N-acetylglucosamine phosphotransferase
From Proteopedia
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N-acetylglucosamine (GlcNAc) phosphotransferase is a cis-Golgi-localized enzyme that recognizes the specific protein sequence in newly synthesized lysosomal enzymes and transfers phosphorylated GlcNAc groups <ref>Bioconjugate Chem., 2014, 25 (6), pp 1025–1030</ref>,<ref>Lodish, H. F., et al. Molecular cell biology, 8th ed.; W.H. Freeman-Macmillan Learning: New York, 2016.</ref>. This enzyme is hexameric, composed of two alpha, two beta, and two gamma subunits <ref>Bao, M., Elmendorf, B. J., Booth, J. L., Drake, R. R., Canfield, W. M. Bovine UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase: II. Enzymatic characterization and identification of the catalytic subunit. J. Biol. Chem. 271: 31446-31451, 1996.<ref/>. | N-acetylglucosamine (GlcNAc) phosphotransferase is a cis-Golgi-localized enzyme that recognizes the specific protein sequence in newly synthesized lysosomal enzymes and transfers phosphorylated GlcNAc groups <ref>Bioconjugate Chem., 2014, 25 (6), pp 1025–1030</ref>,<ref>Lodish, H. F., et al. Molecular cell biology, 8th ed.; W.H. Freeman-Macmillan Learning: New York, 2016.</ref>. This enzyme is hexameric, composed of two alpha, two beta, and two gamma subunits <ref>Bao, M., Elmendorf, B. J., Booth, J. L., Drake, R. R., Canfield, W. M. Bovine UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase: II. Enzymatic characterization and identification of the catalytic subunit. J. Biol. Chem. 271: 31446-31451, 1996.<ref/>. | ||
| + | == Phosphotransferases == | ||
| + | Phosphotransferases are a large group of enzymes that not only include those that transfer phosphate but also diphosphate, nucleotidyl residues, and others<ref>https://www.ncbi.nlm.nih.gov/mesh/68010770</ref>. The category of enzymes is EC 2.7 and are classified according to acceptor molecules. EC 2.7.1 has an alcohol as an acceptor, EC 2.7.2 has a carboxyl group as an acceptor, EC 2.7.3 has a nitrogenous group as an acceptor, and EC 2.7.4 has a phosphate group as an acceptor. EC 2.7.9 has paired acceptor in which a single triphosphate-nucleotide transfers two phosphates to two different acceptor molecules, resulting in a monophosphate-nucleotide and two phosphorylated products. N-acetylglucosamine Phosphotransferase in particular belongs to EC 2.7.1 <ref>https://en.wikipedia.org/wiki/Phosphotransferase#Phosphotransferase_system</ref>. | ||
== Function == | == Function == | ||
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The alpha and beta subunits result from a single cDNA and formed by proteolysis at a lysine-aspartate bond on the alpha/beta precursor <ref>Canfield, W. M., Bao, M., Pan, J., Brewer, A. D. K., Pan, H., Roe, B., Raas-Rothschild, A. Mucolipidosis II and mucolipidosis IIIA are caused by mutations in the GlcNAc-phosphotransferase alpha/beta gene on chromosome 12p. Am. J. Hum. Genet. 63: A15 only, 1998.</ref>. The alpha and beta subunits are encoded by the GNPTAB gene, but the gamma subunit is encoded independently by the GNPTG gene, making GlcNAc an exception to the Garrod-Beadle principle that one enzyme is encoded by one gene <ref>Hartz, P. A. N-Acetylglucosamine-1-phosphotransferase, Alpha/Beta Subunits; GNPTAB.</ref>,<ref>Kudo, M., Bao, M., D'Souza, A., Ying, F., Pan, H., Roe, B. A., Canfield, W. M. The alpha- and beta-subunits of the human UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase are encoded by a single cDNA. J. Biol. Chem. 280: 36141-36149, 2005.</ref>. | The alpha and beta subunits result from a single cDNA and formed by proteolysis at a lysine-aspartate bond on the alpha/beta precursor <ref>Canfield, W. M., Bao, M., Pan, J., Brewer, A. D. K., Pan, H., Roe, B., Raas-Rothschild, A. Mucolipidosis II and mucolipidosis IIIA are caused by mutations in the GlcNAc-phosphotransferase alpha/beta gene on chromosome 12p. Am. J. Hum. Genet. 63: A15 only, 1998.</ref>. The alpha and beta subunits are encoded by the GNPTAB gene, but the gamma subunit is encoded independently by the GNPTG gene, making GlcNAc an exception to the Garrod-Beadle principle that one enzyme is encoded by one gene <ref>Hartz, P. A. N-Acetylglucosamine-1-phosphotransferase, Alpha/Beta Subunits; GNPTAB.</ref>,<ref>Kudo, M., Bao, M., D'Souza, A., Ying, F., Pan, H., Roe, B. A., Canfield, W. M. The alpha- and beta-subunits of the human UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase are encoded by a single cDNA. J. Biol. Chem. 280: 36141-36149, 2005.</ref>. | ||
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<Structure load='6f99' size='350' frame='true' align='right' caption='An approximation of N-acetylglucosamine phosphotransferase gamma subunit<ref>Q9UJJ9 N-acetylglucosamine-1-phosphotransferase subunit gamma. Swiss-Model. 2019.</ref>.' scene='Gamma Subunits' /> | <Structure load='6f99' size='350' frame='true' align='right' caption='An approximation of N-acetylglucosamine phosphotransferase gamma subunit<ref>Q9UJJ9 N-acetylglucosamine-1-phosphotransferase subunit gamma. Swiss-Model. 2019.</ref>.' scene='Gamma Subunits' /> | ||
