Reactivity of the human hemoglobin "dark side".

Ligand binding to the heme distal side is a paradigm of biochemistry. However, X-ray crystallographic studies highlighted the possibility that O2 and NO2- may bind to the proximal heme side of ferrous human hemoglobin (Hb) alpha-chains complexed with the alpha-hemoglobin stabilizing protein and to ferric human hemoglobin beta-chains, respectively. Strikingly, the role generally played by the proximal HisF8 residue is played by the distal HisE7 side chain forming the trans axial ligand of the hemeFe atom. This: i) brings to light that Hb may utilize both heme distal and proximal sides for ligand discrimination, ii) draws attention to the nonequivalence of alpha- and beta-chains, and iii) highlights the possibility that partially unfolded Hb derivatives may display transient ligand-binding properties different from those of the native globin

Cholesterol Homeostasis Failure in the Brain: Implications for Synaptic Dysfunction and Cognitive Decline.

Cholesterol is one of the most important molecules in cell physiology because of its involvement in several biological processes: for instance, it determines both physical and biochemical properties of cell membranes and proteins. Disruption to cholesterol homeostasis leads to coronary heart disease, atherosclerosis and metabolic syndrome. Strong evidence suggests that cholesterol also has a crucial role in the brain as various neurological and neurodegenerative disorders, including Alzheimer's, Huntington's and Parkinson diseases are associated with disruptions to cholesterol homeostasis. Here, we summarize the current knowledge about the role cholesterol plays at synaptic junctions and the pathological consequences caused by disruptions in the homeostatic maintenance of this compound

Cyanide binding to human plasma heme-hemopexin: a comparative study

Hemopexin (HPX) displays a pivotal role in heme scavenging and delivery to the liver. In turn, heme-Fe-hemopexin (HPX-heme-Fe) displays heme-based spectroscopic and reactivity properties. Here, kinetics and thermodynamics of cyanide binding to ferric and ferrous hexa-coordinate human plasma HPXheme-Fe (HHPX-heme-Fe(III) and HHPX-heme-Fe(11), respectively), and for the dithionite-mediated reduction of the HHPX-heme-Fe(III)-cyanide complex, at pH 7.4 and 20.0 C, are reported. Values of thermodynamic and kinetic parameters for cyanide binding to HFIPX-heme-Fe(111) and HHPX-herneFe(II) are K= (4.1 +/- 0.4) x 10(-6) M. = (6.9 +/- 0.5) x 10(1) M-1 s(-1) and k(off) = 2.8 x 10(-4) s(-1); and H = (6 +/- 1) x 10(-1) M, h(on) = 1.2 x 10(-1) M-1 s(-1), and h(off) = (7.1 +/- 0.8) x 10(-2) s(-1), respectively. The value of the rate constant for the dithionite-mediated reduction of the HHPX-heme-Fe(II1)-cyanide complex is l = 8.9 0.8 M-1/2 s(-1). HHPX-heme-Fe reactivity is modulated by proton acceptor/donor amino acid residue(s) (e.g., His236) assisting the deprotonation and protonation of the incoming and outgoing ligand, respectively

An Update on the Antifungal Activities of Lactoferrin: New Promising Applications in Diagnostic, Therapeutics and Biotechnology

""Abstract: Lactoferrin is an iron binding protein belonging to the transferrin superfamily. Its main function is the protection. towards infections. In a previous article (Leboffe et al., Anti-Infective Agents in Medicinal Chemistry, 2009), we. have reviewed the antifungal and antiparasitic activity of lactoferrin. In the present updated review we focused the attention. on the newly discovered antifungal properties of lactoferrin and its derived peptides in clinical, diagnostic and biotechnological. applications. In particular, we discuss the new findings on diagnosis of fungal infections utilizing Lf and on. emerging pharmacological treatments exploiting combined effects of Lf and classical antifungal drugs. We also reported. recent studies on the use of Lf antifungal activity for food and beverage preservation. These new properties have found. applications both “in vitro” and “in vivo”, opening new scenarios about the use of this protein as an antinfective agent. both in translational medicine and biotechnology"

Ferric microperoxidase-11 catalyzes peroxynitrite isomerization

Microperoxidase-11 (MP11) is an undecapeptide derived from horse heart cytochrome c offering the possibility to study the reactivity of the heme group relatively unshielded by the protein. Here, the peroxynitrite isomerizadon to NO3- catalyzed by ferric MP11 (MP11-Fe(III)) is reported. Data were obtained between pH 3.6 and 8.1, at 20.0 degrees C. The value of the second-order rate constant (k(on)) for peroxynitrite isomerization to NO3- by MP11-Fe(III) decreases from (1.1 +/- 0.1) x 10(5) M-1 s(-1), at pH 3.6, to (6.1 +/- 0.6) x 10(3) M(-1)s(-1), at pH 8.1.The pH dependence of k(on) (pK(a) = 6.9) suggests that peroxynitrous acid reacts preferentially with MP11-Fe(III). The MP11-Fe(III)-catalyzed isomerization of peroxynitrite to NO3- has been ascribed to the reactive penta-coordinated heme-Fe atom of MP11-Fe(III). In fact, cyanide binding to the sixth coordination position of the heme-Fe atom inhibits the MP11-Fe(III)-catalyzed isomerization of peroxynitrite to NW. The values of the first-order rate constant (K-0) for isomerization of peroxynitrite to NO3- in the presence of the MP11-Fe(III)-CN complex are superimposable to those obtained in the absence of MP-Fe(III). Values of k(on) for peroxynitrite isomerization to NO3- by MP11-Fe(III) overlap those obtained for penta-coordinated cardiolipin-cytochrome c complex and for carboxymethylated cytochrome c in absence and presence of cardiolipin. Present results highlight the role of the heme-Fe(III) co-ordination state in the modulation of cytochrome c reactivity. (C) 2014 Elsevier Inc. All rights reserved

Physiological roles of ovotransferrin

Background: Ovotransferrin is an iron-binding glycoprotein, found in avian egg white and in avian serum, belonging to the family of transferrin iron-binding glycoproteins. All transferrins show high sequence homology. In mammals are presents two different soluble glycoproteins with different functions: i) serum transferrin that is present in plasma and committed to iron transport and iron delivery to cells and ii) lactoferrin that is present in extracellular fluids and in specific granules of polymorphonuclear lymphocytes and committed to the so-called natural immunity. To the contrary, in birds, ovotransferrin remained the only soluble glycoprotein of the transferrin family present both in plasma and egg white. Scope of review: Substantial experimental evidences are summarized, illustrating the multiple physiological roles of ovotransferrin in an attempt to overcome the common belief that ovotransferrin is a protein dedicated only to iron transport and to iron withholding antibacterial activity. Major conclusions: Similarly to the better known familymember protein lactoferrin, ovotransferrin appears to be a multi-functional protein with a major role in avian natural immunity. General significance: Biotechnological applications of ovotransferrin and ovotransferrin-related peptides could be considered in the near future, stimulating further research on this remarkable protein. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders