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Advanced Biochemistry CHM486A
Science Building Room 306
MWF, 10:00a.m.–11:00a.m.
Instructor: Dr Matthew Saderholm

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Anthony Reynolds_at_berea.edu

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            Human serum albumin (HSA) is one of the most abundant proteins in the circulatory system and plays a key role in the transport of fatty acids, metabolites, and drugs. (1)  The transport protein plays important roles in protein binding for many drugs, which is of key importance to drug distribution in the body. (2)  Without a protein to distribute drugs such as antibiotics, it would be much harder to fight sickness and disease; albumin allows for certain curable substances for diseases and illnesses to bind and be carried throughout the body.

Protein Structure

            The structure of human serum albumin is very simple, but represents a quaternary model; it does not have any prosthetic groups, glycans or lipids.  The human albumin gene is 16,961 nucleotides long from the putative ‘cap’ site to the first poly (A) addition site.  The molecular mass of the protein is 67000, which is quite large, with 585 amino acids. (3) 

Figure 1: Biological Assembly Image for 1E78 taken from the Protein Data Bank.  It is the crystallized version of human serum albumin.  Chains A and B are represented.

As shown in the figure above, the protein has about 67% alpha-helix and surprisingly no beta-sheets.  The structure allows HSA to bind to a large variety of natural and foreign molecules. (3)

Mechanism and Metabolism

             In humans, albumin synthesis takes place in the liver.  Albumin is not stored by the liver, but is secreted into the portal circulation as soon as it is manufactured.  Human serum albumin is synthesized in the liver as pre-proalbumin, a tetrameric protein with four equal chains.  The N-terminal peptide is removed before the nascent protein is released from the rough endoplasmic reticulum—eukaryotic organelle.  The product, proalbumin, in the Golgi vesicles allows for the glycosylation of the protein. (3)  Glycosylation is the biochemical process of carbohydrates to other chemicals, esp. proteins.  It is modified to produce the isolated albumin through secretion.

            The total amount of albumin in an adult is about 300g.  There is a constant movement in the vascular compartments (intravascular and extravascular) equivalent to the total plasma content (120g) leaving the intravascular space; most returns with the lymphatic system—a network of conduits that carry a clear fluid called lymph. (3)  The mechanism of albumin passing through the intravascular compartments depends on the hydrostatic pressure, the colloid osmotic pressure, and the pore size of the capillaries. (2)  In the organs with continuous capillaries (ex. skin, muscle, fat), there is a transport system using albumin binding sites to enable passage across the capillaries.  About 50% of albumin is catabolized in the muscle and skin.  It is noted that 10% of albumin is lost due to the digestive tract where digestion releases absorbed peptides and amino acids. (3)

Function

            Human serum albumin is the most abundant plasma protein; it provides an important characteristic as a circulating carrier of endogenous and exogenous ligands in the blood.  Albumin has a strong negative charge, but shows no correlation to the binding of a molecule. (4)  The flexible structure of albumin allows for substances to bind to the molecule and be buried within it.  The most strongly bound molecules are hydrophobic organic anions, such as long-chained fatty acids.  Fatty acids are carboxylic acids with long, non-branch aliphatic tails. (3)  Non-ester fatty acids are transported by albumin and facilitate the removal from donor cells. 

Not only does it transport fatty acids, but also thyroid hormones as well.  Thyroid hormones are tyrosine-based hormones that are produced by the thyroid gland. (1)  Most of the thyroid hormones found in the blood are bound to transport proteins, including human serum albumin.  Thyroid hormones act on almost every cell in the body, which is an important factor in the development of the human body.  They increase the body’s basal metabolic rate, protein synthesis, regulating bone growth and maturation.  HSA also transports other hormones which are fat soluble. (3)

            Human serum albumin is involved in maintaining colloid osmotic pressure as well.  Colloid osmotic pressure is a form of the pressure that must be applied to prevent excessive amount of water to the semi-permeable membrane.  It is exerted by human serum albumin in blood plasma that sometimes pulls water to the circulatory system. (3)  Using van’t Hoff’s equation:

Osmotic pressure = RTc/M + kc2 ; R is the universal gas constant, T is the absolute temperature(K), c is the concentration of the substance(g/l), M is the molecular mass, and k being a constant.

It is shown that osmotic pressure of a substance is directly proportional to its concentration and inversely proportional to its molecular weight. (2)  Albumin has a molecular weight of 69 kDa, but is responsible for around 75-80% of direct osmotic pressure due to its abundance. (3)

Human serum albumin plays a key role in the transportation of drugs and strongly affects drug distributions in the plasma.  HSA and drugs have been thoroughly experimented for over 30 years.  Scientists have determined that there are two primary binding sites that drugs use in HSA, known as Sudlow’s site I and site II. (2)  Site I lies along a long loop of the subdomain IIa and site II has a hydrophobic pocket with a short loop. (4)  Distribution is controlled by human serum albumin because most drugs that travel in plasma bind to the sites (Figure 2).  Hydrophobic compounds will not freely dissolve in the bloodstream.  The abundance and flexibility of human serum albumin allows these molecules to bind onto it, and carried in the blood stream throughout the body. (1)

