Serum albumin (ALB) is a kind of multifunctional circulating protein, is one of the most abundant water soluble protein in plasma. It is mainly synthesized by liver, and can also be synthesized in bone tissue and brain microglia[1][2]. It has important physiological functions, such as maintaining colloidal osmotic pressure and microvascular integrity, regulating metabolism and vascular function, providing substance binding ligand, antioxidant activity and anticoagulation.
Since albumin precipitated from urine, its properties and effects have been studied for more than 70 years. Now we have a better understanding of the albumin information.
Figure 1. The structure of human serum albumin
*(The image is derived from the wikipedia)
Human serum albumin (HSA) is single stranded composed of 585 amino acids, mature human serum albumin is a heart-shaped molecule with a molecular weight of 67KDa, which consists of three similar α -helix domains. Its amino acid sequence and spatial structure are quite conservative, HSA molecule has good elasticity, and its shape is easy to change after binding with different ligands under different environmental conditions. However, due to the existence of large number of disulfide bonds, it is easy for the molecule to recover its shape under physiological conditions. The degeneration of serum albumin occurs only in severe changes in temperature, pH value, ionic strength, or chemical environment.
The synthesis rate of HSA is mainly controlled by the changes of colloid osmotic pressure and extravascular osmotic pressure. The colloid osmotic pressure around the hepatocytes and interstitial fluid osmotic pressure are the most important regulatory factors for HSA biosynthesis. In addition, hormones can also control HSA mRNA. For example, insulin is necessary for adequate HSA synthesis, HSA synthesis decreases in diabetic patients and increases with insulin injection. Thyroxine and cortisol also stimulate the production of albumin, and estrogen has an effect on HSA. The synthesis rate of HSA may be limited by a lack of amino acids, but is rarely seen clinically, unless in a state of extreme malnutrition. In addition, nutritional status and systemic inflammation also affect the synthesis of serum albumin.
The main physiological functions of serum albumin include: the regulation of colloid osmotic pressure and capillary membrane permeability, ligand binding and transport, scavenging of free radicals, and antioxidant and blood circulation protection properties[3]. In addition, serum albumin regulates neutrophil adhesion and cell signal fragments, which is inversely proportional to the inflammatory process[4][5].
HSA tertiary structure allows it to bind and transport diverse molecules, including metabolites (such as cholesterol, fatty acids, cations and anions), gases (such as NO), exogenous substances (such as drugs and dietary derivatives)[6] and metal ions. HSA has the ability to bind to fatty acids [7][8] and is the main carrier of fatty acids. Under physiological conditions, it not only binds to endogenous and exogenous low molecular weight compounds, but also binds to polypeptide and protein[9]. 35 proteins were found to be associated with HSA, including known high and low abundant proteins (e.g., angiotensinogen, apolipoprotein, hemoglobin (Hb), plasminogen, serozyme and transferrin).
The binding of serum albumin to drugs is reversible. The binding of HSA to drugs improves the drug's plasma solubility and half-life, but also lowers the free activity concentration of drugs[10]. As a result, the metabolism, transport and clearance of the drug are affected, and serum albumin is involved in the pharmacokinetics of the drug and acts as a toxic waste disposer[11].
Serum albumin usually accounts for about half of intravascular protein and can maintain 75%-80% of plasma colloid osmotic pressure. Its negative charge also contributes to osmotic maintenance[12].
It is well known that HSA has antioxidant activity in plasma as a scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The cysteine residue of serum albumin is the main source of the reduced sulfhydryl in blood vessels, and it can be combined with copper ion to limit the production of free radical[13].
The anticoagulant and antithrombotic effects of HSA are unclear. Some studies suggest that the anticoagulant effect of serum albumin may be due to its combination of NO-, inhibiting their rapid inactivation and prolonging platelet aggregation.
HSA can inhibit inflammatory response by affecting inflammatory cells and transcription factor expression. There is evidence that the sulfydryl of HSA can mediate the regulatory signal of inflammatory cells according to its redox state.
Sometimes, HSA shows enzyme activity and enzyme inhibitor activity, and is an effective buffer of plasma.
Figure 1. The function of serum albumin
When you have some of the following symptoms, you may need to be tested for serum albumin. Unexpected weight loss; swelling around the stomach, eyes or legs; jaundice, which causes yellowing of the skin and eyes; unexplained fatigue.
It is generally believed that the normal value of serum albumin is 40-55 g/L.
Abnormal levels of albumin can indicate problems in the liver or kidney, and it can also indicate a lack of nutrition. When treating kidney disease or chronic pancreatitis, a serum albumin test can help doctors determine whether the treatment is progressing well. The decrease of HSA level in blood is a common feature of disease, The HSA/globulin ratio is widely used as a health indicator.
One is analbuminemia, a very rare recessive genetic disorder, in which HSA either does not exist or is significantly reduced. When persistent and unexplained hypoalbuminemia was observed, the diagnosis was hypothesized to be aplastic and confirmed by the absence of the HSA bands in the plasma protein electrophoresis pattern.
In addition, familial dysalbuminemic hyperthyroxinemia and familial dysalbuminemic hypertriiodothyroninemia syndromes, an autosomal dominant genetic disease, are also caused by the mutation of HSA.
Familial hyperzincemia is caused by the increased ability of HSA to bind to Zn (II), the main transporter of Zn (II) in blood, a metal ion required by a physiological process, which is absorbed by various drugs and toxins.
