DPAGT1 catalyzes the transformation of dolichyl-phosphate N-acetylglucosamine from Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and dolichyl-phosphata, which is the first step in N-glycan biosynthesis in mammalian cells.
The generated dolichyl-phosphate N-acetylglucosamine is modified via sequential glycosyltransferases, forming Glc3Man9GlcNAc2-P-P-dolichyl which is used for glycosylation of asparagine (Asn or N) residue of polypeptides.
Synthesis of Dolichyl-P-P-GlcNAc from UPD-GlcNAc and Dolichyl-P via DPAGT1 in N-Glycan Biosynthesis
Structureedit
Despite the challenge of obtaining eukaryotic membrane protein structure, co-crystal structures of DPAGT1 with tunicamycin or UDP-GlcNAc have been reported in 2018. [8][9] DPAGT1 consists of 10 transmembrane segments (TM1 to 10). Three loops on the endoplasmic reticulum (ER) side and five loops on the cytoplasmic side (Loops A-E) connect the transmembrane segments, where TM4, TM5, TM7, TM8, TM9, Loop A, Loop E form the UDP-GlcNAc binding domain. Dolichyl-phosphate (Dol-P) is predicted to bind the “hydrophobic tunnel” created by TM4, TM5 and TM9 within the lipid bilayer. The uridine moiety of tunicamycin occupies the identical binding sites of UDP-GlcNAc. The lipid tail moiety of tunicamycin occupies the hydrophobic tunnel. Significant conformational changes are observed in the C-terminal end of TM-9, Loop A, and Loop E in DPAGT1-ligand bound structures.
Topology of DPAGT1
Biochemistryedit
Changes and diversification of the expression profile of cell surface glycans based on the underlying glycobiology have received significant attention from the scientific community. N-Linked and O-linked glycans are the most abundant forms of protein glycosylation and occur on proteins destined for the secretory pathway. Recent studies of cancer immunotherapy are based on the immunogenicity of truncated O-glycan chains (e.g., Tn, sTn, T, and sLea/x). Despite the prevalence of N-linked glycan changes in the development of tumor cells, therapeutic antibodies against N-linked glycans have not been developed. This is likely attributable to the lack of specificity of N-linked glycans between normal and malignant cells. Abnormal branching of N-linked glycans has been observed in certain cancer cells. Altered glycosylation of N-linked glycans in cancers is typically associated with upregulation of ß1,6-N-acetylglucosaminyltransferase-3/5 (GnT3/5), enhancing ß1,6-branching.
Referencesedit
^ abcGRCh38: Ensembl release 89: ENSG00000172269 – Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000032123 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Smith MW, Clark SP, Hutchinson JS, Wei YH, Churukian AC, Daniels LB, et al. (September 1993). "A sequence-tagged site map of human chromosome 11". Genomics. 17 (3): 699–725. doi:10.1006/geno.1993.1392. PMID 8244387.
^Selcen D, Shen XM, Brengman J, Li Y, Stans AA, Wieben E, Engel AG (May 2014). "DPAGT1 myasthenia and myopathy: genetic, phenotypic, and expression studies". Neurology. 82 (20): 1822–1830. doi:10.1212/WNL.0000000000000435. PMC4035711. PMID 24759841.
^Yoo J, Mashalidis EH, Kuk AC, Yamamoto K, Kaeser B, Ichikawa S, Lee SY (March 2018). "GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation". Nature Structural & Molecular Biology. 25 (3): 217–224. doi:10.1038/s41594-018-0031-y. PMC5840018. PMID 29459785.
^Dong YY, Wang H, Pike AC, Cochrane SA, Hamedzadeh S, Wyszyński FJ, et al. (November 2018). "Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design". Cell. 175 (4): 1045–1058.e16. doi:10.1016/j.cell.2018.10.037. PMC6218659. PMID 30388443.
Further readingedit
Freeze HH (December 2001). "Update and perspectives on congenital disorders of glycosylation". Glycobiology. 11 (12): 129R–143R. doi:10.1093/glycob/11.12.129R. PMID 11805072.
Freeze HH (December 2002). "Human disorders in N-glycosylation and animal models". Biochimica et Biophysica Acta (BBA) - General Subjects. 1573 (3): 388–393. doi:10.1016/S0304-4165(02)00408-7. PMID 12417423.