Figure 2:  The serum albumin binding activity of the ABD (human serum binding domain), after injection into the blood stream, has great importance to distribute drugs throughout the body. (13)

 

  Very strong or weak bindings of drugs to human serum albumin will lead to poor drug distribution. (2)  If the correct binding is present, it allows for albumin to transport the drug that binds to it.  As for patients with diseases in the liver, drug targeting devices are developed to treat inflammatory diseases.  Human serum albumin is used as a protein backbone to increase the therapeutic efficiency of drugs. (2)  Human serum albumin also affects the half-life of drugs.  The anti-oxidant property of albumin helps improve the conditions of critically ill patients. (3)  These effects are achieved by the binding of molecules such as copper and iron.  The binding of these molecules make albumin less susceptible to react with oxygen to form reactive oxygen species (ROS). (5)  Two human serum albumin molecules can be genetically fused together to produce a recombinant albumin dimer.  The Dimerization of human albumin is reported to extend the half-life. (6)

Genetic Diseases

            HSA is associated with many genetic diseases in our society today.  Scientists today find albumin to be a key component in determining a variety of diseases associated with a person.  An albumin test can be ordered that monitors and treats the progression of a particular disease, depending on the situation.   Low albumin levels can sometimes indicate diseases; the kidneys cannot prevent albumin from leaking from the blood into the urine and being lost. (4)  As a result, hypoalbuminemia shows to be a concern to patients.  Hypoalbuminemia is a medical condition where levels of albumin in blood serum are abnormally low.  Albumin, being a major protein in the human body, makes up 60% of the total human plasma protein by mass.  Low albumin levels may lead to liver failure or chronic disorders.  There is loss of albumin, but globulin levels are usually maintained, making it a low Albumin: Globulin ratio.  Globulin is one of the two types of serum proteins (the other being albumin). (3)  As a result of Hypoalbuminemia, Edema may form when plasma proteins, such as Human Serum Albumin, is reduced.   The result of edema, or low osmotic pressure, is an excess of fluid buildup in the tissues.

            Another disease is Hyperalbuminemia, which is less likely to occur than hypoalbuminemia.  Hyperalbuminemia is an excessive amount of albumin in the blood, which is not likely to occur.  The possibility of this is increased if a person is taking certain drugs that increase the number of albumin in the body, such as anabolic steroids, androgens, growth hormones, and insulin.  This condition is a sign of severe or chronic dehydration.  This disease can be treated with zinc and   water. (3)  The zinc will be able to reduce the swelling of the cells by increasing the amount of water intake and increasing the retention of salt.  In the dehydrated state the body has too high of an osmolarity and discards the zinc in preventing this. The zinc may also regulate transportation of cellular taurine and albumin is known to increase cellular taurine absorption. (7)

            A disease dealing with the thyroid hormones may occur if the human serum albumin transport function is not carried out.  If HSA does not transport thyroid hormones throughout the body, this allows for thyroid hormones to run freely.  They are soluble enough to roam free in the body.  Hyperthyroidism is the clinical syndrome caused by an excess of free thyroxin, free triiodothyronine, or both.  It currently affects almost 2% of women and 0.2% of men. (7)

Conclusion

            The scientific evidence shows the importance of human serum albumin inside the body, which promotes human growth, detection, maturation, and maintaining osmotic pressure.  Without these things, our system would eventually shut down.  Human serum albumin has important medical uses in the pharmaceutical field today.  It can act as an active site for which different drugs can bind to in the liver and carried throughout the body by the blood stream.  Human serum albumin has a number of physiologically important characteristics.  A decrease in serum albumin concentration’s in critical illness is known to be associated with hyperthyroidism, hypoalbuminemia, and edema.

 


 

 

 

 

 

 






References

1.

Bhattacharya, A. A.; Curry, S.; Franks, N. P. Binding of the General Anesthetics Propofol and Halothane to Human Serum Albumin. The Journal of Biological Chemistry 2000, No. 275.

2.

Yang, Feng, et al. "Effect of human serum albumin on drug metabolism: Structural evidence of esterase activity of human serum albumin." Journal of Structural Biology (2006).

3.

Vincent, J. L. Revelance of albumin in modern critical care medicine. Bailličre's best practice & research. Clinical anaesthesiology 2009, 23 (2), 183.

4. Nicholson, J P, M R Wolmarans and G R Park. "The role of albumin in critical illness." British Journal

       of Anaesthesia (2000): 599-610.

5. Roche M, Rondeau P, Singh NR et al. The antioxidant properties of serum albumin. FEBS Letters 2008; 582:

      1783-1787.

6.

Otagirl, M. Pharmaceutically Important Pre- and Posttranslational Modifications on Human Serum Albumin. Biological & pharmaceutical bulletin 2009, 32 (4), 527.

7. Suzuki (July 2006). "All-trans retinoic acid down-regulates human albumin gene expression through the 

       induction of C/EBPbeta-LIP". Biochem J. 397 (2): 345–53.