10 results on '"Fanali, G"'
Search Results
2. Heme-based catalytic properties of human serum albumin
- Author
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Ascenzi, P, primary, di Masi, A, additional, Fanali, G, additional, and Fasano, M, additional
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- 2015
- Full Text
- View/download PDF
Catalog
3. Warfarin inhibits allosterically the reductive nitrosylation of ferric human serum heme-albumin
- Author
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Mauro Fasano, Gabriella Fanali, Magda Gioia, Paolo Ascenzi, Massimo Coletta, Alessio Bocedi, Ascenzi, P, Bocedi, A, Gioia, M, Fanali, G, Fasano, M, and Coletta, M.
- Subjects
0301 basic medicine ,Allostery ,Ferric human serum heme-albumin ,Ferrous human serum heme-albumin ,Nitrogen monoxide binding ,Reductive nitrosylation ,Warfarin ,Biochemistry ,Inorganic Chemistry ,Stereochemistry ,Iron ,Allosteric regulation ,Serum Albumin, Human ,Heme ,Ligands ,Nitric Oxide ,Ferrous ,03 medical and health sciences ,chemistry.chemical_compound ,Fatty acid binding ,medicine ,Humans ,Reactivity (chemistry) ,Settore BIO/10 ,Serum Albumin ,chemistry.chemical_classification ,030102 biochemistry & molecular biology ,Nitrosylation ,Hydrogen-Ion Concentration ,body regions ,Kinetics ,030104 developmental biology ,Enzyme ,chemistry ,embryonic structures ,Thermodynamics ,Ferric ,Oxidation-Reduction ,Protein Binding ,Human ,medicine.drug - Abstract
Human serum heme-albumin (HSA-heme-Fe) displays heme-based ligand binding and (pseudo-)enzymatic properties. Here, the effect of the prototypical drug warfarin on kinetics and thermodynamics of NO binding to ferric and ferrous HSA-heme-Fe (HSA-heme-Fe(III) and HSA-heme-Fe(II), respectively) and on the NO-mediated reductive nitrosylation of the heme-Fe atom is reported; data were obtained between pH 5.5 and 9.5 at 20.0 °C. Since warfarin is a common drug, its effect on the reactivity of HSA-heme-Fe represents a relevant issue in the pharmacological therapy management. The inhibition of NO binding to HSA-heme-Fe(III) and HSA-heme-Fe(II) as well as of the NO-mediated reductive nitrosylation of the heme-Fe(III) atom by warfarin has been ascribed to drug binding to the fatty acid binding site 2 (FA2), shifting allosterically the penta-to-six coordination equilibrium of the heme-Fe atom toward the low reactive species showing the six-coordinated metal center by His146 and Tyr161 residues. These data: (i) support the role of HSA-heme-Fe in trapping NO, (ii) highlight the modulation of the heme-Fe-based reactivity by drugs, and (iii) could be relevant for the modulation of HSA functions by drugs in vivo. more...
- Published
- 2017
- Full Text
- View/download PDF
4. The drug-dependent five- to six-coordination transition of the heme-Fe atom modulates allosterically human serum heme-albumin reactivity
- Author
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Alessandra di Masi, Loris Leboffe, Gabriella Fanali, Mauro Fasano, Paolo Ascenzi, Ascenzi, Paolo, DI MASI, Alessandra, Leboffe, Lori, Fanali, G, and Fasano, M.
- Subjects
0301 basic medicine ,Allosteric modulation ,Heme-based reactivity ,Heme-Fe atom coordination ,Human serum heme-albumin ,2300 ,Agricultural and Biological Sciences (all) ,Earth and Planetary Sciences (all) ,Allosteric regulation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Heme ,General Environmental Science ,Albumin ,Hemopexin ,Human serum albumin ,Blood proteins ,body regions ,030104 developmental biology ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,embryonic structures ,General Earth and Planetary Sciences ,Ferric ,General Agricultural and Biological Sciences ,Peroxynitrite ,medicine.drug - Abstract
Human serum albumin (HSA), the most abundant protein in plasma, displays several functions including heme transfer from high- and low-density lipoproteins to hemopexin; therefore, the HSA-heme complex acquires transiently heme-based (pseudo-)enzymatic properties. In particular, ferric human serum heme-albumin (HSA-heme) and ferrous nitrosylated HSA-heme inactivate peroxynitrite, and ferrous HSA-heme catalyzes the conversion of nitrite to nitrogen monoxide. The (pseudo-)enzymatic properties of HSA-heme are modulated allosterically by endogenous and exogenous ligands, such as drugs. The modulation of ligand binding to plasma proteins is relevant not only under physiological conditions but also in the pharmacological therapy management. Here, drug-dependent HSA-heme properties are reviewed from the functional and structural viewpoints. In particular, the drug-dependent five- to six-coordination transition of the heme-Fe atom is at the root of the allosteric modulation of the HSA-heme reactivity. more...
