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A comprehensive insight into binding of hippuric acid to human serum albumin: a study to uncover its impaired elimination through hemodialysis.

ABSTRACT: Binding of hippuric acid (HA), a uremic toxin, with human serum albumin (HSA) has been examined by isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), molecular docking, circular dichroism (CD) and fluorescence spectroscopy to understand the reason that govern its impaired elimination through hemodialysis. ITC results shows that the HA binds with HSA at high (K b ~10(4)) and low affinity (K b ~10(3)) sites whereas spectroscopic results predict binding at a single site (K b~10(3)). The HA form complex with HSA that involves electrostatic, hydrogen and hydrophobic binding forces as illustrated by calculated thermodynamic parameters. Molecular docking and displacement studies collectively revealed that HA bound to both site I and site II; however, relatively strongly to the later. Esterase-like activity of HSA confirms the involvement of Arg410 and Tyr411 of Sudlow site II in binding of HA. CD results show slight conformational changes occurs in the protein upon ligation that may be responsible for the discrepancy in van't Hoff and calorimetric enthalpy change. Furthermore, an increase in T(1)(m) and T(2)(m) is observed from DSC results that indicate increase in stability of HSA upon binding to HA. The combined results provide that HA binds to HSA and thus its elimination is hindered.

SUBMITTER: Zaidi N

PROVIDER: S-EPMC3739763 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A comprehensive insight into binding of hippuric acid to human serum albumin: a study to uncover its impaired elimination through hemodialysis.

Zaidi Nida N Ajmal Mohammad Rehan MR Rabbani Gulam G Ahmad Ejaz E Khan Rizwan Hasan RH Khan Rizwan Hasan RH

PloS one 20130809 8

Binding of hippuric acid (HA), a uremic toxin, with human serum albumin (HSA) has been examined by isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), molecular docking, circular dichroism (CD) and fluorescence spectroscopy to understand the reason that govern its impaired elimination through hemodialysis. ITC results shows that the HA binds with HSA at high (K b ~10(4)) and low affinity (K b ~10(3)) sites whereas spectroscopic results predict binding at a single sit ...[more]

PMID: 23951159

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Project description:gamma-Aminobutyric acid (GABA) is a naturally occurring inhibitory neurotransmitter and some of its derivatives showed potential to act as neuroprotective agents. With the aim of developing potential leads for anti-Alzheimer's drugs, in this study we synthesized a novel GABA derivative, methyl 4-(4-((2-(tert-butoxy)-2-oxoethyl)(4-methoxyphenyl)amino)benzamido)butanoate by a unique method of Buchwald-Hartwig cross coupling synthesis; with some modification the yield was significant (97 %) and spectroscopic analysis confirmed that the compound was highly pure (98.8 % by HPLC). The druglikeness properties such as logP, logS, and polar surface area were 3.87, -4.86 and 94.17 Å(2) respectively and it satisfied the Lipinski's rule of five. We examined the binding behavior of the molecule to human serum albumin (HSA) and bovine serum albumin (BSA) which are known as universal drug carrier proteins. The molecule binds to the proteins with low micromolar efficiency and the calculated binding constants were 3.85 and 2.75 micromolar for BSA and HSA, respectively. Temperature dependent study using van't Hoff equation established that the binding was thermodynamically favorable and the changes in the Gibb's free energy, ?G for the binding process was negative. However, the binding of the molecule to HSA was enthalpy driven and the change of enthalpy (?H) was -10.63 kJ/mol, whereas, the binding to BSA was entropy driven and the change in entropy ?S was 222 J/mol. The molecular docking analysis showed that the binding sites of the molecule lie in the groove between domain I and domain III of BSA, whereas it is within the domain I in case of HSA, which also supported the different thermodynamic nature of binding with HSA and BSA. Molecular dynamics analysis suggested that the binding was stable with time and provided further details of the binding interaction. Molecular dynamics study also highlighted the effect of this ligand binding on the serum albumin structure.

