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Nat Chem Biol. 2017 Apr;13(4):439-445. doi: 10.1038/nchembio.2300. Epub 2017 Feb 13.

The GlcN6P cofactor plays multiple catalytic roles in the glmS ribozyme.

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Department of Chemistry and Center for RNA Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
X-ray Crystallography Facility, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, USA.
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.


RNA enzymes (ribozymes) have remarkably diverse biological roles despite having limited chemical diversity. Protein enzymes enhance their reactivity through recruitment of cofactors; likewise, the naturally occurring glmS ribozyme uses the glucosamine-6-phosphate (GlcN6P) organic cofactor for phosphodiester bond cleavage. Prior structural and biochemical studies have implicated GlcN6P as the general acid. Here we describe new catalytic roles of GlcN6P through experiments and calculations. Large stereospecific normal thio effects and a lack of metal-ion rescue in the holoribozyme indicate that nucleobases and the cofactor play direct chemical roles and align the active site for self-cleavage. Large stereospecific inverse thio effects in the aporibozyme suggest that the GlcN6P cofactor disrupts an inhibitory interaction of the nucleophile. Strong metal-ion rescue in the aporibozyme reveals that this cofactor also provides electrostatic stabilization. Ribozyme organic cofactors thus perform myriad catalytic roles, thereby allowing RNA to compensate for its limited functional diversity.

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