Analysis of Potential Binding Sites of 3,5,4′-Trihydroxystilbene (Resveratrol) and trans-3,3′,5,5′-Tetrahydroxy-4′-methoxystilbene (THMS) to the GAPDH Molecule Using a Computational Ligand-Docking Method: Structural and Functional Changes in GAPDH Induced by the Examined Polyphenols

Abstract

The presented study analyzed potential binding sites of 3,5,4'-trihydroxystilbene (resveratrol, RSV) and its derivative, trans-3,3',5,5'-tetrahydroxy-4'-methoxystilbene (THMS) to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The effects of stilbene analogs on the structure of GAPDH were determined by fluorescence spectroscopy and ζ potential measurements. To what extent the studied compounds affect the activity of the enzyme was also assessed. A computational ligand-docking study showed that there are 11 potential binding sites of RSV and 8 such sites of THMS in the GAPDH molecule. While resveratrol does not significantly affect the activity of the dehydrogenase upon binding to it, THMS leads to approximately 10% inactivation of this enzyme. THMS has no effect on GAPDH inactivation induced by the superoxide anion radical, in contrast to resveratrol, which increases dehydrogenase inactivation.

Functional consequences of piceatannol binding to glyceraldehyde-3-phosphate dehydrogenase

“…Reduction of potential amounted from -5.1 ± 0.6 mV in the absence of the ligand to -11.2 ± 0.7 mV in its presence. Previous studies indicated slightly smaller changes of charge on the GAPDH surface in the presence of resveratrol (decrease from -4.7mV to -9mV) [ 8 ]. The observed differences result from various pKa of both stilbene derivatives which determines the amount of protonated and nonprotonated forms at a specific pH.…”

“…In addition, piceatannol molecule locates inside the GAPDH, much further down the binding cleft as compared to resveratrol (the detailed location of RSV inside the GAPDH tetramer was presented by Rodacka et. al, 2015 [ 8 ].…”

“…Piceatannol embedded in the active site pocket of GAPDH is likely to be a hindrance and interferes with the binding of the substrate and/or coenzyme, thereby the enzymatic activity of the enzyme is decreasing. In previous studies, we have shown that other stilbene derivatives such as resveratrol and trans-3,3′,5,5′-tetrahydroxy-4′-methoxystilbene (THMS) are incorporated into the GAPDH active center, similar to piceatannol [ 8 ]. However, resveratrol interactions are much weaker and involve fewer amino acid residues in this area [ 8 ].…”

“…In previous studies, we have shown that other stilbene derivatives such as resveratrol and trans-3,3′,5,5′-tetrahydroxy-4′-methoxystilbene (THMS) are incorporated into the GAPDH active center, similar to piceatannol [ 8 ]. However, resveratrol interactions are much weaker and involve fewer amino acid residues in this area [ 8 ]. As a result, resveratrol did not affect the enzyme activity significantly.…”

Determination of trans-resveratrol action on two different types of neuronal cells, neuroblastoma and hippocampal cells

“…Numerous studies have revealed that especially the 4'-OH group in the phenol ring of resveratrol dominates in the radical-scavenging efficiency and it is responsible for its biological activity (Stojanović et al 2001). The free-radical scavenging mechanism utilized by resveratrol involves the generation of 4'-phenoxy radicals followed by semiquinone and quinone structures (Rodacka et al 2015). It also improves endogenous Food Chemistry and Safety doi: 10.17221/401/2015-CJFS cellular antioxidant systems -superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and the content of glutathione (GSH).…”