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Elimination of endogenous toxin, creatinine from blood plasma depends on albumin conformation: site specific uremic toxicity & impaired drug binding.

Varshney A, Rehan M, Subbarao N, Rabbani G, Khan RH - PLoS ONE (2011)

Bottom Line: Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination.The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding.These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.

ABSTRACT
Uremic syndrome results from malfunctioning of various organ systems due to the retention of uremic toxins which, under normal conditions, would be excreted into the urine and/or metabolized by the kidneys. The aim of this study was to elucidate the mechanisms underlying the renal elimination of uremic toxin creatinine that accumulate in chronic renal failure. Quantitative investigation of the plausible correlations was performed by spectroscopy, calorimetry, molecular docking and accessibility of surface area. Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination. The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding. These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state.

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Molecular docking of HSA complexed with site II specific markers.(A) Molecular surface representations of HSA showing site II specific markers [ibuprofen (light orange); diazepam (magenta)] and the toxin CTN (red) at binding site II. (B) The toxin molecule forming repulsive interaction (white colour) with Phe488 of HSA (as highlighted by the white dashed line). (C) Other site II amino acid residues of HSA interacting with CTN within 5 Å distance.
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pone-0017230-g009: Molecular docking of HSA complexed with site II specific markers.(A) Molecular surface representations of HSA showing site II specific markers [ibuprofen (light orange); diazepam (magenta)] and the toxin CTN (red) at binding site II. (B) The toxin molecule forming repulsive interaction (white colour) with Phe488 of HSA (as highlighted by the white dashed line). (C) Other site II amino acid residues of HSA interacting with CTN within 5 Å distance.

Mentions: The locations of uremic toxin creatinine in the active sites (site I and site II) of HSA was explored by conducting docking simulations using GOLD [29] as presented in Figure 8 and 9. The principal regions of ligand binding to HSA were located in hydrophobic cavities in subdomains IIA and IIIA, which are consistent with site I and site II, respectively [20]. The creatinine, site I markers (phenylbutazone and warfarin) were docked to HSA and the results have been shown in Table 4 and 5. The Gold Fitness Score, measure of binding affinity was found to be low for CTN at both of the sites when compared to respective markers used in this study; however specificity was higher for site I as evident from the presence of hydrogen bond and hydrophobic interactions. The spectroscopic experimental results were substantiated by docking results which shows that high and low affinity binding sites of toxin on plasma protein are located within the binding pocket of subdomain IIA and IIIA. The creatinine binds deep inside the cavity at site I (Figure 8) whereas in site II (Figure 9), it binds at peripheral side of the cavity. The inside wall of the pocket was lined by hydrophobic side chains whereas the entrance to the pocket was surrounded by several non-polar residues (Leu238, Val241, Ala258, Leu260, Ala261, Ile264, Ile290, Ala291); one polar (Ser287) and few charged residues (His242, Arg257) in the proximity distance of 5 Å of the bound toxin (Figure 8, Table 4). Although the involvement of non polar residues makes the interactions to be hydrophobic in nature but the strong intermolecular hydrogen bond between carbonyl oxygen atom of Arg257 and N2 atom of creatinine (2.85 Å, 124.36°), makes the electrostatic interaction as the primary binding force responsible for the retention of toxin in the plasma. The hydrogen bond residue of site I (Arg 257) was part of helix 4 and 6 of subdomain IIA (represented as IIa-h4 & IIa-h6, Table 4). While at site II, the complex was stabilized by hydrophobic interactions without involvement of any hydrogen bond. Additionally, electrostatic repulsive force between oxygen atom of Phe488 with N3 of creatinine (2.62 Å) destabilizes the complex (Figure 9, Table 5). To further identify the residues taking part in the interaction, we have calculated the accessible surface area (ASA) of the amino acid residues. The changes in ASA of the interacting residues are presented in Table 4 and 5.


