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Human serum albumin (HSA) is the most abundant protein in plasma, contributing actively to oncotic pressure maintenance and fluid distribution between body compartments. HSA acts as the main carrier of fatty acids, recognizes metal ions, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless, accounts for most of the anti-oxidant capacity of human plasma, and displays esterase, enolase, glucuronidase, and peroxidase (pseudo)-enzymatic activities. HSA-based catalysis is physiologically relevant, affecting the metabolism of endogenous and exogenous compounds including proteins, lipids, cholesterol, reactive oxygen species (ROS), and drugs. Catalytic properties of HSA are modulated by allosteric effectors, competitive inhibitors, chemical modifications, pathological conditions, and aging. HSA displays anti-oxidant properties and is critical for plasma detoxification from toxic agents and for pro-drugs activation. The enzymatic properties of HSA can be also exploited by chemical industries as a scaffold to produce libraries of catalysts with improved proficiency and stereoselectivity for water decontamination from poisonous agents and environmental contaminants, in the so called “green chemistry” field. Here, an overview of the intrinsic and metal dependent (pseudo-)enzymatic properties of HSA is reported to highlight the roles played by this multifaced protein.

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Reactive oxygen and nitrogen species (ROS and RNS, respectively) activate the redox-sensitive Ras small GTPases. The three canonical genes ( HRAS, NRAS, and KRAS ) are archetypes of the superfamily of small GTPases and are the most common oncogenes in human cancer. Oncogenic Ras is intimately linked to redox biology, mainly in the context of tumorigenesis. The Ras protein structure is highly conserved, especially in effector-binding regions. Ras small GTPases are redox-sensitive proteins thanks to the presence of the NKCD motif (Asn116-Lys 117-Cys118-Asp119). Notably, the ROS- and RNS-based oxidation of Cys118 affects protein stability, activity, and localization, and protein-protein interactions. Cys residues at positions 80, 181, 184, and 186 may also help modulate these actions. Moreover, oncogenic mutations of Gly12Cys and Gly13Cys may introduce additional oxidative centres and represent actionable drug targets. Here, the pathophysiological involvement of Cys-redox regulation of Ras proteins is reviewed in the context of cancer and heart and brain diseases.

The pathogenicity of group A Streptococcus (GAS) is mediated by direct bacterial invasivity and toxin-associated damage. Among the extracellular products, the exotoxin streptolysin O (SLO) is produced by almost all GAS strains. SLO is a pore forming toxin (PFT) hemolitically active and extremely toxic in vivo. Recent evidence suggests that human serum albumin (HSA), the most abundant protein in plasma, is a player in the innate immunity “orchestra.” We previously demonstrated that HSA acts as a physiological buffer, partially neutralizing Clostridioides difficile toxins that reach the bloodstream after being produced in the colon. Here, we report the in vitro and ex vivo capability of HSA to neutralize the cytotoxic and hemolytic effects of SLO. HSA binds SLO with high affinity at a non-conventional site located in domain II, which was previously reported to interact also with C. difficile toxins. HSA:SLO recognition protects HEp-2 and A549 cells from cytotoxic effects and cell membrane permeabilization induced by SLO. Moreover, HSA inhibits the SLO-dependent hemolytic effect in red blood cells isolated from healthy human donors. The recognition of SLO by HSA may have a significant protective role in human serum and sustains the emerging hypothesis that HSA is an important constituent of the innate immunity system.

Rhodnius prolixus nitrophorins (Rp-NPs), Arabidopsis thaliana nitrobindin (At-Nb), and Homo sapiens THAP4 (Hs-THAP4) are the unique known proteins that use a b-barrel fold to bind ferric heme, which is devoted to NO transport and/or catalysis. The eight-stranded antiparallel b-barrel Rp-NPs, which represent the only heme-binding lipocalins, are devoted to deliver NO into the blood vessel of the host and to scavenge histamine during blood sucking. Regarding Nbs, crystallographic data suggest the ability of At-Nb and Hs-THAP4 to bind ferric heme; however, no data are available with respect to these functions in the natural host. Here, a bioinformatics investigation based on the amino acid sequences and threedimensional structures of At-Nb and Hs-THAP4 suggests a conservation of the 10-stranded antiparallel b-barrel Nb structural module in all life kingdoms of the evolutionary ladder. In particular, amino acid residues involved in the heme recognition and in the structure stabilization of the Nb structural module are highly conserved (identity > 29%; homology > 83%). Moreover, molecular models of putative Nbs from different organisms match very well with each other and known threedimensional structures of Nbs. Furthermore, phylogenetic tree reconstruction indicates that NPs and Nbs group in distinct clades. These data indicate that 10-stranded b-barrel Nbs constitute a new ubiquitous heme protein family spanning from bacteria to Homo sapiens. V C 2016 IUBMB Life, 68(6): [423][424][425][426][427][428] 2016

Nitrobindins (Nbs), constituting a heme‐protein family spanning from bacteria to Homo sapiens , display an all‐β‐barrel structural organization. Human Nb has been described as a domain of the nuclear protein named THAP 4, whose physiological function is still unknown. We report the first evidence of the heme‐Fe( III )‐based detoxification of peroxynitrite by the all‐β‐barrel C ‐terminal Nb‐like domain of THAP 4. Ferric human Nb (Nb( III )) catalyzes the conversion of peroxynitrite to and impairs the nitration of free l ‐tyrosine. The rate of human Nb( III )‐mediated scavenging of peroxynitrite is similar to those of all‐α‐helical horse heart and sperm whale myoglobin and human hemoglobin, generally taken as the prototypes of all‐α‐helical heme‐proteins. The heme‐Fe( III ) reactivity of all‐β‐barrel human Nb( III ) and all‐α‐helical prototypical heme‐proteins possibly reflects the out‐to‐in‐plane transition of the heme‐Fe( III )‐atom preceding peroxynitrite binding. Human Nb( III ) not only catalyzes the detoxification of peroxynitrite but also binds NO , possibly representing a target of reactive nitrogen species.