Human serum albumin (HSA) is a molecule that is critical for our health. Mature HSA is a monomeric globular protein secreted from our livers, comprising 585 amino acid residues, 17-disulphide bonds and one free thiol at cysteine-34. It folds into three distinct domains creating numerous different binding sites for the transport of important ligands, such as fatty acids, metal ions and drugs. After delivering its cargo into our cells, it binds to the FcRn receptor for effective recycling of the albumin molecule back into the blood.
Multi-site binding
Albumin is described as having nine binding sites for fatty acids, each exhibiting varying affinities for different fatty acids. This multi-site binding capacity allows HSA to transport and regulate fatty acid availability, which is important for many of our metabolic and cellular functions. It also has binding sites for many other molecules, including thyroxin, bacterial surfaces (via PAB protein), bilirubin, and nucleic acids. The role of albumin in human innate immunity is also being recognised through its ability to bind and inactivate toxins such as Clostridium difficile toxins.
Albumin’s unique structural and biochemical features provide an exceptional ability to bind multiple ligands of different sizes and shapes, with remarkable conformational flexibility, it adapts when binding to different ligands. Because it is a promiscuous binder, it can also transport many important drugs, including warfarin, ibuprofen and diazepam.
Scavenging and transporting
HSA also plays a role in scavenging and transporting heme to hemopexin, thereby preventing oxidative damage. However, the free sulfhydryl group (–SH) of cysteine-34, is responsible for most antioxidant properties in plasma. This feature makes HSA a major player in, and a mirror of, overall health status, ageing, and neurodegeneration. The HSA antioxidant property is attributed to the metal-binding and redox properties of this cysteine residue.
Although albumin is not primarily recognised as an enzyme, it displays numerous physiologically relevant enzyme activities, including esterase, enolase, glucuronidase, and peroxidase (pseudo)-enzymatic activities. Albumin has also become a valuable biomarker for liver disease, obesity, ischemia, cancer, diabetes, and rheumatoid arthritis.
Problems with plasma-derived albumin
As albumin circulates in our bodies, it naturally becomes damaged and chemically modified over time by processes such as glycation, oxidation and proteolysis. Damaged albumin is ultimately removed from circulation and broken down, mainly by the liver. Consequently, HSA derived from human plasma donations is a mixture of albumins with different degrees of modification. While these ‘post-translational’ modifications are naturally occurring, they can compromise the function of the albumin obtained from blood donors because some of the albumin is damaged. A possible solution is to manufacture recombinant albumins which have not been damaged by circulation in the human bloodstream. This can also avoid risks of pathogenic viruses or prion diseases associated with HSA from blood donations.
Premium recombinant albumin
While recombinant albumins can successfully mitigate risks from blood-borne pathogens, it is critical that they are nature-identical and do not contain unnatural modifications, which could trigger harmful immunogenic responses when used in therapeutic products. An independent study by Frahm et al. 2014 demonstrated that recombinant albumins from sources such as rice or the yeast, Pichia pastoris, can be highly inconsistent or contain non-human modifications, which might compromise their function and safety. This research demonstrated the consistently high quality of recombinant albumin from baker’s yeast, Saccharomyces cerevisiae, which has been used safely for the manufacture of biopharmaceuticals, such as insulins, for many decades.
The role of baker’s yeast
Research confirms that baker’s yeast is an established source of the safest and highest quality recombinant human albumin available, which has been proven in Phase I clinical testing by Bosse et al., 2005 and was used to define the United States Pharmacopeia (USP) monograph reference standard recombinant albumin.
