW (July 1994). "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. doi: 10.1016/S0021-9258(17)32170-1 . PMID   8034696.
  10. ↑ Pagesy P, Bouaboud A, Feng Z, Hulin P, Issad T (June 2022). "Short O-GlcNAcase is targeted to the mitochondria and regulates mitochondrial reactive oxygen species level". Cells. 11 (11): 1827. doi: 10.3390/cells11111827 . PMC   9180253 . PMID   35681522. S2CID   9180253.
  11. ↑ Li J, Huang CL, Zhang LW, Lin L, Li ZH, Zhang FW, Wang P (July 2010). "Isoforms of human O-GlcNAcase show distinct catalytic efficiencies". Biochemistry. Biokhimiia. 75 (7): 938–43. doi:10.1134/S0006297910070175. PMID   20673219. S2CID   2414800.
  12. ↑ Greig, Ian; Vocadlo, David. "Glycoside Hydrolase Family 84". Cazypedia. Retrieved 28 March 2017.
  13. ↑ Gao Y, Wells L, Comer FI, Parker GJ, Hart GW (March 2001). "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. doi: 10.1074/jbc.M010420200 . PMID   11148210.
  14. ↑ Lima VV, Rigsby CS, Hardy DM, Webb RC, Tostes RC (2009). "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. doi:10.1016/j.jash.2009.09.004. PMC   3022480 . PMID   20409980.
  15. ↑ Förster S, Welleford AS, Triplett JC, Sultana R, Schmitz B, Butterfield DA (September 2014). "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. doi:10.1016/j.bbadis.2014.05.014. PMC   4140188 . PMID   24859566.
  16. ↑ Shafi R, Iyer SP, Ellies LG, O'Donnell N, Marek KW, Chui D, et al. (May 2000). "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. Bibcode:2000PNAS...97.5735S. doi: 10.1073/pnas.100471497 . PMC   18502 . PMID   10801981.
  17. ↑ Love DC, Ghosh S, Mondoux MA, Fukushige T, Wang P, Wilson MA, et al. (April 2010). "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. Bibcode:2010PNAS..107.7413L. doi: 10.1073/pnas.0911857107 . PMC   2867743 . PMID   20368426.
  18. ↑ Dennis RJ, Taylor EJ, Macauley MS, Stubbs KA, Turkenburg JP, Hart SJ, et al. (April 2006). "Structure and mechanism of a bacterial beta-glucosaminidase having O-GlcNAcase activity". Nature Structural & Molecular Biology. 13 (4): 365–71. doi:10.1038/nsmb1079. PMID   16565725. S2CID   9239755.
  19. ↑ Alonso J, Schimpl M, van Aalten DM (December 2014). "O-GlcNAcase: promiscuous hexosaminidase or key regulator of O-GlcNAc signaling?". The Journal of Biological Chemistry. 289 (50): 34433–9. doi: 10.1074/jbc.R114.609198 . PMC   4263850 . PMID   25336650.
  20. ↑ Lim S, Haque MM, Nam G, Ryoo N, Rhim H, Kim YK (August 2015). "Monitoring of Intracellular Tau Aggregation Regulated by OGA/OGT Inhibitors". International Journal of Molecular Sciences. 16 (9): 20212–24. doi: 10.3390/ijms160920212 . PMC   4613198 . PMID   26343633.
  21. ↑ Roth C, Chan S, Offen WA, Hemsworth GR, Willems LI, King DT, et al. (June 2017). "Structural and functional insight into human O-GlcNAcase". Nature Chemical Biology. 13 (6): 610–612. doi:10.1038/nchembio.2358. PMC   5438047 . PMID   28346405.

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