Dissecting substrate specificity of two rice BADH isoforms: Enzyme kinetics, docking and molecular dynamics simulation studies

Jiamsomboon, Kultida; Treesuwan, Witcha; Boonyalai, Nonlawat

doi:10.1016/j.biochi.2012.04.009

Cited by 7 publications

(5 citation statements)

References 24 publications

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“…Other MD studies with betaine aldehyde dehydrogenases from Oryza sativa also found that the NAD + binding region is the most flexible within the entire protein. 24,25 While the distance of the NAD + C38 to the catalytically active sulfur of Cys281 stayed at 1.3 ± 0.1 nm for both variants, the RMSD of NAD + slightly increased for M42 in comparison to the backbone (see the Supporting Information). Moreover, the RMSF of the NAD + cofactor increased in the area of the reactive nicotinamide (Figure 6) due to the mutations.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

Molecular Dynamics Analysis of a Rationally Designed Aldehyde Dehydrogenase Gives Insights into Improved Activity for the Non-Native Cofactor NAD⁺

2020

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The aldehyde dehydrogenase from Thermoplasma acidophilum was previously implemented as a key enzyme in a synthetic cellfree reaction cascade for the production of alcohols. In order to engineer the enzyme's cofactor specificity from NADP + to NAD + , we identified selectivity-determining residues with the CSR-SALAD tool and investigated further positions based on the crystal structure. Stepwise combination of the initially discovered six point mutations allowed us to monitor the cross effects of each mutation, resulting in a final variant with reduced K M for the non-native cofactor NAD + (from 18 to 0.6 mM) and an increased activity for the desired substrate D-glyceraldehyde (from 0.4 to 1.5 U/mg). Saturation mutagenesis of the residues at the entrance of the substrate pocket could eliminate substrate inhibition. Molecular dynamics simulations showed a significant gain of flexibility at the cofactor binding site for the final variant. The concomitant increase in stability against isobutanol and only a minor reduction in its temperature stability render the final variant a promising candidate for future optimization of our synthetic cell-free enzymatic cascade.

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Section: ■ Results and Discussionmentioning

confidence: 97%

Molecular Dynamics Analysis of a Rationally Designed Aldehyde Dehydrogenase Gives Insights into Improved Activity for the Non-Native Cofactor NAD⁺

2020

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“…When predicting the binding mode of the ligand to the receptor, molecular docking provides a good starting to evaluate the stability of the predicted interactions involved in binding. But for MD simulations, it allowed the receptor-ligand complex to be fully relaxed in the solvent environment (i.e., taking into account the protein flexibility, which cannot be fulfilled by the molecular docking process), thereby generating more reliable binding properties 99 . As a well-established method, MD simulation computationally probes the structure and dynamics of biological macromolecules.…”

Section: Resultsmentioning

confidence: 99%

A New Strategy for Deleting Animal drugs from Traditional Chinese Medicines based on Modified Yimusake Formula

