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Enzymatic characterization and inhibition of the nuclear variant of human O-GlcNAcase

Academic Article
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Overview

authors

  • Macauley, Matthew
  • Vocadlo, D. J.

publication date

  • June 2009

journal

  • Carbohydrate Research  Journal

abstract

  • Increasing cellular O-GlcNAc levels through pharmacological inhibition of O-GlcNAcase, the enzyme responsible for removal of the O-GlcNAc post-translational modification, is being increasingly used to aid in discerning the roles played by this form of intracellular glycosylation. Interestingly, two forms of O-GlcNAcase have been studied; a full-length isoform that is better characterized, and a shorter nuclear-localized variant, arising from failure to splice out one intron, which has not been as well characterized. Given the increasing use of O-GlcNAcase inhibitors as research tools, we felt that a clear understanding of how these inhibitors affect both isoforms of O-GlcNAcase is important for proper interpretation of studies making use of these inhibitors in cell culture and in vivo. Here we describe an enzymatic characterization of the nuclear variant of human O-GlcNAcase. We find that this short nuclear variant of O-GlcNAcase, which has the identical catalytic domain as the full-length enzyme, has similar trends in a pH-rate profile and Taft linear free energy analysis as the full-length enzyme. These findings strongly suggest that both enzymes use broadly similar transition states. Consistent with this interpretation, the short isoform is potently inhibited by several previously described inhibitors of full-length O-GlcNAcase including PUGNAc, NAG-thiazoline, and the selective O-GlcNAcase inhibitor NButGT. These findings contrast with earlier studies and suggest that studies using O-GlcNAcase inhibitors in cultured cells or in vivo can be interpreted with the knowledge that both these forms of O-GlcNAcase are inhibited when present.

subject areas

  • Alternative Splicing
  • Amino Acid Sequence
  • Cell Nucleus
  • Cloning, Molecular
  • Enzyme Inhibitors
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Molecular Sequence Data
  • Recombinant Fusion Proteins
  • Sequence Deletion
  • beta-N-Acetylhexosaminidases
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Research

keywords

  • MGEA5
  • Nuclear variant
  • O-GlcNAc
  • O-GlcNAcase
  • OGA isoform
  • beta-N-Acetylglucosaminidase
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Identity

International Standard Serial Number (ISSN)

  • 0008-6215

Digital Object Identifier (DOI)

  • 10.1016/j.carres.2009.04.017

PubMed ID

  • 19423084
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Additional Document Info

start page

  • 1079

end page

  • 1084

volume

  • 344

issue

  • 9

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