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O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis.

ABSTRACT: Protein O-GlcNAcylation is an essential post-translational modification on hundreds of intracellular proteins in metazoa, catalyzed by O-linked ?-N-acetylglucosamine (O-GlcNAc) transferase (OGT) using unknown mechanisms of transfer and substrate recognition. Through crystallographic snapshots and mechanism-inspired chemical probes, we define how human OGT recognizes the sugar donor and acceptor peptide and uses a new catalytic mechanism of glycosyl transfer, involving the sugar donor ?-phosphate as the catalytic base as well as an essential lysine. This mechanism seems to be a unique evolutionary solution to the spatial constraints imposed by a bulky protein acceptor substrate and explains the unexpected specificity of a recently reported metabolic OGT inhibitor.

SUBMITTER: Schimpl M

PROVIDER: S-EPMC3509171 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis.

Schimpl Marianne M Zheng Xiaowei X Borodkin Vladimir S VS Blair David E DE Ferenbach Andrew T AT Schüttelkopf Alexander W AW Navratilova Iva I Aristotelous Tonia T Albarbarawi Osama O Robinson David A DA Macnaughtan Megan A MA van Aalten Daan M F DM

Nature chemical biology 20121028 12

Protein O-GlcNAcylation is an essential post-translational modification on hundreds of intracellular proteins in metazoa, catalyzed by O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) using unknown mechanisms of transfer and substrate recognition. Through crystallographic snapshots and mechanism-inspired chemical probes, we define how human OGT recognizes the sugar donor and acceptor peptide and uses a new catalytic mechanism of glycosyl transfer, involving the sugar donor α-phosphate ...[more]

PMID: 23103942

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