Elimination of endogenous toxin, creatinine from blood plasma depends on albumin conformation: site specific uremic toxicity & impaired drug binding.

Varshney A, Rehan M, Subbarao N, Rabbani G, Khan RH - PLoS ONE (2011)

Molecular docking of HSA complexed with site II specific markers.(A) Molecular surface representations of HSA showing site II specific markers [ibuprofen (light orange); diazepam (magenta)] and the toxin CTN (red) at binding site II. (B) The toxin molecule forming repulsive interaction (white colour) with Phe488 of HSA (as highlighted by the white dashed line). (C) Other site II amino acid residues of HSA interacting with CTN within 5 Å distance.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3046181&req=5

pone-0017230-g009: Molecular docking of HSA complexed with site II specific markers.(A) Molecular surface representations of HSA showing site II specific markers [ibuprofen (light orange); diazepam (magenta)] and the toxin CTN (red) at binding site II. (B) The toxin molecule forming repulsive interaction (white colour) with Phe488 of HSA (as highlighted by the white dashed line). (C) Other site II amino acid residues of HSA interacting with CTN within 5 Å distance.
Mentions: The locations of uremic toxin creatinine in the active sites (site I and site II) of HSA was explored by conducting docking simulations using GOLD [29] as presented in Figure 8 and 9. The principal regions of ligand binding to HSA were located in hydrophobic cavities in subdomains IIA and IIIA, which are consistent with site I and site II, respectively [20]. The creatinine, site I markers (phenylbutazone and warfarin) were docked to HSA and the results have been shown in Table 4 and 5. The Gold Fitness Score, measure of binding affinity was found to be low for CTN at both of the sites when compared to respective markers used in this study; however specificity was higher for site I as evident from the presence of hydrogen bond and hydrophobic interactions. The spectroscopic experimental results were substantiated by docking results which shows that high and low affinity binding sites of toxin on plasma protein are located within the binding pocket of subdomain IIA and IIIA. The creatinine binds deep inside the cavity at site I (Figure 8) whereas in site II (Figure 9), it binds at peripheral side of the cavity. The inside wall of the pocket was lined by hydrophobic side chains whereas the entrance to the pocket was surrounded by several non-polar residues (Leu238, Val241, Ala258, Leu260, Ala261, Ile264, Ile290, Ala291); one polar (Ser287) and few charged residues (His242, Arg257) in the proximity distance of 5 Å of the bound toxin (Figure 8, Table 4). Although the involvement of non polar residues makes the interactions to be hydrophobic in nature but the strong intermolecular hydrogen bond between carbonyl oxygen atom of Arg257 and N2 atom of creatinine (2.85 Å, 124.36°), makes the electrostatic interaction as the primary binding force responsible for the retention of toxin in the plasma. The hydrogen bond residue of site I (Arg 257) was part of helix 4 and 6 of subdomain IIA (represented as IIa-h4 & IIa-h6, Table 4). While at site II, the complex was stabilized by hydrophobic interactions without involvement of any hydrogen bond. Additionally, electrostatic repulsive force between oxygen atom of Phe488 with N3 of creatinine (2.62 Å) destabilizes the complex (Figure 9, Table 5). To further identify the residues taking part in the interaction, we have calculated the accessible surface area (ASA) of the amino acid residues. The changes in ASA of the interacting residues are presented in Table 4 and 5.

Bottom Line: Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination.The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding.These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.

ABSTRACT
Uremic syndrome results from malfunctioning of various organ systems due to the retention of uremic toxins which, under normal conditions, would be excreted into the urine and/or metabolized by the kidneys. The aim of this study was to elucidate the mechanisms underlying the renal elimination of uremic toxin creatinine that accumulate in chronic renal failure. Quantitative investigation of the plausible correlations was performed by spectroscopy, calorimetry, molecular docking and accessibility of surface area. Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination. The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding. These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state.

Show MeSH
Related in: MedlinePlus