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Literature summary extracted from

  • Kurosu, M.
    Structure-based drug discovery by targeting N-glycan biosynthesis, dolichyl-phosphate N-acetylglucosaminephosphotransferase (2019), Future Med. Chem., 11, 927-933 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
2.7.8.15 medicine selective DPAGT1 inhibitors have the promising therapeutic potential for certain solid cancers that require increased branching of N-linked glycans in their growth progressions. Inhibition of DPAGT1 may be the Achilles' heel of the biosynthesis of essential N-glycan in solid tumors Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.7.8.15 aminouridyl phenoxypiperidinbenzyl butanamide APPB, APPB shows a strong DPAGT1 inhibitory activity and selectively inhibits growth of the solid tumors at low micromolar concentrations, but does not inhibit growth of a leukemia cell and the healthy cells at these concentrations. Growth inhibition of APPB against the solid cancers is correlated with the expression level of DPAGT1. Docking studies of APPB to DPAGT1, overview Homo sapiens
2.7.8.15 additional information IC50 of compounds in cytotoxic inhibition of growth of several cancer cell lines, overview. Introduction of pharmacologically benign hydrophobic groups which occupy the proposed Dol-P binding site is essential to exhibit DPAGT1 inhibitory activity. Significant conformational changes are observed in the C-terminal end of TM-9, CL-9 and CL-1 in DPAGT1-ligand bound structures, the other portions of DPAGT1 are subtly changed upon binding Homo sapiens
2.7.8.15 tunicamycin enzyme binding structure analysis, interferes with the first committed enzyme of N-glycan biosynthesis, DPAGT1. A Mg2+ ion is not involved in the binding mode. Arg301, Asn185, and Asp252 residues directly form hydrogen bonding with the C4-OH, C2-NH and C3-OH groups of the GalNAc moiety. The fatty acid chain of tunicamycin is occupied in the hydrophobic tunnel Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.7.8.15 endoplasmic reticulum membrane integral membrane protein Homo sapiens 5789
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.8.15 UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate Homo sapiens
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 UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.7.8.15 Homo sapiens Q9H3H5
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.8.15 additional information the uridine moiety of UDP-GlcNAc is coordinated with eight hydrogen bonds between the one backbone amide (Leu46), seven side chains of the amino acids and two water molecules. The uridine moiety of tunicamycin occupies the identical binding sites of UDP-GlcNAc Homo sapiens ?
-
-
2.7.8.15 UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
-
 Homo sapiens UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
-
 ?

Subunits

EC Number Subunits Comment Organism
2.7.8.15 More in solution, DPAGT1 exists predominantly as a dimer Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
2.7.8.15 dolichyl-phosphate N-acetylglucosaminephosphotransferase
-
 Homo sapiens
2.7.8.15 DPAGT1
-
 Homo sapiens

General Information

EC Number General Information Comment Organism
2.7.8.15 malfunction N-glycan biosynthesis can be inhibited by disruption of the first committed enzyme, DPAGT1 Homo sapiens
2.7.8.15 additional information catalytic mechanism of DPAGT1, overview Homo sapiens
2.7.8.15 physiological function DPAGT1 is an integral membrane protein localized in the endoplasmic reticulum (ER) that catalyzes the transformation from UDP-GlcNAc to N-acetyl-D-glucosaminyl-diphosphodolichol. Anchored N-acetyl-D-glucosaminyldiphosphodolichol in the ER membrane is modified by sequential glycosyltransferases to form dolichol-linked oligosaccharide precursors that are transferred to selected asparagine residues of polypeptide chains by oligosaccharyltransferase. DPAGT1 catalyzes N-glycosylation of beta-catenin and E-cadherin Homo sapiens