- Published
- 2016
5. Heme-based catalytic properties of human serum albumin
- Author
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Paolo Ascenzi, Mauro Fasano, Gabriella Fanali, A. Di Masi, Ascenzi, Paolo, DI MASI, Alessandra, Fanali, G, and Fasano, M.
- Subjects
chemistry.chemical_classification ,Oncotic pressure ,Cancer Research ,Antioxidant ,medicine.medical_treatment ,Immunology ,Allosteric regulation ,Hemopexin ,Review Article ,Cell Biology ,Human serum albumin ,body regions ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Enzyme ,chemistry ,Biochemistry ,medicine ,Solubility ,Heme ,medicine.drug - Abstract
Human serum albumin (HSA): (i) controls the plasma oncotic pressure, (ii) modulates fluid distribution between the body compartments, (iii) represents the depot and carrier of endogenous and exogenous compounds, (iv) increases the apparent solubility and lifetime of hydrophobic compounds, (v) affects pharmacokinetics of many drugs, (vi) inactivates toxic compounds, (vii) induces chemical modifications of some ligands, (viii) displays antioxidant properties, and (ix) shows enzymatic properties. Under physiological and pathological conditions, HSA has a pivotal role in heme scavenging transferring the metal-macrocycle from high- and low-density lipoproteins to hemopexin, thus acquiring globin-like reactivity. Here, the heme-based catalytic properties of HSA are reviewed and the structural bases of drug-dependent allosteric regulation are highlighted. more...
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- 2015
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- View/download PDF
6. All-trans-retinoic acid and retinol binding to the FA1 site of human serum albumin competitively inhibits heme-Fe(III) association
- Author
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Gabriella Fanali, Paolo Ascenzi, Elena Di Muzio, Fabio Polticelli, Alessandra di Masi, Mauro Fasano, DI MUZIO, Elena, Polticelli, Fabio, DI MASI, Alessandra, Fanali, G, Fasano, M, and Ascenzi, Paolo
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0301 basic medicine ,Heme binding ,Protein Conformation ,Iron ,Biophysics ,Retinoic acid ,Serum albumin ,Competitive inhibition ,Tretinoin ,Heme ,Interphotoreceptor matrix ,All-trans-retinoic acid ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Human serum albumin ,Molecular docking ,Retinol ,Molecular Biology ,medicine ,Humans ,Vitamin A ,Serum Albumin ,Binding Sites ,biology ,Retinoid binding protein ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Models, Chemical ,biology.protein ,Retinol binding ,medicine.drug ,Protein Binding - Abstract
Retinoids are a class of chemicals derived from vitamin A metabolism, playing important and diverse functions. Vitamin A, also named all-trans-retinol (all-trans-ROL), is coverted into two classes of biologically active retinoids, i.e. 11-cis-retinoids and acidic retinoids. Among acidic retinoids, all-trans-retinoic acid (all-trans-RA) and 9-cis-retinoic acid (9-cis-RA) represent the main metabolic products. Specific and aspecific proteins solubilize, protect, and detoxify retinoids in the extracellular environment. The retinoid binding protein 4 (RBP4), the epididymal retinoid-binding protein (ERBP), and the inter photoreceptor matrix retinoid-binding protein (IRBP) play a central role in ROL transport, whereas lipocalin-type prostaglandin D synthase (also named beta-trace) and human serum albumin (HSA) transport preferentially all-trans-RA. Here, the modulatory effect of all-trans-RA and all-trans-ROL on ferric heme (heme-Fe(III)) binding to HSA is reported. All-trans-RA and all-trans-ROL binding to the FA1 site of HSA competitively inhibit heme-Fe(III) association. Docking simulations and local structural comparison of HSA with all-trans-RA- and all-trans-ROL-binding proteins support functional data indicating the preferential binding of all-trans-RA and all-trans-ROL to the FA1 site of HSA. Present results may be relevant in vivo, in fact HSA could act as a secondary carrier of retinoids in human diseases associated with reduced levels of RBP4 and IRBP. more...
- Published
- 2015
7. Heme-albumin: an honorary enzyme
- Author
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Gabriella Fanali, Mauro Fasano, A. Di Masi, Paolo Ascenzi, Ascenzi, Paolo, DI MASI, Alessandra, Fanali, G, and Fasano, M.