Miller BS, Freeze HH (March 2003). "New disorders in carbohydrate metabolism: congenital disorders of glycosylation and their impact on the endocrine system". Reviews in Endocrine & Metabolic Disorders. 4 (1): 103–113. doi:10.1023/A:1021883605280. PMID 12618564. S2CID 26028477.
Volpe JJ, Sakakihara Y, Ishii S (June 1987). "Dolichol-linked glycoprotein synthesis in developing mammalian brain: maturational changes of the N-acetylglucosaminylphosphotransferase". Brain Research. 430 (2): 277–284. doi:10.1016/0165-3806(87)90160-x. PMID 3038274.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
Eckert V, Blank M, Mazhari-Tabrizi R, Mumberg D, Funk M, Schwarz RT (January 1998). "Cloning and functional expression of the human GlcNAc-1-P transferase, the enzyme for the committed step of the dolichol cycle, by heterologous complementation in Saccharomyces cerevisiae". Glycobiology. 8 (1): 77–85. doi:10.1093/glycob/8.1.77. PMID 9451016.
Meissner JD, Naumann A, Mueller WH, Scheibe RJ (March 1999). "Regulation of UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosamine-1-phosphate transferase by retinoic acid in P19 cells". The Biochemical Journal. 338 ( Pt 2) (2): 561–568. doi:10.1042/0264-6021:3380561. PMC1220086. PMID 10024536.
Regis S, Dagnino F, Caroli F, Filocamo M (October 2002). "Genomic structure of the human UDP-GlcNAc:dolichol-P GlcNAc-1-P transferase gene". DNA Sequence. 13 (5): 245–250. doi:10.1080/1042517021000017126. PMID 12592703. S2CID 25176842.
Newell JW, Seo NS, Enns GM, McCraken M, Mantovani JF, Freeze HH (July 2003). "Congenital disorder of glycosylation Ic in patients of Indian origin". Molecular Genetics and Metabolism. 79 (3): 221–228. doi:10.1016/S1096-7192(03)00089-1. PMID 12855228.
Wu X, Rush JS, Karaoglu D, Krasnewich D, Lubinsky MS, Waechter CJ, et al. (August 2003). "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij". Human Mutation. 22 (2): 144–150. doi:10.1002/humu.10239. PMID 12872255. S2CID 35331823.
External linksedit
GeneReviews/NCBI/NIH/UW entry on Congenital Disorders of Glycosylation Overview
This article on a gene on human chromosome 11 is a stub. You can help Wikipedia by expanding it.
dpagt1, this, article, technical, most, readers, understand, please, help, improve, make, understandable, experts, without, removing, technical, details, october, 2009, learn, when, remove, this, message, acetylglucosamine, dolichyl, phosphate, acetylglucosami. This article may be too technical for most readers to understand Please help improve it to make it understandable to non experts without removing the technical details October 2009 Learn how and when to remove this message UDP N acetylglucosamine dolichyl phosphate N acetylglucosaminephosphotransferase is an enzyme that in humans is encoded by the DPAGT1 gene 5 6 DPAGT1IdentifiersAliasesDPAGT1 ALG7 CDG Ij CDG1J CMSTA2 D11S366 DGPT DPAGT DPAGT2 G1PT GPT UAGT UGAT CMS13 dolichyl phosphate N acetylglucosaminephosphotransferase 1External IDsOMIM 191350 MGI 1196396 HomoloGene 1058 GeneCards DPAGT1 OMA DPAGT1 orthologsGene location Human Chr Chromosome 11 human 1 Band11q23 3Start119 096 025 bp 1 End119 108 331 bp 1 Gene location Mouse Chr Chromosome 9 mouse 2 Band9 A5 2 9 24 84 cMStart44 237 316 bp 2 End44 245 197 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inbody of pancreasright adrenal glandstromal cell of endometriumleft adrenal glandright lobe of liverright uterine tuberectumbody of stomachcanal of the cervixright lobe of thyroid glandTop expressed inyolk sacseminal vesiculalacrimal glandparotid glandankle jointfacial motor nucleusproximal tubuleendocardial cushionleft lobe of liverneural tubeMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functiontransferase activity UDP N acetylglucosamine lysosomal enzyme N acetylglucosaminephosphotransferase activity phospho N acetylmuramoyl pentapeptide transferase activity glycosyltransferase activity UDP N acetylglucosamine dolichyl phosphate N acetylglucosaminephosphotransferase activity metal ion bindingCellular componentintegral component of endoplasmic reticulum membrane endoplasmic reticulum membrane