Human serum albumin is the principal protein in human serum. It participates in regulation of plasma oncotic pressure and transports endogenous and exogenous ligands such as thyroxine, free fatty acids, bilirubin, and various drugs. Therefore, studying its ligand binding mechanism is important in understanding many functions of the protein.

From Molecular Aspects to Biotechnological Applications

Human serum albumin (HSA), the most abundant protein in plasma, is a monomeric multidomain macromolecule that represents the main determinant of plasma oncotic pressure and the principal modulator of fluid distribution between body compartments. HSA is a valued biomarker in many diseases, (i.e., cancer, rheumatoid arthritis, ischemia, obesity, and diabetes) and finds clinical application in the treatment of several pathologies, including shock, trauma, hemorrhage, acute respiratory distress syndrome, hemodialysis, acute liver failure, chronic liver disease, and hypoalbuminemia. In recent years, a novel role of Human serum albumin is emerging in the innate immunity. Indeed, Human serum albumin acts as a self-defense agent toward Clostridium difficile and Streptococcus pyogenes, as well as against Candida albicans infection by inactivating toxins produced by these pathogens. In this Special Issue, original studies on HSA structural, molecular, and functional aspects in health and disease, as well as those related to its biotechnological applications, are covered.[1]

Starting from the structural aspects of Human serum albumin capability to bind drugs, Liberi and coworkers reported the structural analysis of Gemfibrozil (GEM) in complex with albumin. GEM is an orally administered lipid-regulating fibrate derivative drug, known under the brand name Lopid. GEM is widely used to treat hypertriglyceridemia and other disorders in the lipid metabolism. Though generally well tolerated, GEM can alter the distribution and the free active concentration of some co-administered drugs, leading to adverse effects. In a paper by Liberi and colleagues, the crystal structure of HSA in complex with GEM has been reported. The elucidation of the molecular interaction between GEM and Human serum albumin offered the Authors the possibility to speculate on the development of novel GEM derivatives that can be safely and synergistically co-administered with other drugs, potentially improving its therapeutic efficacy.

From a biotechnological point of view, Human serum albumin represents a promising drug delivery carrier, thanks to the presence of the Cys34 residue and 59 Lys residues that can be used as scaffolds for covalent modifications of drugs. Obara and colleagues developed a Tyr-selective modification technique using the tyrosine click method. By comparing three different protocols, they found that the laccase-catalyzed method can efficiently modify Tyr residue(s) of Human serum albumin under mild reaction conditions without inducing oxidative side reactions. Mass spectrometry analyses suggested that Tyr84, Tyr138, and Tyr401 are the main modification sites of Human serum albumin. Unlike the conventional Lys residue modification, the Tyr modification method proposed by Obata et al. caused a minimal inhibition of drug binding, thus suggesting that this modification could represent a promising method for covalent drug attachment to HSA.

Human serum albumin homeostasis

Human serum albumin (HSA) has been used for a long time as a resuscitation fluid in critically ill patients. It is known to exert several important physiological and pharmacological functions. Among them, the antioxidant properties seem to be of paramount importance as they may be implied in the potential beneficial effects that have been observed in the critical care and hepatological settings. The specific antioxidant functions of the protein are closely related to its structure. Indeed, they are due to its multiple ligand-binding capacities and free radical-trapping properties. The Human serum albumin molecule can undergo various structural changes modifying its conformation and hence its binding properties and redox state. Such chemical modifications can occur during bioprocesses and storage conditions of the commercial Human serum albumin solutions, resulting in heterogeneous solutions for infusion. In this review, we explore the mechanisms that are responsible for the specific antioxidant properties of Human serum albumin in its native form, chemically modified forms, and commercial formulations. To conclude, we discuss the implication of this recent literature for future clinical trials using albumin as a drug and for elucidating the effects of HSA infusion in critically ill patients.[2]

It seems relevant to consider that the specific antioxidant properties of the HSA molecule are involved in the positive therapeutic effects of Human serum albumin infusion, reported in the critical care and hepatological setting. In this hypothesis, using Human serum albumin as a resuscitation fluid could represent an opportunity to enhance endogenous antioxidant protection in critical pathological conditions. Because an increased percentage of oxidized HSA is responsible for impaired Human serum albumin functions, we propose that preference should be given to preparations with a higher reduced HSA percentage.

