Paraoxonase-1: How a xenobiotic detoxifying enzyme has become an actor in the pathophysiology of infectious diseases and cancer

Camps, Jordi; Iftimie, Simona; Arenas, Meritxell; Castañé, Helena; Jiménez-Franco, Andrea; Castro, Antoni; Joven, Jorge

doi:10.1016/j.cbi.2023.110553

Cited by 1 publication

(1 citation statement)

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“…It is very important to recognize that the activities of PON1 that have been reported provide protection against diseases [7][8][9]. Particularly, the PON1 hydrolyze exogenous and endogenous substrates provide protection against substrateinduced toxicity [61,62]. Thereby, using a docking technique, we evaluated the impact of PON1 variant structures on the strength of the interaction with its exogenous and endogenous substrates.…”

Section: Discussionmentioning

confidence: 99%

Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study

M.,

V.,

Ahmad

et al. 2023

Medicina

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Background and Objectives: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety of oxidative-stress-related diseases. Materials and Methods: We implemented structural modeling and molecular dynamics (MD) simulation along with essential dynamics of PON1 and molecular docking with their endogenous (n = 4) and exogenous (n = 6) substrates to gain insights into conformational changes and binding affinity in order to characterize the specific functional ramifications of PON1 variants. Results: The Leu55Met variation had a higher root mean square deviation (0.249 nm) than the wild type (0.216 nm) and Gln192Arg (0.202 nm), implying increased protein flexibility. Furthermore, the essential dynamics analysis confirms the structural change in PON1 with Leu55Met vs. Gln192Arg and wild type. Additionally, PON1 with Leu55Met causes local conformational alterations at the substrate binding site, leading to changes in binding affinity with their substrates. Conclusions: Our findings highlight the structural consequences of the variants, which would increase understanding of the role of PON1 in the pathogenesis of oxidative-stress-related diseases, as well as the management of endogenous and exogenous chemicals in the treatment of diseases.

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