Glycopeptide probes for understanding peptide specificity of the folding sensor enzyme UGGT

Kudo, Takaya; Hirano, Masao; Ishihara, Toshihiro; Shimura, Shun; Totani, Kiichiro

doi:10.1016/j.bmcl.2014.11.013

Cited by 10 publications

(10 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the enzyme is inhibited by UDP, its effect is only modest and not specific to UGGT. Based on these, recent studies addressed the development of G‐II specific inhibitors [53, 68] and glycopeptide‐based ligands of UGGT [69] …”

Section: Functional Analysis Of Gpqc By Synthetic Substratesmentioning

confidence: 99%

Chemical‐Synthesis‐Based Approach to Glycoprotein Functions in the Endoplasmic Reticulum

Ito

Kajihara

Takeda

2020

Chemistry A European J

View full text Add to dashboard Cite

The introduction of Asn‐linked glycans to nascent polypeptides occurs in the lumen of the endoplasmic reticulum of eukaryotic cells. After the removal of specific sugar residues, glycoproteins acquire signals in the glycoprotein quality control (GPQC) system and enter the folding cycle composed of lectin‐chaperones calnexin (CNX) and calreticulin (CRT), glucosidase II (G‐II), and UDP‐Glc:glycoprotein glucosyltransferase (UGGT). G‐II initiates glycoproteins’ entry and exit from the cycle, and UGGT serves as the “folding sensor”. This account summarizes our effort to analyze the properties of enzymes and lectins that play important roles in GPQC, especially those involved in the CNX/CRT cycle. To commence our study, general methods for the synthesis of high‐mannose‐type glycans and glycoproteins were established. Based on these, various substrates to analyze components of the GPQC were created, and properties of CRT, G‐II, and UGGT have been clarified.

show abstract

Section: Functional Analysis Of Gpqc By Synthetic Substratesmentioning

confidence: 99%

Chemical‐Synthesis‐Based Approach to Glycoprotein Functions in the Endoplasmic Reticulum

Ito

Kajihara

Takeda

2020

Chemistry A European J

View full text Add to dashboard Cite

show abstract

“…UGGT is inhibited by its product UDP 24 and by squaryl derivatives of UDP 25 ; by the non-hydrolysable UDP-glucose (UDP-Glc) cofactor analog UDP-2-deoxy-2-fluoro-D-glucose (U2F); and by synthetic analogs of the N-linked Man 9 GlcNAc 2 glycan substrate. 26,27 Obviously, none of these molecules are UGGT-specific. Recently, a fragment-based lead discovery effort 28 yielded a UGGT1 and UGGT2 inhibitor, which is being chemically modified to increase its affinity and selectivity.…”

Section: Introductionmentioning

confidence: 99%

Rescue of secretion of rare‐disease‐associated misfolded mutant glycoproteins in UGGT1 knock‐out mammalian cells

Tax,

Guay,

Pantalone

et al. 2024

Traffic

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) retention of misfolded glycoproteins is mediated by the ER‐localized eukaryotic glycoprotein secretion checkpoint, UDP‐glucose glycoprotein glucosyl‐transferase (UGGT). The enzyme recognizes a misfolded glycoprotein and flags it for ER retention by re‐glucosylating one of its N‐linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT‐mediated ER retention can cause rare disease, even if the mutant glycoprotein retains activity (“responsive mutant”). Using confocal laser scanning microscopy, we investigated here the subcellular localization of the human Trop‐2‐Q118E, E227K and L186P mutants, which cause gelatinous drop‐like corneal dystrophy (GDLD). Compared with the wild‐type Trop‐2, which is correctly localized at the plasma membrane, these Trop‐2 mutants are retained in the ER. We studied fluorescent chimeras of the Trop‐2 Q118E, E227K and L186P mutants in mammalian cells harboring CRISPR/Cas9‐mediated inhibition of the UGGT1 and/or UGGT2 genes. The membrane localization of the Trop‐2 Q118E, E227K and L186P mutants was successfully rescued in UGGT1−/−cells. UGGT1 also efficiently reglucosylated Trop‐2‐Q118E‐EYFP in cellula. The study supports the hypothesis that UGGT1 modulation would constitute a novel therapeutic strategy for the treatment of pathological conditions associated to misfolded membrane glycoproteins (whenever the mutation impairs but does not abrogate function), and it encourages the testing of modulators of ER glycoprotein folding quality control as broad‐spectrum rescue‐of‐secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants.

show abstract

“…6 Upon approaching the correct folding state, the binding between the G1M9-glycoprotein and CNX/CRT is weakened, and subsequent cleavage of the terminal glucose by GII produces the Man 9 GlcNAc 2 (M9)-glyco-protein. 7 The M9-glycoprotein is recognized by the folding sensor enzyme UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), [8][9][10] which checks the folding state. The partially folded glycoprotein is glucosylated by UGGT1 before acceleration of G1M9-glycoprotein folding by CNX/CRT.…”

Section: Introductionmentioning

confidence: 99%

Synthetic trisaccharides reveal discrimination ofendo-glycosidic linkages byexo-acting α-1,2-mannosidases in the endoplasmic reticulum

2021

Self Cite

View full text Add to dashboard Cite

show abstract

Glycopeptide probes for understanding peptide specificity of the folding sensor enzyme UGGT

Cited by 10 publications

References 18 publications

Chemical‐Synthesis‐Based Approach to Glycoprotein Functions in the Endoplasmic Reticulum

Chemical‐Synthesis‐Based Approach to Glycoprotein Functions in the Endoplasmic Reticulum

Rescue of secretion of rare‐disease‐associated misfolded mutant glycoproteins in UGGT1 knock‐out mammalian cells

Synthetic trisaccharides reveal discrimination ofendo-glycosidic linkages byexo-acting α-1,2-mannosidases in the endoplasmic reticulum

Contact Info

Product

Resources

About