membrane intracellular membrane bounded organelle endoplasmic reticulum integral component of membraneBiological processprotein glycosylation dolichol linked oligosaccharide biosynthetic process dolichol metabolic process protein complex oligomerization UDP N acetylglucosamine metabolic process protein N linked glycosylation dolichyl diphosphate biosynthetic processSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez179813478EnsemblENSG00000172269ENSMUSG00000032123UniProtQ9H3H5P42867RefSeq mRNA NM 001382NM 203316NM 007875NM 001364464RefSeq protein NP 001373NP 031901NP 001351393Location UCSC Chr 11 119 1 119 11 MbChr 9 44 24 44 25 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Mutations in DPAGT1 cause myasthenia 7 The protein encoded by this gene is an enzyme that catalyzes the first step in the dolichol linked oligosaccharide pathway also see Genetic pathway for glycoprotein biosynthesis This enzyme belongs to the glycosyltransferase family 4 This protein is an integral membrane protein of the endoplasmic reticulum The congenital disorder of glycosylation type Ij is caused by mutation in the gene encoding this enzyme Alternatively spliced transcript variants encoding different isoforms have been identified 6 Contents 1 Chemistry 2 Structure 3 Biochemistry 4 References 5 Further reading 6 External linksChemistry editDPAGT1 catalyzes the transformation of dolichyl phosphate N acetylglucosamine from Uridine diphosphate N acetylglucosamine UDP GlcNAc and dolichyl phosphata which is the first step in N glycan biosynthesis in mammalian cells Uridine diphosphate N acetylglucosamine dolichyl phosphata dolichyl phosphate N acetylglucosamine UMPThe generated dolichyl phosphate N acetylglucosamine is modified via sequential glycosyltransferases forming Glc3Man9GlcNAc2 P P dolichyl which is used for glycosylation of asparagine Asn or N residue of polypeptides nbsp Synthesis of Dolichyl P P GlcNAc from UPD GlcNAc and Dolichyl P via DPAGT1 in N Glycan BiosynthesisStructure editDespite the challenge of obtaining eukaryotic membrane protein structure co crystal structures of DPAGT1 with tunicamycin or UDP GlcNAc have been reported in 2018 8 9 DPAGT1 consists of 10 transmembrane segments TM1 to 10 Three loops on the endoplasmic reticulum ER side and five loops on the cytoplasmic side Loops A E connect the transmembrane segments where TM4 TM5 TM7 TM8 TM9 Loop A Loop E form the UDP GlcNAc binding domain Dolichyl phosphate Dol P is predicted to bind the hydrophobic tunnel created by TM4 TM5 and TM9 within the lipid bilayer The uridine moiety of tunicamycin occupies the identical binding sites of UDP GlcNAc The lipid tail moiety of tunicamycin occupies the hydrophobic tunnel Significant conformational changes are observed in the C terminal end of TM 9 Loop A and Loop E in DPAGT1 ligand bound structures nbsp Topology of DPAGT1Biochemistry editChanges and diversification of the expression profile of cell surface glycans based on the underlying glycobiology have received significant attention from the scientific community N Linked and O linked glycans are the most abundant forms of protein glycosylation and occur on proteins destined for the secretory pathway Recent studies of cancer immunotherapy are based on the immunogenicity of truncated O glycan chains e g Tn sTn T and sLea x Despite the prevalence of N linked glycan changes in the development of tumor cells therapeutic antibodies against N linked glycans have not been developed This is likely attributable to the lack of specificity of N linked glycans between normal and malignant cells Abnormal branching of N linked glycans has been observed in certain cancer cells Altered glycosylation of N linked glycans in cancers is typically associated with upregulation of ss1 6 N acetylglucosaminyltransferase 3 5 GnT3 5 enhancing ss1 6 branching References edit a b c GRCh38 Ensembl release 89 ENSG00000172269 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000032123 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Smith MW Clark SP Hutchinson JS Wei YH Churukian AC Daniels LB et al September 