Human serum albumin or HSA is one of the major types of proteins that are present in the plasma composition. It is such abundant that its concentration on a common blood sample is 5 grams per 100 milliliters. Due to its high concentration in plasma as well as its physiological and pharmaceutical features, it has been subjected to several studies to determine its 3D structure, function, domains, important binding sites, and diseases. The primary structure of HSA describes a single polypeptide with 585 amino acids with the characteristics of having 17 pairs of disulfide bridges, one free cysteine [1]. It has been discovered that there are highly conserved sequences between bovine, human and rat albumins such as Trp-212, 143-155 and 244-263 sequence [2]. It is composed of three domains at positions 19-210, 211-403, and 404-601 with two subdomains each (Ia&b, IIa&b, and IIIa&b). The subcellular location of these protein is the extracellular region on the outside of the cell membrane or secreted. There are 11 metal binding sites, including 1 copper site, 7 calcium sites, 3 zinc sites, additionally, 1 binding site for bilirubin and 1 site for aspirin-acetylated lysine [3].
Function
HSA functions as the essential protein for the circulatory system, however, it has been discovered that possesses a high affinity an extensive range of amino acids, ligands, fatty acids, metals like copper and zinc, and metabolites such as bilirubin and drugs ingredients [4].Its fundamental role is to transport these varied types of solutes through the bloodstream to specific organs, control the level of pH and osmotic pressure of the plasma, and interaction with the cell membrane exchange of molecules at binding sites [5]. It is considered to be the vital carrier of zinc in the plasma as well as the calcium and magnesium. In terms of affinity, the order from higher to lower affinity follows this pattern: zinc, calcium and magnesium [6]. Pharmaceutically, it has been used to target certain organs with some drugs by HSA being the carrier. By performing experiments on E.coli, it was discovered that it inhibits enterobactin-mediated iron absorption from ferric transferrin due to its binding to the bacterial siderophore limiting the uptake of iron, and consequently, blocking the growth of E.coli [7].
Disease
HSA is involved in two important diseases, Hyperthyroxinemia, familial dysalbuminemic (FDAH) and Analbuminemia (ANALBA).
First, FDAH is a condition based on the genetic composition of the individual. It is caused by a mutation in the ALB gene, which corresponds to an increased affinity of the protein HSA for thyroxine. In detail, this autosomal dominant genetic disorder is characterized by the mutation of HSA causing the assembly of thyroxine in a higher proportion. There are two positions with three natural variants identified on the HSA that mutate to cause this disorder. The first position (red) is at 90 amino acid, where leucine is replaced by a proline. The second position (green) at 242 amino acid, where arginine is substituted by histidine or proline . This disorder could lead to confusion and several misdiagnoses of hyperthyroidism because it is difficult to detect it due to the normal TSH and free thyroxine levels but with an elevated total of thyroxine [8].
Second, ANALBA is an uncommon autosomal recessive genetic mutation characterized by the identification of very low levels of HSA circulating in the bloodstream [9]. The affected individuals have symptoms corresponding to mild edema, hypotension, fatigue, and lower body lipodystrophy in females. The mutagenesis is located in the position 91 where histidine is replaced by alanine impairing metal binding [10]. The complications of this disorder could lead to early atherosclerosis and heart problems.
Relevance
The relevance of this protein, HSA, relies on the its capacity to transports molecules through out the bloodstream. It helps move substances such as metals, amino acids, drugs, fatty acids to every part of the body because it is a protein present in the blood that flows around the body. It is a significant protein because it allows us to use it pharmaceutically to target certain organs with specific drugs. Additionally, it is essential for the control of the levels of pH and the osmotic pressure in the plasma. And finally, it is a protein that allows the cell membrane interact with the outer space of the cell by the help of HSA in the targeting of binding sites.
Structural highlights
The structural highlights of this protein are four: the three domains that compose the protein, the binding site in domain II for salicylates, sulfonamides and several drug ingredients, the bilirubin binding site at position 264, and the free cysteine in the structure of the protein [11].
This is the structural view of by different colors. Digitoxin, cardiac glycoside, could bind domain I for cardiac insufficiency, warfarin, anticouagulant, bind primarily in domain II, and the diazapines like benzodiazapine, muscular relaxor, in domain III. The shared binding site in domain II between zinc and calcium at residue suggests a crosstalk between zinc and calcium transport in the blood. The binding site at position 264, which is significant because it possess important functions as an antioxidant, but it also serves simply as a means to excrete unwanted heme, derived from various heme-containing proteins such as hemoglobin, myoglobin, and various P450 enzymes. located in a loop between helice is the only cysteine residue that does not participate in any disulfide bridges. Its sulfhydryl group is prevented from coupling with the external counterparts giving a structure known as triclinic crystals. Sequence 143 through 155 and sequence 244 through 263 are involved in ligand binding. For example, residues , an aromatic sequence, corresponds with the region of the second major long-chain fatty acid binding site [12].
