Imatinib binding to human serum albumin modulates heme association and reactivity

Muzio, Elena Di; Polticelli, Fabio; Trezza, Viviana; Fanali, Gabriella; Fasano, Mauro; Ascenzi, Paolo

doi:10.1016/j.abb.2014.07.001

Cited by 25 publications

(42 citation statements)

References 79 publications

(162 reference statements)

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“…Heme‐Fe(III) binding to HSA, in the absence and presence of cantharidin, was followed spectrophotometrically between 350 and 450 nm, at pH 7.3 (2.0 × 10 −2 phosphate buffer) and between 10.0°C and 30.0°C . The heme‐Fe(III) concentration was 7.3 × 10 −7 M, the cantharidin concentration ranged between 2.0 × 10 −6 M and 2.0 × 10 −4 M, and the HSA concentration ranged between 1.3 × 10 −7 M and 2.0 × 10 −6 M. Heme‐Fe(III) binding to HSA, in the absence and presence of cantharidin, was investigated at a fixed low heme‐Fe(III) concentration by increasing the amount of HSA …”

Section: Methodsmentioning

confidence: 99%

“…Dansyl‐arginine and dansyl‐sarcosine binding to HSA, in the absence and presence of cantharidin, was followed spectrofluorimetrically at pH 7.3 (2.0 × 10 −2 M phosphate buffer) and 20.0°C. The fluorophore of dansyl‐arginine and dansyl‐sarcosine was excited at 370 nm; the fluorescence emission intensities were measured at the maximum wavelengths (ie, 460 nm for dansyl‐arginine and at 475 nm for dansyl‐sarcosine); the excitation and emission slits were 5 nm . The HSA concentration was 3.1 × 10 −6 M, the dansyl‐arginine and dansyl‐sarcosine concentration ranged between 1.0 × 10 −5 M and 2.0 × 10 −4 M, and the cantharidin concentration ranged between 2.0 × 10 −6 M and 2.0 × 10 −4 M.…”

Section: Methodsmentioning

confidence: 99%

“…Values of the dissociation equilibrium constants for dansyl‐arginine and dansyl‐sarcosine binding to HSA (ie, K da and K ds , respectively), in the absence and presence of cantharidin, (ie, K da 0 and K da app as well as K ds 0 and K ds app , respectively; see Scheme ) were obtained from the dependence of the relative fluorescence intensity change (ie, Δ F /Δ F max ) of the HSA‐dansyl‐arginine and HSA‐dansyl‐sarcosine complexes on the dansylated compound concentration in the absence (ie, K 0 ) and presence (ie, K app ) of cantharidin, according to Equation :

normalΔ F true/ normalΔ F_{\max} = {[HSA]}^{n} true/ ((),, K^{n} + {[HSA]}^{n}),

where K is K da 0 or K da app for dansyl‐arginine binding and K ds 0 or K ds app for dansyl‐sarcosine association, Δ F is the fluorescence intensity change observed at each concentration of either dansyl‐arginine or dansyl‐sarcosine, Δ F max is the maximum fluorescence intensity change, and n is the Hill coefficient.…”

Section: Methodsmentioning

confidence: 99%

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Cantharidin inhibits competitively heme‐Fe(III) binding to the FA1 site of human serum albumin

Polticelli

Leboffe

Tortosa

et al. 2017

J of Molecular Recognition

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Cantharidin, a monoterpene isolated from the insect blister beetle, has long been used as a medicinal agent in the traditional Chinese medicine. Cantharidin inhibits a subgroup of serine/threonine phosphatases, thus inducing cell growth inhibition and cytotoxicity. Cantharidin has anticancer activity in vitro, since it is able of inducing p53-dependent apoptosis and double-strand breakage of DNA in cancer cells. Although the toxicity of cantharidin to the gastrointestinal and urinary tracts prevents its medical use, it is a promising lead compound for chemical modification to develop new anticancer therapeutics. In fact, cantharidin does not cause myelosuppression and displays anticancer activity against cells with a multidrug resistance phenotype. Here, the competitive inhibitory effect of cantharidin on heme-Fe(III) binding to the fatty acid site 1 (FA1) of human serum albumin (HSA) is reported. Docking and molecular dynamics simulations support functional data indicating the preferential binding of cantharidin to the FA1 site of HSA. Present results may be relevant in vivo as HSA could transport cantharidin, which in turn could affect heme-Fe(III) scavenging by HSA.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

normalΔ F true/ normalΔ F_{\max} = {[HSA]}^{n} true/ ((),, K^{n} + {[HSA]}^{n}),

Section: Methodsmentioning

confidence: 99%

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Cantharidin inhibits competitively heme‐Fe(III) binding to the FA1 site of human serum albumin