Wang

Yang

et al. 2017

Sci Rep

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Traditional Chinese medicine (TCM), such as Uyghur Medicine (UM) has been used in clinical treatment for many years. TCM is featured as multiple targets and complex mechanisms of action, which is normally a combination of medicinal herbs and sometimes even contains certain rare animal medicinal ingredients. A question arises as to whether these animal materials can be removed replaced from TCM applications due to their valuable rare resources or animal ethics. Here, we select a classical UM Yimusake formula, which contains 3 animal drugs and other 8 herbs, and has got wealthy experience and remarkable achievements in treating erectile dysfunction (ED) in China. The active components, drug targets and therapeutic mechanisms have been comprehensively analyzed by systemspharmacology methods. Additionally, to validate the inhibitory effects of all candidate compounds on their related targets, in vitro experiments, computational analysis and molecular dynamics simulations were performed. The results show that the modified, original and three animal materials display very similar mechanisms for an effective treatment of ED, indicating that it is quite possible to remove these three animal drugs from the original formula while still keep its efficiency. This work provides a new attempt for deleting animal materials from TCM, which should be important for optimization of traditional medicines.Traditional Chinese medicine (TCM) including Uyghur Medicine (UM) has been used for pharmaceutical and dietary therapy for several millennia 1 . UM is also characterized as multiple chemical components and multiple targets, which has been acknowledged with remarkable curative effects in treating some complex diseases such as arthritis, rheumatism, chronic back leg pain 2 . Due to these extensive use and the remarkable therapeutic effects, the interest in studying UM is gradually increased nowadays.However, UM often contains not only, as usual as common TCMs, a combination of many medicinal herbs, but also certain animal medicinal materials 3 . Some of these animal taxa like rhino, tiger, or musk beer, etc., are now at the brim of extinction due to commercial overexploitation 4 . Additionally, poaching of animals for their medicinal uses has also brought many wild species under the red data book, for a possibility of their extinction. For instance, bear bile has a decades-long history in the treatment of hepatic and biliary disorders, but it is just due to this extensive consumption of bear bile that has made bears become endangered species 5 . Moreover, the rapid deterioration of the natural biodiversity, as well as the loss and destruction of the habitat have also caused many rare animals in danger of extinction 4 . Due to these reasons, animal species for therapeutic purposes are becoming more and more precious, a question of whether animal ingredients in UM preparations can be removed arises, due to the current limitations of experimental approaches and the complex function mechanism of "multiple components, multiple targets" of...

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“…d Approximate k cat per active site value calculated using the reported V max and an assumed monomer molecular weight taken from a phylogenetically close relative. e There are several other reports differing in the absolute values of the kinetic parameters for these enzymes, but in all of them the catalytic efficiency for BAL is at least 10-times lower than that of the glycine betaine synthesizing ALDH10 enzymes [58,[81][82][83]. important for aldehyde specificity in these enzymes ( Fig.…”

Section: Amino Acid Residues Of Other Aldhs Relevant For Their Aldehymentioning

confidence: 94%

Structural determinants of substrate specificity in aldehyde dehydrogenases

Riveros‐Rosas

González‐Segura

Julián‐Sánchez

et al. 2013

Chemico-Biological Interactions

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Dissecting substrate specificity of two rice BADH isoforms: Enzyme kinetics, docking and molecular dynamics simulation studies

Cited by 7 publications

References 24 publications

Molecular Dynamics Analysis of a Rationally Designed Aldehyde Dehydrogenase Gives Insights into Improved Activity for the Non-Native Cofactor NAD⁺

Molecular Dynamics Analysis of a Rationally Designed Aldehyde Dehydrogenase Gives Insights into Improved Activity for the Non-Native Cofactor NAD⁺

A New Strategy for Deleting Animal drugs from Traditional Chinese Medicines based on Modified Yimusake Formula

Structural determinants of substrate specificity in aldehyde dehydrogenases

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Dissecting substrate specificity of two rice BADH isoforms: Enzyme kinetics, docking and molecular dynamics simulation studies

Cited by 7 publications

References 24 publications

Molecular Dynamics Analysis of a Rationally Designed Aldehyde Dehydrogenase Gives Insights into Improved Activity for the Non-Native Cofactor NAD+

Molecular Dynamics Analysis of a Rationally Designed Aldehyde Dehydrogenase Gives Insights into Improved Activity for the Non-Native Cofactor NAD+

A New Strategy for Deleting Animal drugs from Traditional Chinese Medicines based on Modified Yimusake Formula

Structural determinants of substrate specificity in aldehyde dehydrogenases

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Product

Resources

About

Molecular Dynamics Analysis of a Rationally Designed Aldehyde Dehydrogenase Gives Insights into Improved Activity for the Non-Native Cofactor NAD⁺

Molecular Dynamics Analysis of a Rationally Designed Aldehyde Dehydrogenase Gives Insights into Improved Activity for the Non-Native Cofactor NAD⁺