DPAGT1

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Protein-coding gene in the species Homo sapiens

title: "DPAGT1" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public description: "Protein-coding gene in the species Homo sapiens" topic_path: "uncategorized" source: "https://en.wikipedia.org/wiki/DPAGT1" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in the species Homo sapiens ::

UDP-N-acetylglucosamine—dolichyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme that in humans is encoded by the DPAGT1 gene.

Mutations in DPAGT1 cause myasthenia.

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.

Chemistry

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.

Uridine diphosphate N-acetylglucosamine + dolichyl-phosphata ↔ dolichyl-phosphate N-acetylglucosamine + UMP

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. ::figure[src="https://upload.wikimedia.org/wikipedia/commons/f/f0/DPAGT1_Catalysis.tif" caption="Synthesis of Dolichyl-P-P-GlcNAc from UPD-GlcNAc and Dolichyl-P via DPAGT1 in N-Glycan Biosynthesis" alt="DPAGT1 Catalysis"] ::

Structure

Despite the challenge of obtaining eukaryotic membrane protein structure, co-crystal structures of DPAGT1 with tunicamycin or UDP-GlcNAc have been reported in 2018. 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.

::figure[src="https://upload.wikimedia.org/wikipedia/commons/a/a3/DPAGT1_topology.tif" caption="Topology of DPAGT1"] ::

Biochemistry

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.

DPAGT1 inhibitors

Tunicamycins (e.g., tunicamycin V, the major component) have long been used to study endoplasmic reticulum (ER) stress responses induced by the accumulation of unfolded proteins in cancer cells. However, their application in cancer biology has been limited due to off-target effects, restricting their use mainly to in vitro studies and, to a lesser extent, in vivo experiments involving intratumoral administration. More recently, the natural product muraymycin A1 was identified as a more potent inhibitor of DPAGT1 than tunicamycin V. Originally characterized as a strong MraY inhibitor with antibacterial activity against Staphylococcus species, muraymycin A1 has not yet been evaluated for cytotoxicity or systemic toxicity in mouse infection models. Recent findings indicate that muraymycin A1 exhibits selective antiproliferative activity against various solid cancers. This selective toxicity of muraymycin A1, a novel DPAGT1 inhibitor, challenges the prevailing notion that the cytotoxicity of tunicamycins toward mammalian cells arises primarily from DPAGT1 inhibition. Instead, muraymycin A1 appears to induce apoptosis in solid cancers that depend on DPAGT1 overexpression for growth and progression. ::figure[src="https://upload.wikimedia.org/wikipedia/commons/3/3f/Muraymycin_A1_and_TM-V.jpg"] ::

References

References

  1. (September 1993). "A sequence-tagged site map of human chromosome 11". Genomics.
  2. "Entrez Gene: DPAGT1 dolichyl-phosphate (UDP-N-acetylglucosamine) N-acetylglucosaminephosphotransferase 1 (GlcNAc-1-P transferase)".
  3. (May 2014). "DPAGT1 myasthenia and myopathy: genetic, phenotypic, and expression studies". Neurology.
  4. (March 2018). "GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation". Nature Structural & Molecular Biology.
  5. (November 2018). "Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design". Cell.
  6. (August 2025). "Total Synthesis of Muraymycin A1: A Protecting Group Strategy for Nucleoside Antibiotic Synthesis.". Org Lett.
  7. (2025). "DPAGT1-Perspective as an Anticancer Drug Target". Molecules.

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