From bench to bedside

Human serum albumin (HSA), the most abundant protein in plasma, is a monomeric multi-domain macromolecule, representing the main determinant of plasma oncotic pressure and the main modulator of fluid distribution between body compartments. Human serum albumin displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds. Indeed, Human serum albumin represents the main carrier for fatty acids, 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 (pseudo-)enzymatic properties. HSA is a valuable biomarker of many diseases, including cancer, rheumatoid arthritis, ischemia, post-menopausal obesity, severe acute graft-versus-host disease, and diseases that need monitoring of the glycemic control. Moreover, Human serum albumin is widely used clinically to treat several diseases, including hypovolemia, shock, burns, surgical blood loss, trauma, hemorrhage, cardiopulmonary bypass, acute respiratory distress syndrome, hemodialysis, acute liver failure, chronic liver disease, nutrition support, resuscitation, and hypoalbuminemia. Recently, biotechnological applications of Human serum albumin, including implantable biomaterials, surgical adhesives and sealants, biochromatography, ligand trapping, and fusion proteins, have been reported. Here, genetic, biochemical, biomedical, and biotechnological aspects of HSA are reviewed.[3]

Human serum albumin, the most abundant circulating protein in the blood, represents the main determinant of plasma oncotic pressure and the main modulator of fluid distribution between body compartments. Although monomeric, HSA displays extraordinary ligand binding properties which are reminiscent of those of multimeric proteins. Indeed, endogenous and exogenous ligand binding to HSA is modulated not only by ligand-ligand competition for the same site but also by intramolecular communication(s) within multiple clefts. Remarkably, ligand binding to Human serum albumin is a transient event(s); therefore, the HSA–ligand complexes may display time-dependent specific functional properties. These transient ligand-dependent events have been called “chronosteric effects”. HSA is widely used clinically to treat serious burn injuries, hemorrhagic shock, hypoproteinemia, fetal erythroblastosis, and ascites caused by liver cirrhosis. Moreover, Human serum albumin represents a valuable biomarker of many diseases, including cancer, ischemia, severe acute graft-versus-host disease, and diseases that need monitoring of the glycemic control.

Human serum albumin natural and artificial genetic mutants can provide valuable informations concerning structural and reactivity properties. Moreover, they are relevant in biotechnological and biopharmaceutical applications, including O2 transport and delivery, nanodelivery of drugs, fusion peptides, implantable biomaterials, surgical adhesives, and surgical sealants. HSA is also used as an excipient for vaccines or therapeutic protein drugs, and as a cell culture medium supplement. Remarkably, the use of rHSA provides the well recognized benefits of using pdHSA and avoids the risk of transmitting pathogenic contaminants (e.g., virus and prion). rHSA will thus open new doors in its applications and contribute to self-sufficiency in blood and blood products. Lastly, although Human serum albumin is one of the most investigated proteins, some questions are in order. Is HSA essential? Indeed, humans almost totally lacking HSA safely survive. Does occur a specific HSA receptor in humans? Interestingly, the albuminoid protein AFP is recognized by a specific receptor. Answers to these and other questions could unveil several still unrecognized physiological roles of Human serum albumin.

References

[1]di Masi A. Human Serum Albumin: From Molecular Aspects to Biotechnological Applications. Int J Mol Sci. 2023 Feb 17;24(4):4081.

[2]Taverna M, Marie AL, Mira JP, Guidet B. Specific antioxidant properties of human serum albumin. Ann Intensive Care. 2013 Feb 15;3(1):4.

[3]Fanali G, di Masi A, Trezza V, Marino M, Fasano M, Ascenzi P. Human serum albumin: from bench to bedside. Mol Aspects Med. 2012 Jun;33(3):209-90.