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Publication Abstract from PubMed

Mucin-type O-glycosylation is the most abundant type of O-glycosylation. It is initiated by the members of polypeptide N-acetyl-alpha-galactosaminyltransferase (ppGalNAc-T) family and closely associated with both physiological and pathological conditions such as coronary artery disease or Alzheimer' s disease. The lack of direct and selective inhibitors of ppGalNAc-Ts has largely impeded research progress in understanding the molecular events in mucin-type O-glycosylation. Here, we report that a small molecule, the plant flavonoid luteolin, selectively inhibits ppGalNAc-Ts in vitro and in cells. We found that luteolin inhibits ppGalNAc-T2 through a peptide/protein-competitive manner but not promiscuously, e.g. via aggregation-based activity. X-ray structural analysis revealed that luteolin binds to the PxP motif-binding site found in most protein substrates, which was further validated by comparing the interactions between luteolin with wildtype enzyme and mutants using 1H NMR-based binding experiments. Functional studies disclosed that luteolin at least partially reduced production of beta-amyloid (Abeta) protein by selectively inhibiting the activity of ppGalNAc-T isoforms. In conclusion, our study provides key structural and functional details on luteolin inhibiting ppGalNAc-T activity, opening up the way for further optimization of more potent and specific ppGalNAc-T inhibitors. Moreover, our findings may inform future investigations into site-specific O-GalNAc glycosylation and into the molecular mechanism of luteolin-mediated ppGalNAc-T inhibition.

The small molecule luteolin inhibits N-acetyl-alpha-galactosaminyltransferases and reduces mucin-type O-glycosylation of amyloid precursor protein.,Liu F, Xu K, Xu Z, Rivas ML, Li X, Lu J, Delso I, Merino P, Hurtado-Guerrero R, Zhang Y J Biol Chem. 2017 Oct 23. pii: jbc.M117.814202. doi: 10.1074/jbc.M117.814202. PMID:29061849^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.