Polticelli

Leboffe

Tortosa

et al. 2017

J of Molecular Recognition

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“…The apparent K d,heme value of VcCyaY for heme is estimated to be 21 nM (Figure 2A), which is in the same range as that for other heme-binding proteins, such as human serum albumin (K d,heme = 34 nM), 61 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25 ( Figure 6), indicating that heme binding facilitates the release of iron from VcCyaY. To determine how heme binding affects K d,Fe , we examined secondary structural changes in VcCyaY upon heme binding using CD spectroscopy (Figure 7).…”

Section: Vccyaymentioning

confidence: 66%

The Iron Chaperone Protein CyaY from Vibrio cholerae Is a Heme-Binding Protein

et al. 2017

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CyaY is an iron transport protein for iron-sulfur (Fe-S) cluster biosynthetic systems. It also transports iron to ferrochelatase that catalyzes insertion of Fe into protoporphyrin IX. Here, we find that CyaY has the ability to bind heme as well as iron, exhibiting an apparent dissociation constant for heme of 21 ± 6 nM. Absorption and resonance Raman spectra revealed that both ferric and ferrous forms of heme were bound to an anionic ligand (e.g., tyrosine and/or cysteine). Consistent with this, mutagenesis studies showed that Tyr67 and Cys78 are possible heme ligands of CyaY. The binding of heme to CyaY increased the apparent dissociation constant of CyaY for iron from 65.2 to 87.9 μM. Circular dichroism spectra of CyaY suggested that binding of heme to CyaY induces rearrangement of aromatic residues. Furthermore, size-exclusion column chromatography demonstrated heme-mediated oligomerization of CyaY. These results suggest that heme binding induces conformational changes, including oligomerization of CyaY, that result in a decrease in the affinity of CyaY for iron. Accordingly, the presence of excess heme in cells would lead to modulation of Fe-S cluster or heme biosynthesis. This report provides the first description of heme dependence of iron transport by CyaY.

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“…Values of the dissociation equilibrium constants for HSA binding to heme‐Fe(III), in the absence and presence of neonicotinoids (i.e., K h 0 and K h app respectively; see Scheme 1), were obtained spectrophotometrically from the dependence of the relative absorbance intensity change (i.e., Δ A /Δ A max ) of the HSA:heme‐Fe(III) complex on the concentration of free HSA (i.e., [HSA]), according to Equation (1):

normalΔ A / normalΔ A_{\max} = {[HSA]}^{n} / ((), {K_{normalh}}^{n} + {[HSA]}^{n}),

where Δ A is the absorbance intensity change occurring at each concentration of HSA, Δ A max is the maximum absorbance intensity change occurring under saturating conditions, and n is the Hill coefficient. The concentration of free HSA was determined subtracting the HSA:heme‐Fe(III) concentration from that of total HSA.…”

Section: Methodsmentioning

confidence: 99%

Neonicotinoid trapping by the FA1 site of human serum albumin

et al. 2019

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Neonicotinoids are a widely used class of insecticides that target the acetylcholine recognition site of the nicotinic acetylcholine receptors in the central nervous system of insects. Although neonicotinoids display a high specificity for insects, their use has been recently debated since several studies led to the hypothesis that they may have adverse ecological effects and potential risks to mammals and even humans. Due to their hydrophobic nature, neonicotinoids need specific carriers to allow their distribution in body fluids. Human serum albumin (HSA), the most abundant plasma protein, is a key carrier of endogenous and exogenous compounds. The in silico docking and ligand binding properties of acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam to HSA are here reported. Neonicotinoids bind to multiple fatty acid (FA) binding sites, preferentially to the FA1 pocket, with high affinity. Values of the dissociation equilibrium constant for neonicotinoid binding FA1 of HSA (i.e., calcKn) derived from in silico docking simulations (ranging between 3.9 × 10−5 and 6.3 × 10−4 M) agree with those determined experimentally from competitive inhibition of heme‐Fe(III) binding (i.e., expKn; ranging between 2.1 × 10−5 and 6.9 × 10−5 M). Accounting for the HSA concentration in vivo (~7.5 10−4 M), values of Kn here determined suggest that the formation of the HSA:neonicotinoid complexes may occur in vivo. Therefore, HSA appears to be an important determinant for neonicotinoid transport and distribution to tissues and organs, particularly to the liver where they are metabolized.

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Imatinib binding to human serum albumin modulates heme association and reactivity

Cited by 25 publications

References 79 publications

Cantharidin inhibits competitively heme‐Fe(III) binding to the FA1 site of human serum albumin

Cantharidin inhibits competitively heme‐Fe(III) binding to the FA1 site of human serum albumin

The Iron Chaperone Protein CyaY from Vibrio cholerae Is a Heme-Binding Protein

Neonicotinoid trapping by the FA1 site of human serum albumin

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