Theoretical investigation on the reaction mechanism of UTP cyclohydrolase

Ouyang, Qingwen; Pang, Yunjie; Chang, Yuan; Tan, Hongwei; Li, Xichen; Chen, Guangju

doi:10.1039/d2cp01740g

Cited by 3 publications

(2 citation statements)

References 34 publications

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“…This was demonstrated for the breakdown of uracil, in which the nucleoside triphosphate cyclohydrolase (UrcA) catalyzes the two-step hydrolysis of uridine triphosphate (UTP). MD simulations showed that hydrogen bond interaction helps the reaction intermediate undergo spontaneous conformation overturn in the active site of UrcA [ 72 ].…”

Section: Electrostatics Of Wild-type Biological Macromoleculesmentioning

confidence: 99%

Electrostatics in Computational Biophysics and Its Implications for Disease Effects

Sun

Poudel

Alexov

et al. 2022

IJMS

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This review outlines the role of electrostatics in computational molecular biophysics and its implication in altering wild-type characteristics of biological macromolecules, and thus the contribution of electrostatics to disease mechanisms. The work is not intended to review existing computational approaches or to propose further developments. Instead, it summarizes the outcomes of relevant studies and provides a generalized classification of major mechanisms that involve electrostatic effects in both wild-type and mutant biological macromolecules. It emphasizes the complex role of electrostatics in molecular biophysics, such that the long range of electrostatic interactions causes them to dominate all other forces at distances larger than several Angstroms, while at the same time, the alteration of short-range wild-type electrostatic pairwise interactions can have pronounced effects as well. Because of this dual nature of electrostatic interactions, being dominant at long-range and being very specific at short-range, their implications for wild-type structure and function are quite pronounced. Therefore, any disruption of the complex electrostatic network of interactions may abolish wild-type functionality and could be the dominant factor contributing to pathogenicity. However, we also outline that due to the plasticity of biological macromolecules, the effect of amino acid mutation may be reduced, and thus a charge deletion or insertion may not necessarily be deleterious.

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Section: Electrostatics Of Wild-type Biological Macromoleculesmentioning

confidence: 99%

Electrostatics in Computational Biophysics and Its Implications for Disease Effects

Sun

Poudel

Alexov

et al. 2022

IJMS

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show abstract

“…Besides, in numerous zinc-dependent enzymes, such as metallo-β-lactamases and matrix metalloproteinases, zinc cations and carboxylate groups of some Asp or Glu residues in the active sites of these enzymes often collaboratively catalyze a nonradical-mediated dissociation of the C–N bond (see Schemes S4–S6). − With the assistance of the flavin-dependent acyl-CoA dehydrogenase, γ-butyrobetaine undergoes a metal-independent redox-neutral transformation to produce trimethylamine through cleavage of the C–N bond (see Scheme S6). Studying and comparing these radical dependent or independent reaction mechanisms can enhance our understanding of the different chemical strategies used in different protein families.…”

Section: Introductionmentioning

confidence: 99%

Cysteine Radical and Glutamate Collaboratively Enable C–H Bond Activation and C–N Bond Cleavage in a Glycyl Radical Enzyme HplG

Deng,

Liao

2024

J. Chem. Inf. Model.

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Hydroxyprolines are abundant in nature and widely utilized by many living organisms. Isomerization of trans-4-hydroxy-d-proline (t4D-HP) to generate 2-amino-4-ketopentanoate has been found to need a glycyl radical enzyme HplG, which catalyzes the cleavage of the C–N bond, while dehydration of trans-4-hydroxy-l-proline involves a homologous enzyme of HplG. Herein, molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) calculations are employed to understand the reaction mechanism of HplG. Two possible reaction pathways of HplG have been explored to decipher the origin of its chemoselectivity. The QM/MM calculations reveal that the isomerization proceeds via an initial hydrogen shift from the Cγ site of t4D-HP to a catalytic cysteine radical, followed by cleavage of the Cδ−N bond in t4D-HP to form a radical intermediate that captures a hydrogen atom from the cysteine. Activation of the Cδ−H bond in t4D-HP to bring about dehydration of t4D-HP possesses an extremely high energy barrier, thus rendering the dehydration pathway implausible in HplG. On the basis of the current calculations, conserved residue Glu429 plays a pivotal role in the isomerization pathway: the hydrogen bonding between it and t4D-HP weakens the hydroxyalkyl Cγ–Hγ bond, and it acts as a proton acceptor to trigger the cleavage of the C–N bond in t4D-HP. Our current QM/MM calculations rationalize the origin of the experimentally observed chemoselectivity of HplG and propose an H-bond-assisted bond activation strategy in radical-containing enzymes. These findings have general implications on radical-mediated enzymatic catalysis and expand our understanding of how nature wisely and selectively activates the C–H bond to modulate catalytic selectivity.

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Degradation of the novel herbicide tiafenacil in aqueous solution: Kinetics, various influencing factors, hydrolysis products identification, and toxicity assessment

Li,

Chen,

Luo

et al. 2024

Science of The Total Environment

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Theoretical investigation on the reaction mechanism of UTP cyclohydrolase

Abstract: Nucleoside triphosphate cyclohydrolase (UrcA) is a critical enzyme of the uracil catabolism pathway that catalyses the two-step hydrolysis of uridine triphosphate (UTP). Although the recently resolved X-ray structure of UrcA...

Cited by 3 publications

References 34 publications

Electrostatics in Computational Biophysics and Its Implications for Disease Effects

Electrostatics in Computational Biophysics and Its Implications for Disease Effects

Cysteine Radical and Glutamate Collaboratively Enable C–H Bond Activation and C–N Bond Cleavage in a Glycyl Radical Enzyme HplG

Degradation of the novel herbicide tiafenacil in aqueous solution: Kinetics, various influencing factors, hydrolysis products identification, and toxicity assessment

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