- Subjects
Cancer Research ,Stereochemistry ,Immunology ,Allosteric regulation ,Serum albumin ,Plasma protein binding ,Heme ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Allosteric Regulation ,Hemopexin ,medicine ,Humans ,Binding site ,Serum Albumin ,biology ,Cell Biology ,News and Commentary ,Human serum albumin ,body regions ,Biochemistry ,chemistry ,embryonic structures ,biology.protein ,Biocatalysis ,Peroxidase ,medicine.drug ,Protein Binding - Abstract
Human serum albumin displays time-dependent heme-based catalytic properties,1 representing a case for ‘chronosteric effects'.2 In fact, HSA has a pivotal role in heme transfer from high- and low-density lipoproteins to hemopexin. After endocytosis of the hemopexin-heme complex into the hepatic parenchymal cells through the CD91 receptor, hemopexin releases the heme, which undergoes degradation. Then, hemopexin is released intact into the bloodstream.3, 4 The three-domain organization of HSA is at the root of its extraordinary ligand-binding capacity and allosteric control. The most relevant clefts hosting ligands are the so-called fatty acid (FA) binding sites (named FA1 to FA9). Bacterial protein-recognition cleft(s), thyroxine-binding pockets and metal ion-recognition sites also participate to HSA actions.4 Noteworthy, the HSA structure and reactivity is affected not only reversibly by pH and ligands (e.g., heme, FAs and drugs), but also irreversibly by chemical modifications, which in turn confer antigenicity properties.4 Ferrous human serum heme-albumin (HSA-heme-Fe(II)) binds reversibly to NO and CO. Although the heme-Fe atom of HSA-heme-Fe(II) is rapidly oxidized by O2, HSA-heme-Fe(II) mutants bearing residues pivotal for O2 recognition have been proposed not only as red blood cell substitutes, but also as O2-therapeutic agents.1, 4, 5 Moreover, HSA-heme-Fe(II) catalyzes the nitrite conversion to nitrogen monoxide under acidosis and anaerobic conditions,6 HSA-heme-Fe(II)-NO reacts with O2 and peroxynitryte leading to the formation of NO3−,7, 8 and ferric HSA-heme-Fe (HSA-heme-Fe(III)) catalyzes the conversion of peroxynitryte to NO3−,9 and displays weak catalase and peroxidase activities.10 The heme-based catalytic properties of HSA are allosterically modulated by drugs (Figure 1).1 Domains I and II have a major role in the allosteric modulation of ligand-binding and reactivity properties of HSA, the FA1, FA2, FA6 and FA7 sites being functionally linked. Allosteric modulators (e.g., drugs) of the heme-based catalytic properties of HSA-heme affect the coordination state of the heme-Fe atom. In ligand-free active HSA-heme, the heme-Fe atom displays a four- or five-coordinated heme-Fe atom, whereas inactive HSA-heme shows a six-coordinated heme-Fe atom. Upon drug binding to HSA-heme (most probably to the FA2 site), the re-orientation of the Glu131-Arg145 α-helix and the axial coordination of the heme-Fe atom by His146 and Tyr161 occur; as a consequence, the unreactive six-coordinated HSA-heme species becomes predominant.1, 11, 12 Figure 1 Human serum albumin displays time-dependent heme-based catalytic properties, which are allosterically modulated by drugs As a whole, the allosteric modulation of heme-based reactivity properties of HSA-heme by drugs represents a pivotal issue in the pharmacological therapy management, heme-binding switching HSA from a plasmatic carrier to a transient metal-enzyme. more...
- Published
- 2015
8. Cantharidin inhibits competitively heme-Fe(III) binding to the FA1 site of human serum albumin.
- Author
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Polticelli F, Leboffe L, Tortosa V, Trezza V, Fanali G, Fasano M, and Ascenzi P
- Subjects
- Cantharidin chemistry, Dansyl Compounds chemistry, Dansyl Compounds metabolism, Humans, Ligands, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding drug effects, Sarcosine analogs & derivatives, Sarcosine chemistry, Sarcosine metabolism, Serum Albumin, Human chemistry, Thermodynamics, Binding, Competitive, Cantharidin pharmacology, Fatty Acids metabolism, Heme metabolism, Serum Albumin, Human metabolism
- Abstract
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., (Copyright © 2017 John Wiley & Sons, Ltd.) more...
- Published
- 2017
- Full Text
- View/download PDF
9. All-trans-retinoic acid and retinol binding to the FA1 site of human serum albumin competitively inhibits heme-Fe(III) association.