1993 A sequence tagged site map of human chromosome 11 Genomics 17 3 699 725 doi 10 1006 geno 1993 1392 PMID 8244387 a b Entrez Gene DPAGT1 dolichyl phosphate UDP N acetylglucosamine N acetylglucosaminephosphotransferase 1 GlcNAc 1 P transferase Selcen D Shen XM Brengman J Li Y Stans AA Wieben E Engel AG May 2014 DPAGT1 myasthenia and myopathy genetic phenotypic and expression studies Neurology 82 20 1822 1830 doi 10 1212 WNL 0000000000000435 PMC 4035711 PMID 24759841 Yoo J Mashalidis EH Kuk AC Yamamoto K Kaeser B Ichikawa S Lee SY March 2018 GlcNAc 1 P transferase tunicamycin complex structure reveals basis for inhibition of N glycosylation Nature Structural amp Molecular Biology 25 3 217 224 doi 10 1038 s41594 018 0031 y PMC 5840018 PMID 29459785 Dong YY Wang H Pike AC Cochrane SA Hamedzadeh S Wyszynski FJ et al November 2018 Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design Cell 175 4 1045 1058 e16 doi 10 1016 j cell 2018 10 037 PMC 6218659 PMID 30388443 Further reading editFreeze HH December 2001 Update and perspectives on congenital disorders of glycosylation Glycobiology 11 12 129R 143R doi 10 1093 glycob 11 12 129R PMID 11805072 Freeze HH December 2002 Human disorders in N glycosylation and animal models Biochimica et Biophysica Acta BBA General Subjects 1573 3 388 393 doi 10 1016 S0304 4165 02 00408 7 PMID 12417423 Miller BS Freeze HH March 2003 New disorders in carbohydrate metabolism congenital disorders of glycosylation and their impact on the endocrine system Reviews in Endocrine amp Metabolic Disorders 4 1 103 113 doi 10 1023 A 1021883605280 PMID 12618564 S2CID 26028477 Volpe JJ Sakakihara Y Ishii S June 1987 Dolichol linked glycoprotein synthesis in developing mammalian brain maturational changes of the N acetylglucosaminylphosphotransferase Brain Research 430 2 277 284 doi 10 1016 0165 3806 87 90160 x PMID 3038274 Maruyama K Sugano S January 1994 Oligo capping a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides Gene 138 1 2 171 174 doi 10 1016 0378 1119 94 90802 8 PMID 8125298 Bonaldo MF Lennon G Soares MB September 1996 Normalization and subtraction two approaches to facilitate gene discovery Genome Research 6 9 791 806 doi 10 1101 gr 6 9 791 PMID 8889548 Suzuki Y Yoshitomo Nakagawa K Maruyama K Suyama A Sugano S October 1997 Construction and characterization of a full length enriched and a 5 end enriched cDNA library Gene 200 1 2 149 156 doi 10 1016 S0378 1119 97 00411 3 PMID 9373149 Eckert V Blank M Mazhari Tabrizi R Mumberg D Funk M Schwarz RT January 1998 Cloning and functional expression of the human GlcNAc 1 P transferase the enzyme for the committed step of the dolichol cycle by heterologous complementation in Saccharomyces cerevisiae Glycobiology 8 1 77 85 doi 10 1093 glycob 8 1 77 PMID 9451016 Meissner JD Naumann A Mueller WH Scheibe RJ March 1999 Regulation of UDP N acetylglucosamine dolichyl phosphate N acetylglucosamine 1 phosphate transferase by retinoic acid in P19 cells The Biochemical Journal 338 Pt 2 2 561 568 doi 10 1042 0264 6021 3380561 PMC 1220086 PMID 10024536 Regis S Dagnino F Caroli F Filocamo M October 2002 Genomic structure of the human UDP GlcNAc dolichol P GlcNAc 1 P transferase gene DNA Sequence 13 5 245 250 doi 10 1080 1042517021000017126 PMID 12592703 S2CID 25176842 Newell JW Seo NS Enns GM McCraken M Mantovani JF Freeze HH July 2003 Congenital disorder of glycosylation Ic in patients of Indian origin Molecular Genetics and Metabolism 79 3 221 228 doi 10 1016 S1096 7192 03 00089 1 PMID 12855228 Wu X Rush JS Karaoglu D Krasnewich D Lubinsky MS Waechter CJ et al August 2003 Deficiency of UDP GlcNAc Dolichol Phosphate N Acetylglucosamine 1 Phosphate Transferase DPAGT1 causes a novel congenital disorder of Glycosylation Type Ij Human Mutation 22 2 144 150 doi 10 1002 humu 10239 PMID 12872255 S2CID 35331823 External links editGeneReviews NCBI NIH UW entry on Congenital Disorders of Glycosylation Overview nbsp This article on a gene on human chromosome 11 is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title DPAGT1 amp oldid 1187771545, wikipedia, wiki, book, books, library,
