Quantum Mechanical Calculations of Nucleophilic Attack in the Pseudouridine Synthesis Reaction

T, Lee; Kollman, Peter A.

doi:10.1021/ja991088n

Cited by 3 publications

(3 citation statements)

References 28 publications

(49 reference statements)

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“…No minimum of the potential energy in the investigated range of the C-N bond distance was observed (Fig. 8), which is in accordance with previous calculations in a smaller QM system [38] (see SI Figure S4 for the geometries corresponding to the end points of the coordinate scan).…”

Section: Michael Additionsupporting

confidence: 91%

“…Despite the experimental results, the exact function of the active site amino acids is still unclarified. Lee and Kollman studied the first step of the Michael addition scheme and the acylal scheme in a small QM model system containing only the aspartate and the uridine concluding that the attack of the C6 carbon by the catalytic Asp does not lead to a stable intermediate; however, the glycal scheme was not considered as a possible mechanism yet at that time [38].…”

Section: Introductionmentioning

confidence: 99%

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Quantum chemical calculations support pseudouridine synthase reaction through a glycal intermediate and provide details of the mechanism

et al. 2018

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Pseudouridylation affects almost all types of RNAs and the malfunction of pseudouridine synthases, the enzymes responsible for the uridine-pseudouridine transformation, is linked to severe diseases, like cancer and X-linked dyskeratosis congenita. Stand-alone and guide-dependent pseudouridine synthases share a common active site structure and are assumed to share the catalytic mechanism whose details are not yet elucidated. We performed quantum chemical calculations on model systems to investigate the initial steps of several pathways proposed in the literature or based on biochemical analogy and chemical intuition. Results suggest that the Michael addition scheme is unlikely since no stable adduct is formed between the C6-atom of the uridine and the catalytic aspartate. The nucleophilic substitution scheme is ruled out owing to the unfavorable steric arrangement of the reactants. Our results are in favor of the glycal scheme and provide details for the mechanism that is likely to start with the glycosidic bond cleavage between the ribose and uracil, followed by or coupled to the deprotonation of the C2′-atom of the sugar by the conserved catalytic aspartate. A possible role of the latter step is suggested to be the regulation of the intermediate reactivity: C2′ deprotonation leads to a low-energy intermediate with sufficient lifetime to allow base repositioning before reattachment to ribose by C-C bond formation.

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Section: Michael Additionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Quantum chemical calculations support pseudouridine synthase reaction through a glycal intermediate and provide details of the mechanism

et al. 2018

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“…The aspartate that is part of the highly conserved RTDKGV sequence in region II of Figure 1 has been shown to be essential in several Ψ synthases (33,34,55,56). The Asp residue is currently thought to be directly involved in catalysis (53,57,58). Since E. coli PSUI was sensitive to thiol reagents, it was suggested that cysteines would play a role in the mechanism of Ψ formation (20).…”

Section: Discussionmentioning

confidence: 99%

Pseudouridine Synthase 3 from Mouse Modifies the Anticodon Loop of tRNA

Chen

Patton

2000

Biochemistry

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A cDNA encoding mouse pseudouridine synthase 3 (mPus3p) has been cloned. The predicted protein has 34% identity with yeast pseudouridine synthase 3 (Pus3), an enzyme known to form pseudouridine at positions 38 and 39 in yeast tRNA. The cDNA is 1.7 kb, and when used as a probe on a Northern blot of total RNA from mouse tissues or cells in culture, a band at 1.8 kb was observed. The open reading frame codes for a protein of 481 amino acids with a predicted molecular mass of 55 552 Da. When mPus3p was in vitro translated and used in reactions with tRNA substrates from both yeast and humans, uridines at position 39 were modified to pseudouridine. In a tRNA substrate with a uridine at position 38 (human tRNA(Leu)), there was very slight formation of pseudouridine at that position after incubation with mPus3p.

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Recent Advances in Computing Heteroatom-Rich Five- and Six-Membered Ring Systems

Rauhut¹

2001

Advances in Heterocyclic Chemistry

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Quantum Mechanical Calculations of Nucleophilic Attack in the Pseudouridine Synthesis Reaction

Cited by 3 publications

References 28 publications

Quantum chemical calculations support pseudouridine synthase reaction through a glycal intermediate and provide details of the mechanism

Quantum chemical calculations support pseudouridine synthase reaction through a glycal intermediate and provide details of the mechanism

Pseudouridine Synthase 3 from Mouse Modifies the Anticodon Loop of tRNA

Recent Advances in Computing Heteroatom-Rich Five- and Six-Membered Ring Systems

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