Heme impairs allosterically drug binding to human serum albumin Sudlow’s site I

Ascenzi, Paolo; Bocedi, Alessio; Notari, Stefania; Menegatti, Enea; Fasano, Mauro

doi:10.1016/j.bbrc.2005.06.127

Biochemical and Biophysical Research Communications

2005

DOI: 10.1016/j.bbrc.2005.06.127

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Heme impairs allosterically drug binding to human serum albumin Sudlow’s site I

Paolo Ascenzi

Alessio Bocedi

Stefania Notari

et al.

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Cited by 60 publications

(127 citation statements)

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“…Moreover, HSA affects pharmacokinetics of many drugs, holds some ligands in a strained orientation, providing their metabolic modification, renders potential toxins harmless transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and displays (pseudo-)enzymatic properties [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

mentioning

confidence: 99%

“…Bulky heterocyclic molecules (e.g., warfarin) bind preferentially to Sudlow's site I, whereas Sudlow's site II is preferred by aromatic carboxylates with an extended conformation (e.g., ibuprofen) [1][2][3][5][6][7][8][9][10][11][12][13][14]26,[31][32][33][34][35][36].…”

mentioning

confidence: 99%

“…Indeed, Sudlow's site I ligands affect thermodynamics and/or kinetics of heme binding to HSA and vice versa, thus affecting the heme-Fe-atom spectroscopic properties and reactivity [10][11][12][13][14][26][27][28]30,[37][38][39][40][41][42]. Similarly, the secondary ibuprofen binding site (FA6) has been suggested to be allosterically-coupled with the heme site [30,40,42].…”

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confidence: 99%

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Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Ascenzi

Masi

Sanctis

et al. 2009

Biochemical and Biophysical Research Communications

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a b s t r a c tHuman serum albumin (HSA) is a monomeric allosteric protein. Here, the effect of ibuprofen on denitrosylation kinetics (k off ) and spectroscopic properties of HSA-heme-Fe(II)-NO is reported. The k off value increases from (1.4 ± 0.2) Â 10 À4 s À1 , in the absence of the drug, to (9.5 ± 1.2) Â 10 À3 s À1 , in the presence of 1.0 Â 10 À2 M ibuprofen, at pH 7.0 and 10.0°C. From the dependence of k off on the drug concentration, values of the dissociation equilibrium constants for ibuprofen binding to HSA-heme-Fe(II)-NO (K 1 = (3.1 ± 0.4) Â 10 À7 M, K 2 = (1.7 ± 0.2) Â 10 À4 M, and K 3 = (2.2 ± 0.2) Â 10 À3 M) were determined. The K 3 value corresponds to the value of the dissociation equilibrium constant for ibuprofen binding to HSA-heme-Fe(II)-NO determined by monitoring drug-dependent absorbance spectroscopic changes (H = (2.6 ± 0.3) Â 10 À3 M). Present data indicate that ibuprofen binds to the FA3-FA4 cleft (Sudlow's site II), to the FA6 site, and possibly to the FA2 pocket, inducing the hexa-coordination of HSA-heme-Fe(II)-NO and triggering the heme-ligand dissociation kinetics.

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Ascenzi

Masi

Sanctis

et al. 2009

Biochemical and Biophysical Research Communications

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“…Human serum albumin (HSA), the most prominent protein in plasma, provides a depot and carrier for many compounds, affects pharmacokinetics of many drugs, holds some ligands in a strained orientation providing their metabolic modification, renders harmless potential toxins transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and displays (pseudo-)enzymatic properties [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15].…”

mentioning

confidence: 99%

“…Heme propionates point towards the interface between domains I and III and are stabilized by salt bridges with His146 and Lys190 [18,19]. Bulky heterocyclic molecules bind preferentially to Sudlow's site I, whereas Sudlow's site II is preferred by aromatic carboxylates with an extended conformation [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]20].…”

mentioning

confidence: 99%

Abacavir and warfarin modulate allosterically kinetics of NO dissociation from ferrous nitrosylated human serum heme-albumin

Ascenzi

Imperi

Coletta

et al. 2008

Biochemical and Biophysical Research Communications

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Human serum albumin (HSA) participates to heme scavenging, in turn HSA-heme binds gaseous diatomic ligands at the heme-Featom. Here, the effect of abacavir and warfarin on denitrosylation kinetics of HSA-heme-Fe(II)-NO (i.e., k off ) is reported. In the absence of drugs, the value of k off is (1.3 ± 0.2) Â 10 À4 s À1 . Abacavir and warfarin facilitate NO dissociation from HSA-heme-Fe(II)-NO, the k off value increases to (8.6 ± 0.9) Â 10 À4 s À1 . From the dependence of k off on the drug concentration, values of the dissociation equilibrium constant for the abacavir and warfarin binding to HSA-heme-Fe(II)-NO (i.e., K = (1.2 ± 0.2) Â 10 À3 M and (6.2 ± 0.7) Â 10 À5 M, respectively) were determined. The increase of k off values reflects the stabilization of the basic form of HSA-heme-Fe by ligands (e.g., abacavir and warfarin) that bind to Sudlow's site I. This event parallels the stabilization of the six-coordinate derivative of the HSAheme-Fe(II)-NO atom. Present data highlight the allosteric modulation of HSA-heme-Fe(II) reactivity by heterotropic effectors.

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Ligand binding strategies of human serum albumin: How can the cargo be utilized?

et al. 2009

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Human serum albumin (HSA), being the most abundant carrier protein in blood and a modern day clinical tool for drug delivery, attracts high attention among biologists. Hence, its unfolding/refolding strategies and exogenous/endogenous ligand binding preference are of immense use in therapeutics and clinical biochemistry. Among its fellow proteins albumin is known to carry almost every small molecule. Thus, it is a potential contender for being a molecular cargo/or nanovehicle for clinical, biophysical and industrial purposes. Nonetheless, its structure and function are largely regulated by various chemical and physical factors to accommodate HSA to its functional purpose. This multifunctional protein also possesses enzymatic properties which may be used to convert prodrugs to active therapeutics. This review aims to highlight current overview on the binding strategies of protein to various ligands that may be expected to lead to significant clinical applications.

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Heme impairs allosterically drug binding to human serum albumin Sudlow’s site I

Cited by 60 publications

References 40 publications

Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Abacavir and warfarin modulate allosterically kinetics of NO dissociation from ferrous nitrosylated human serum heme-albumin

Ligand binding strategies of human serum albumin: How can the cargo be utilized?

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