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RNA folding and catalysis mediated by iron (II).

ABSTRACT: Mg²? shares a distinctive relationship with RNA, playing important and specific roles in the folding and function of essentially all large RNAs. Here we use theory and experiment to evaluate Fe²? in the absence of free oxygen as a replacement for Mg²? in RNA folding and catalysis. We describe both quantum mechanical calculations and experiments that suggest that the roles of Mg²? in RNA folding and function can indeed be served by Fe²?. The results of quantum mechanical calculations show that the geometry of coordination of Fe²? by RNA phosphates is similar to that of Mg²?. Chemical footprinting experiments suggest that the conformation of the Tetrahymena thermophila Group I intron P4-P6 domain RNA is conserved between complexes with Fe²? or Mg²?. The catalytic activities of both the L1 ribozyme ligase, obtained previously by in vitro selection in the presence of Mg²?, and the hammerhead ribozyme are enhanced in the presence of Fe²? compared to Mg²?. All chemical footprinting and ribozyme assays in the presence of Fe²? were performed under anaerobic conditions. The primary motivation of this work is to understand RNA in plausible early earth conditions. Life originated during the early Archean Eon, characterized by a non-oxidative atmosphere and abundant soluble Fe²?. The combined biochemical and paleogeological data are consistent with a role for Fe²? in an RNA World. RNA and Fe²? could, in principle, support an array of RNA structures and catalytic functions more diverse than RNA with Mg²? alone.

SUBMITTER: Athavale SS

PROVIDER: S-EPMC3365117 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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RNA folding and catalysis mediated by iron (II).

Athavale Shreyas S SS Petrov Anton S AS Hsiao Chiaolong C Watkins Derrick D Prickett Caitlin D CD Gossett J Jared JJ Lie Lively L Bowman Jessica C JC O'Neill Eric E Bernier Chad R CR Hud Nicholas V NV Wartell Roger M RM Harvey Stephen C SC Williams Loren Dean LD

PloS one 20120531 5

Mg²⁺ shares a distinctive relationship with RNA, playing important and specific roles in the folding and function of essentially all large RNAs. Here we use theory and experiment to evaluate Fe²⁺ in the absence of free oxygen as a replacement for Mg²⁺ in RNA folding and catalysis. We describe both quantum mechanical calculations and experiments that suggest that the roles of Mg²⁺ in RNA folding and function can indeed be served by Fe²⁺. The results of quantum mechanical calculations show that th ...[more]

PMID: 22701543

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Project description:PHF8 (KDM7B) is a human non-heme 2-oxoglutarate (2OG) JmjC domain oxygenase that catalyzes the demethylation of the di/mono-Nε-methylated K9 residue of histone H3. Altered PHF8 activity is linked to genetic diseases and cancer; thus, it is an interesting target for epigenetic modulation. We describe the use of combined quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulations to explore the mechanism of PHF8, including dioxygen activation, 2OG binding modes, and substrate demethylation steps. A PHF8 crystal structure manifests the 2OG C-1 carboxylate bound to iron in a nonproductive orientation, i.e., trans to His247. A ferryl-oxo intermediate formed by activating dioxygen bound to the vacant site in this complex would be nonproductive, i.e., "off-line" with respect to reaction with Nε-methylated K9. We show rearrangement of the "off-line" ferryl-oxo intermediate to a productive "in-line" geometry via a solvent exchange reaction (called "ferryl-flip") is energetically unfavorable. The calculations imply that movement of the 2OG C-1 carboxylate prior to dioxygen binding at a five-coordination stage in catalysis proceeds with a low barrier, suggesting that two possible 2OG C-1 carboxylate geometries can coexist at room temperature. We explored alternative mechanisms for hydrogen atom transfer and show that second sphere interactions orient the Nε-methylated lysine in a conformation where hydrogen abstraction from a methyl C-H bond is energetically more favorable than hydrogen abstraction from the N-H bond of the protonated Nε-methyl group. Using multiple HAT reaction path calculations, we demonstrate the crucial role of conformational flexibility in effective hydrogen transfer. Subsequent hydroxylation occurs through a rebound mechanism, which is energetically preferred compared to desaturation, due to second sphere interactions. The overall mechanistic insights reveal the crucial role of iron-center rearrangement, second sphere interactions, and conformational flexibility in PHF8 catalysis and provide knowledge useful for the design of mechanism-based PHF8 inhibitors.

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RNA folding and catalysis mediated by iron (II).

Publications

RNA folding and catalysis mediated by iron (II).

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