Moreover, the increase in all-cause mortality and cardiovascular (CV) mortality is associated with low serum albumin concentration[14], serum albumin has traditionally been considered a biomarker for reliable risk prediction in various clinical settings. The role of serum albumin in cardiovascular disease is important for understanding the prognostic value of serum albumin in total cardiovascular disease (CVD).
A special kind of disease related to serum albumin, called Bird-Egg Syndrome. It means that some people may develop an allergy to eggs after developing an allergy to birds. This is an allergy related to chicken serum albumin. The symptoms are common in people who are in frequent contact with birds and may be sensitive to proteins in bird bird's feathers, droppings, or dander that can cause the development of an allergy to eggs (It's primarily an allergy to chicken albumin). The main symptoms of egg allergies including: skin allergies, such as hives or rashes; nausea, diarrhea, stomach pain, and vomiting; throat, lips, tongue, or facial swelling; to wheezing, coughing, or a runny nose. Egg allergies disproportionately affect children.
Serum albumin is an important biological product, which is widely used in clinic and biotechnology.
Serum albumin 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.
Hypoalbuminemia often occurs in patients with active rheumatoid arthritis, mainly caused by high HSA uptake in inflammatory sites. As a biomarker of blood glucose control during pregnancy, glycosylated serum albumin reflects the short-term state of blood glucose control and is considered as a good biomarker of blood glucose control.
Determination of serum albumin level in blood is one of the methods to evaluate the nutritional status, severity and progression of cancer patients. Serum albumin has also been described as an independent prognosticator of survival in various cancers, such as lung cancer[15], pancreas[16], gastric cancer[17], colorectal cancer[18] and breast cancer[19].
Albumin can be widely used as a plasma volume extender in many clinical conditions, such as hypovolemic, shock, burn, surgery, trauma, acute respiratory distress syndrome, hemodialysis, acute liver failure, hypoalbuminosis, etc[20]. Albumin also plays a role in protecting ischemic and hypoxic liver injury, mainly due to its strong antioxidant characteristics.
As a carrier of drugs, serum albumin reversibly binds to most drugs in the blood circulation. The binding with serum albumin has great influence on the pharmacokinetics and pharmacodynamics of most commonly used prescription drugs. For example, binding to serum albumin increases the solubility of lipophilic drugs, allowing them to reach the site of action. However, conjugated drugs cannot easily leave the capillary, only unbound drugs can be distributed into tissues, thus exerting pharmacological activity or toxicity. Therefore, the high affinity between drugs and serum albumin may be beneficial or detrimental to its efficacy. In addition to affecting the distribution of drugs, binding to serum albumin also affects drug metabolism and elimination.
Recently, biotechnological applications of HSA, including implantable biomaterials, surgical adhesives and sealants, biochromatography, ligand trapping, and fusion proteins, have been reported. HSA is also used as an excipient for vaccines or therapeutic protein drugs and as a cell culture medium supplement in the production of vaccines and pharmaceuticals[21]. Moreover, HSA could act as a carrier of O2[22], drugs[23], and fusion peptides[24].
Supplements: As a supplement to cell growth and productivity, serum albumin is added to the cell culture medium[25]. As serum albumin has the ability to carry and deliver important nutrients to cells, it can improve the overall health of cells. Serum albumin can also bind free radicals to reduce damage to cells.
HSA nanotubes: Recently, HSA nanotubes trapping either HSA binding molecules or biotin or hepatitis B virus and displaying catalytic activity have been obtained.
Remove bilirubin: Serum albumin can be used to remove bilirubin during dialysis. What we know about bilirubin is that a significant increase in plasma bilirubin levels may lead to severe neurological damage, especially in newborns. Therefore, regulating the cell content of bilirubin by binding, oxidation and output is essential to cell health.
Serum albumin fusion protein: The fusion of serum albumin and peptide with therapeutic function has also been used effectively. Furukawa et al. have produced fusion proteins of human serum albumin and thioredoxin (HSA-TRX), HSA TRX fusion protein has proven to be therapeutically effective in the septic shock mouse model[24]. Using the characteristic of HSA accumulation in tumor and long half-life, it can be used for tumor localization by binding it to tumor monoclonal antibody.
It is estimated that the global market demand for HSA exceeds 500 tons per year. Currently, the commercial production of HSA is mainly based on collected human plasma. This method is limited by the availability of blood donation and the high risk of virus transmission of blood donors. In order to meet market demand, various expression systems have been used in the past decades to produce recombinant human serum albumin (rHSA), including E.coli, Saccharomyces cerevisiae, Lactobacillus, Pichia pastoris, transgenic animals and transgenic plants.
Plant seeds, especially cereal seeds, are promising carriers for producing recombinant proteins, because they can achieve high levels of protein accumulation, showing high levels of protein stability and long storage times. Human lysozyme and lactoferrin used for oral administration have been successfully expressed in rice seeds[26][27].
The results of the production of Oryza sativa recombinant HSA (OsrHSA) show that the recombinant HSA produced by the rice seed bioreactor is safe. OsrHSA is comparable to plasma-derived HSA (pHSA) in terms of biochemical characteristics, physical structure, function and immunogenicity. The use of this technology can help meet the growing demand for human serum albumin worldwide[28]. The use of transgenic rice seeds to produce functional human serum albumin on a large scale can be widely used in clinical and cell culture.
References:
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