The effects of acrylamide on brain creatine kinase: Inhibition kinetics and computational docking simulation

Department of Environmental Health, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, PR China.
International journal of biological macromolecules (Impact Factor: 2.86). 12/2008; 44(2):128-32. DOI: 10.1016/j.ijbiomac.2008.11.003
Source: PubMed


The occurrence of acrylamide is frequently observed in processed foods. Therefore, the harmful effects of acrylamide on metabolic enzymes are important to understand. We studied the inhibitory effects of acrylamide on the brain creatine kinase (CK-BB). We found that CK-BB was kinetically inactivated by acrylamide accompanied by the disruption of the hydrophobic surface. Acrylamide mainly interacted with the thiol (-SH) residue of CK-BB and resulted in alkylation. A computational docking simulation supported that acrylamide directly bound to the active site of CK-BB where cysteine and glycine residues interacted mainly. The inhibition kinetics combined with computational prediction can be useful in order to have insights into the mechanisms regarding environmentally hazardous factors at the molecular level.

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    • "vironment [Candiano et al., 2009]. Our docking procedure could identify binding poses for AC in neither proteins. This suggests that conformational rearrangements, which are not taken into account in the docking procedure, might allow AC to bind to one or more Cys residues. For mouse aldolase, the SI Fig. 4. 3D structure of creatine kinase enzyme [Lü Z-R. et al, 2009]. The Cys283, which is located in the active side is named and indicated in licorice representation. Fig. 5. AC interactions with Leu201, Thr59 and Cys283 residues inside creatine kinase active site. Fig. 6. 3D structure of enolase enzyme [Howland et. al., 1980]. The Cys388, which binds AC is named and indicated in licorice representatio"
    Computational Biology and Applied Bioinformatics, 09/2011; , ISBN: 978-953-307-629-4
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    • "The shift of the band at acrylamide concentrations below 400 mM indicated that the tertiary structure of HBCK was modified by acrylamide, while the quaternary structure was not. The splitting of the band at acrylamide concentrations above 400 mM suggested that the thiol groups was alkylated by acrylamide, as proposed previously [30]. "
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    ABSTRACT: Acrylamide is widely used worldwide in industry and it can also be produced by the cooking and processing of foods. It is harmful to human beings, and human brain CK (HBCK) has been proposed to be one of the important targets of acrylamide. In this research, we studied the effects of acrylamide on HBCK activity, structure and the potential binding sites. Compared to CKs from rabbit, HBCK was fully inactivated at several-fold lower concentrations of acrylamide, and exhibited distinct properties upon acrylamide-induced inactivation and structural changes. The binding sites of acrylamide were located at the cleft between the N- and C-terminal domains of CK, and Glu232 was one of the key binding residues. The effects of acrylamide on CK were proposed to be isoenzyme- and species-specific, and the underlying molecular mechanisms were discussed.
    International Journal of Molecular Sciences 10/2009; 10(10):4210-22. DOI:10.3390/ijms10104210 · 2.86 Impact Factor
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    ABSTRACT: There is a great deal of interest in neurotrophin therapy to prevent neuronal degeneration. The present study aimed at synthesizing new functionalized indole derivatives with structures justifying neuroprotective activity using L-tryptophan (TRP) as starting material. The potential neuroprotective effect of these newly synthesized agents against acrylamide (ACR) induced neurotoxicity was investigated in adult female rats. The novel indole derivatives, indolylmethyl pyridine derivatives 9a,b, pyrimidinylindolyl propanone derivatives 12a-c, pyrazolylindolyl propanone derivatives 14a,b, and indolyl tetrazolopropanoic acid derivative 17 were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The administration of ACR [ip, 50mgkg(-1) body weight (b. wt.)] alone resulted in significant increase in brain malondialdehyde level (MDA) and lactate dehydrogenase (LDH) activity whereas it caused significant decrease in brain monoamines levels and antioxidant enzymes activity. Treatment with the indole derivatives 9b, 12c, 14a, and 17 (ip, 50mgkg(-1) b. wt.) prior to ACR produced neuroprotective activity with various intensities depending on the structure of each compound. Compound 17 in which the tetrazole ring was attached to the TRP moiety ranked as the strongest neuroprotective agent. All the tested compounds have been shown to possess antioxidant properties offering promising efficacy against oxidative stress induced by ACR administration.
    Bioorganic & medicinal chemistry 05/2011; 19(9):2966-74. DOI:10.1016/j.bmc.2011.03.031 · 2.79 Impact Factor
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