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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    • "As presented in Figure 1, each subunit of CK contains two domains: a smaller N-terminal domain and a larger C-terminal domain, and the active site of CK is located at the cleft of the two domains [19]. This cleft or pocket is thought to facilitate the entry of substrates as well as inhibitors [19,30]. The HBCK pocket, which is estimated to be as large as ∼2,500 Å2, is shown in Figures 6A and 6B. "
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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: Acrylamide (ACR) has been shown to be a neurotoxic agent for both laboratory animals and human. The present study aimed at synthesizing new functionalized melatonin derivatives bearing promising heterocyclic moiety that could be expected to have protective effect against ACR-induced neurotoxicity in adult female rats. The novel melatonin derivatives 4, 6, 7 and 11 were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The administration of ACR [i.p., 50 mg kg(-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 melatonin derivatives 4, 6, 7 and 11 (i.p., 50 mg kg(-1) b. wt) prior to ACR produced significant decrease in brain MDA level and LDH activity with concomitant significant increase in brain monoamines and antioxidant enzymes activity. It could be concluded that the new synthesized melatonin derivatives exhibited promising protective activity against ACR-induced neurotoxicity.
    European Journal of Medicinal Chemistry 11/2010; 45(11):5452-9. DOI:10.1016/j.ejmech.2010.09.017 · 3.45 Impact Factor
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