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From the same journal

From the same journal

Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis

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  • Matthew K Bilyard
  • Henry J Bailey
  • Lluís Raich
  • Maria A Gafitescu
  • Takuya Machida
  • Javier Iglésias-Fernández
  • Seung Seo Lee
  • Christopher D Spicer
  • Carme Rovira
  • Wyatt W Yue
  • Benjamin G Davis


Publication details

DateAccepted/In press - 31 Aug 2018
DateE-pub ahead of print - 24 Oct 2018
DatePublished (current) - 8 Nov 2018
Issue number7730
Number of pages6
Pages (from-to)235–240
Early online date24/10/18
Original languageEnglish


Biosynthesis of glycogen, the essential glucose (and hence energy) storage molecule in humans, animals and fungi1, is initiated by the glycosyltransferase enzyme, glycogenin (GYG). Deficiencies in glycogen formation cause neurodegenerative and metabolic disease2-4, and mouse knockout5 and inherited human mutations6 of GYG impair glycogen synthesis. GYG acts as a 'seed core' for the formation of the glycogen particle by catalysing its own stepwise autoglucosylation to form a covalently bound gluco-oligosaccharide chain at initiation site Tyr 195. Precise mechanistic studies have so far been prevented by an inability to access homogeneous glycoforms of this protein, which unusually acts as both catalyst and substrate. Here we show that unprecedented direct access to different, homogeneously glucosylated states of GYG can be accomplished through a palladium-mediated enzyme activation 'shunt' process using on-protein C-C bond formation. Careful mimicry of GYG intermediates recapitulates catalytic activity at distinct stages, which in turn allows discovery of triphasic kinetics and substrate plasticity in GYG's use of sugar substrates. This reveals a tolerant but 'proof-read' mechanism that underlies the precision of this metabolic process. The present demonstration of direct, chemically controlled access to intermediate states of active enzymes suggests that such ligation-dependent activation could be a powerful tool in the study of mechanism.

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