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<Structure load='2n6d' size='350' frame='true' align='right' caption='N-acetylglucosamine-1-phosphotransferase alpha and beta subunits <ref>RCSB Protein Data Bank. NMR structure of the 140-315 fragment of the N-acetylglucosamine-1-phosphotransferase, alpha and beta subunits.</ref>.' scene='Alpha and Beta Subunits' /> | <Structure load='2n6d' size='350' frame='true' align='right' caption='N-acetylglucosamine-1-phosphotransferase alpha and beta subunits <ref>RCSB Protein Data Bank. NMR structure of the 140-315 fragment of the N-acetylglucosamine-1-phosphotransferase, alpha and beta subunits.</ref>.' scene='Alpha and Beta Subunits' /> | ||
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10. Q9UJJ9 N-acetylglucosamine-1-phosphotransferase subunit gamma. Swiss-Model. 2019. | 10. Q9UJJ9 N-acetylglucosamine-1-phosphotransferase subunit gamma. Swiss-Model. 2019. | ||
11. RCSB Protein Data Bank. NMR structure of the 140-315 fragment of the N-acetylglucosamine-1-phosphotransferase, alpha and beta subunits. | 11. RCSB Protein Data Bank. NMR structure of the 140-315 fragment of the N-acetylglucosamine-1-phosphotransferase, alpha and beta subunits. | ||
| + | 12. https://en.wikipedia.org/wiki/Phosphotransferase#Phosphotransferase_system | ||
| + | 13. https://www.ncbi.nlm.nih.gov/mesh/68010770 | ||
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[[User:Elizabeth Schneider|Elizabeth Schneider]] Student; Erskine College, Due West, SC, United States | [[User:Elizabeth Schneider|Elizabeth Schneider]] Student; Erskine College, Due West, SC, United States | ||
Revision as of 04:14, 15 April 2019
N-acetylglucosamine (GlcNAc) phosphotransferase is a cis-Golgi-localized enzyme that recognizes the specific protein sequence in newly synthesized lysosomal enzymes and transfers phosphorylated GlcNAc groups [1],[2]. This enzyme is hexameric, composed of two alpha, two beta, and two gamma subunits [3]. The category of enzymes is EC 2.7 and are classified according to acceptor molecules. EC 2.7.1 has an alcohol as an acceptor, EC 2.7.2 has a carboxyl group as an acceptor, EC 2.7.3 has a nitrogenous group as an acceptor, and EC 2.7.4 has a phosphate group as an acceptor. EC 2.7.9 has paired acceptor in which a single triphosphate-nucleotide transfers two phosphates to two different acceptor molecules, resulting in a monophosphate-nucleotide and two phosphorylated products. N-acetylglucosamine Phosphotransferase in particular belongs to EC 2.7.1 [4].
Function
Lysosomal enzymes are required for the detection of phosphotransferases in the Golgi apparatus. The structure of many of these lysosomal enzymes is unknown, so the interactions among such enzymes and N-acetylglucosamine phosphotransferase is largely undefined; one known fact is the lysine plays a major role.
Yaghootfam et al. substituted lysine residues on the lysosomal arylsulfatases A and B to find any correlation between this substitution and phosphorylation. The results showed that the effects differed depending on the specific residue and its location on the arylsulfatases. Substitution of only lysine 457 on arylsulfatase A reduced phosphorylation by seventy-seven percent and increased release of the altered enzyme. The location of lysine 457 is in a helix, unlike typical lysine residues which are typically located in an unstructured loop. This could cause an effect, but lysines 497 and 507 were analyzed in arylsulfatases B with similar locations on the enzyme and there was no effect on the phosphorylation with the substitutions on arylsulfatases A and B. Yaghootfam et al. concluded that even homologous enzymes can vary in phosphorylation rates because of the great fluctuation in phosphotransferase recognition by lysosomal enzymes [5].
Disease
Mucolipidosis II is an autosomal recessive hereditary phenotypic disease caused by disruptions of the alpha and beta subunits. This disease presents symptoms of mental retardation and skeletal changes as acid mucopolysaccharides, sphingolipids, and/or glycolipids concentrate in visceral and mesenchymal cells in neural tissue [6],[7]. In a study by Kudo et al, patients with the disease had either absent or reduced alpha/beta transcription; however, all patients had normal gamma subunit levels [8]. This suggests that the alpha and/or the beta subunit contains enzymatic qualities.
Post-translational modifications such as interchain and intramolecular disulfide bonds may occur via GlcNAc-phosphotransferase in the cytoplasm outside of the nucleus, including the protein glycosylation on serine and threonine residues. Any imbalance of phosphorylation can lead to diseases including cancer, diabetes, and neurodegenerative diseases [9]. Management of phosphorylation and other modifications performed by GlcNAc-phosphotransferase can allow for better diagnoses and treatments of such diseases.
Structural highlights
The alpha and beta subunits result from a single cDNA and formed by proteolysis at a lysine-aspartate bond on the alpha/beta precursor [10]. The alpha and beta subunits are encoded by the GNPTAB gene, but the gamma subunit is encoded independently by the GNPTG gene, making GlcNAc an exception to the Garrod-Beadle principle that one enzyme is encoded by one gene [11],[12].
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