- Author
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Di Muzio E, Polticelli F, di Masi A, Fanali G, Fasano M, and Ascenzi P
- Subjects
- Binding Sites, Humans, Iron chemistry, Models, Chemical, Protein Binding, Protein Conformation, Heme chemistry, Molecular Docking Simulation, Serum Albumin chemistry, Serum Albumin ultrastructure, Tretinoin chemistry, Vitamin A chemistry
- Abstract
Retinoids are a class of chemicals derived from vitamin A metabolism, playing important and diverse functions. Vitamin A, also named all-trans-retinol (all-trans-ROL), is coverted into two classes of biologically active retinoids, i.e. 11-cis-retinoids and acidic retinoids. Among acidic retinoids, all-trans-retinoic acid (all-trans-RA) and 9-cis-retinoic acid (9-cis-RA) represent the main metabolic products. Specific and aspecific proteins solubilize, protect, and detoxify retinoids in the extracellular environment. The retinoid binding protein 4 (RBP4), the epididymal retinoid-binding protein (ERBP), and the interphotoreceptor matrix retinoid-binding protein (IRBP) play a central role in ROL transport, whereas lipocalin-type prostaglandin D synthase (also named β-trace) and human serum albumin (HSA) transport preferentially all-trans-RA. Here, the modulatory effect of all-trans-RA and all-trans-ROL on ferric heme (heme-Fe(III)) binding to HSA is reported. All-trans-RA and all-trans-ROL binding to the FA1 site of HSA competitively inhibit heme-Fe(III) association. Docking simulations and local structural comparison of HSA with all-trans-RA- and all-trans-ROL-binding proteins support functional data indicating the preferential binding of all-trans-RA and all-trans-ROL to the FA1 site of HSA. Present results may be relevant in vivo, in fact HSA could act as a secondary carrier of retinoids in human diseases associated with reduced levels of RBP4 and IRBP., (Copyright © 2015 Elsevier Inc. All rights reserved.) more...
- Published
- 2016
- Full Text
- View/download PDF
10. Ligand binding to the FA3-FA4 cleft inhibits the esterase-like activity of human serum albumin.
- Author
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Ascenzi P, Leboffe L, di Masi A, Trezza V, Fanali G, Gioia M, Coletta M, and Fasano M
- Subjects
- Diazepam pharmacology, Diflunisal pharmacology, Esterases chemistry, Esterases drug effects, Esterases metabolism, Humans, Hydrogen-Ion Concentration, Hydrolysis drug effects, Ibuprofen pharmacology, Models, Molecular, Propofol pharmacology, Serum Albumin drug effects, Esters chemistry, Serum Albumin chemistry, Serum Albumin metabolism, Tyrosine antagonists & inhibitors, Tyrosine metabolism
- Abstract
The hydrolysis of 4-nitrophenyl esters of hexanoate (NphOHe) and decanoate (NphODe) by human serum albumin (HSA) at Tyr411, located at the FA3-FA4 site, has been investigated between pH 5.8 and 9.5, at 22.0°C. Values of Ks, k+2, and k+2/Ks obtained at [HSA] ≥ 5×[NphOXx] and [NphOXx] ≥ 5×[HSA] (Xx is NphOHe or NphODe) match very well each other; moreover, the deacylation step turns out to be the rate limiting step in catalysis (i.e., k+3 << k+2). The pH dependence of the kinetic parameters for the hydrolysis of NphOHe and NphODe can be described by the acidic pKa-shift of a single amino acid residue, which varies from 8.9 in the free HSA to 7.6 and 7.0 in the HSA:NphOHe and HSA:NphODe complex, respectively; the pK>a-shift appears to be correlated to the length of the fatty acid tail of the substrate. The inhibition of the HSA-Tyr411-catalyzed hydrolysis of NphOHe, NphODe, and 4-nitrophenyl myristate (NphOMy) by five inhibitors (i.e., diazepam, diflunisal, ibuprofen, 3-indoxyl-sulfate, and propofol) has been investigated at pH 7.5 and 22.0°C, resulting competitive. The affinity of diazepam, diflunisal, ibuprofen, 3-indoxyl-sulfate, and propofol for HSA reflects the selectivity of the FA3-FA4 cleft. Under conditions where Tyr411 is not acylated, the molar fraction of diazepam, diflunisal, ibuprofen, and 3-indoxyl-sulfate bound to HSA is higher than 0.9 whereas the molar fraction of propofol bound to HSA is ca. 0.5. more...
- Published
- 2015
- Full Text
- View/download PDF
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