期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 4, 页码 439-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nchembio.2300
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资金
- US National Institutes of Health [GM056207]
- US National Science Foundation [CHE-1213667]
- National Institutes of Health Chemistry-Biology Interface [NRSA 1-T-32-GM070421]
- National Science Foundation
- National Institutes of Health/National Institute of General Medical Sciences [DMR-0936384]
- National Institutes of Health, through the National Institute of General Medical Sciences [GM-103485]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1213667] Funding Source: National Science Foundation
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 glucosamine6- 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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