Project description:Serum albumin level predicts mortality in dialysis patients and is used to assess their health status and the quality of delivered care. Whether the threshold level of serum albumin at which mortality risk increases in peritoneal dialysis (PD) patients is the same as for hemodialysis (HD) patients has not been studied.Observational cohort study of dialysis patients undertaken to determine the survival-predictability of serum albumin level in PD patients and compare it with that in HD patients.130,052 dialysis patients (PD, 12,171; HD, 117,851) who received treatment in any of the 580 dialysis units owned by DaVita Inc between July 1, 2001, through June 30, 2006, followed up through June 30, 2007.Baseline and time-averaged serum albumin level (assayed using bromcresol green) and change in serum albumin level over 6 months.All-cause, cardiovascular, and infection-related mortality.PD patients with baseline serum albumin level <3.0 g/dL had a more than 3-fold higher adjusted risk of all-cause and cardiovascular mortality and 3.4-fold higher risk of infection-related mortality (reference group: serum albumin, 4.00-4.19 g/dL). Adjusted all-cause mortality was significantly lower in PD patients with a ?0.3-g/dL increase in serum albumin level over 6 months and significantly higher in those for whom it decreased by ?0.2 g/dL (reference group: serum albumin change, +0.1 to -0.1 g/dL). A significant increase in death risk was evident for HD patients with serum albumin level <4.0 g/dL, but at <3.8 g/dL for PD patients. For each albumin category, overall death risk for PD patients was lower than for HD patients (reference group: HD patients with serum albumin of 4.00-4.19 g/dL).Study can identify associations only without attribution of causality and residual confounding cannot be excluded.Serum albumin predicts all-cause, cardiovascular, and infection-related mortality in both PD and HD patients. However, the threshold at which risk of death increases varies by dialysis modality, and this difference should be considered by agencies or organizations that set quality standards.

Project description:BackgroundSeveral epidemiological studies have demonstrated associations between variability in a number of biological parameters and adverse outcomes. As the variability may reflect impaired homeostatic regulation, we assessed albumin variability over time in chronic hemodialysis (HD) patients.MethodsData from 1346 subjects who received chronic HD treatment from May 2001 to February 2015 were analyzed according to three phases of HD treatment: post-HD initiation, during maintenance HD treatment, and before death. The serum albumin values were grouped according to the time interval from HD initiation or death, and the yearly trends for both the albumin levels and the intra-individual albumin variability (quantified by the residual coefficient of variation: Alb-rCV) were examined. The HD initiation and death-associated changes were also analyzed using generalized additive mixed models. Furthermore, the long-term trend throughout the maintenance treatment period was evaluated separately using linear regression models.ResultsAlbumin levels and variability showed distinctive changes during each of the 3 periods. After HD initiation, albumin variability decreased and reached a nadir within a year. During the subsequent maintenance treatment period (interquartile range = 5.2-11.0 years), the log Alb-rCV showed a significant upward trend (mean slope: 0.011 ± 0.035 /year), and its overall mean was -1.49 ± 0.08 (equivalent to an Alb-rCV of 3.22%). During the 1-2 years before death, this upward trend clearly accelerated, and the mean log Alb-rCV in the last year of life was -1.36 ± 0.17. The albumin levels and variability were negatively correlated with each other and exhibited exactly opposite movements throughout the course of chronic HD treatment. Different from the albumin levels, albumin variability was not dependent on chronological age but was independently associated with an individual's aging and death process.ConclusionThe observed upward trend in albumin variability seems to be consistent with a presumed aging-related decline in homeostatic capacity.

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A comprehensive insight into binding of hippuric acid to human serum albumin: a study to uncover its impaired elimination through hemodialysis.

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A comprehensive insight into binding of hippuric acid to human serum albumin: a study to uncover its impaired elimination through hemodialysis.

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