Lactoferrin: Structure And Functions

The lactoferrin , also known as apolactoferrina or lactotransferrin, is a glycoprotein produced by many mammalian species having the ability to bind and transfer iron ions (Fe3 +). It is found in much of the body fluids and is related to the plasma iron-binding protein known as “transferrin.”

It was isolated in 1939 by Sorensen and Sorensen from bovine milk, and almost 30 years later, in 1960, Johannson determined its presence in human milk (its name derives from its classification as the most abundant iron-binding protein in the world). milk).

Subsequent research identified lactoferrin in other exocrine gland secretions such as bile, pancreatic juice and secretions of the small intestine, as well as in the secondary granules of neutrophils, plasma cells belonging to the immune system.

This protein is also found in tears, saliva, semen, vaginal fluids, bronchial and nasal secretions, and urine, although it is particularly abundant in milk (it is the second highest concentration protein after casein) and colostrum.

Although initially it was considered simply as a protein with bacteriostatic activity in milk, it is a protein with a wide variety of biological functions, although not all of them have to do with its ability to transfer iron ions.

Structure of the lactoferrin

Lactoferrin, as mentioned, is a glycoprotein with a molecular weight of around 80 kDa, which is composed of 703 amino acid residues whose sequence has great homology between different species. It is a basic protein, positively charged and with an isoelectric point between 8 and 8.5.

N lobe and C lobe

It is made up of a single polypeptide chain that is folded to form two symmetric lobes called the N lobe (residues 1-332) and the C lobe (residues 344-703) that share 33-41% homology with each other.

Both the N lobe and the C lobe are made up of β-folded sheets and alpha helices, which constitute two domains per lobe, domain I and domain II (C1, C2, N1 and N2).

Both lobes are connected through a “hinge” region that is composed of an alpha helix between residues 333 and 343, which provides greater molecular flexibility to the protein.

Analysis of the amino acid sequence of this protein reveals a large number of potential sites for glycosylation. The degree of glycosylation is highly variable and determines resistance to protease activity or to considerably low pH. The most common saccharide in its carbohydrate portion is mannose, with about 3% hexose sugars and 1% hexosamines.

Each lobe of lactoferrin is capable of reversibly binding to two metal ions, either iron (Fe2 +, Fe3 +), copper (Cu2 +), zinc (Zn2 +), cobalt (Co3 +) or manganese (Mn2 +), in synergy with a bicarbonate ion.

Other molecules

It can also bind, although with a lower affinity, to other molecules such as lipopolysaccharides, glycosaminoglycans, DNA, and heparin.

When the protein is bound to two iron ions it is known as hololactoferrin, while when it is in its “free” form it is called apolactoferrin and when it is only bound to one iron atom it is known as monoferric lactoferrin.

Apolactoferrin has an open conformation, while hololactoferrin has a closed configuration, making it more resistant to proteolysis.

Other forms of lactoferrin

Some authors describe the existence of three isoforms of lactoferrin: α, β and γ. The lactoferrin-α form is denoted as that with iron-binding capacity and no ribonuclease activity. The lactoferrin-β and lactoferrin-γ forms have ribonuclease activity, but are not capable of binding to metal ions.

Features

Lactoferrin is a glycoprotein with a much higher affinity for iron binding than transferrin, an iron transporter protein in blood plasma, which gives it the ability to bind iron ions in a wide range of pH.

Given that it has a net positive charge and is distributed in various tissues, it is a multifunctional protein that is involved in various physiological functions such as:

– Regulation of intestinal iron absorption

– Immune response processes

– The body’s antioxidant mechanisms

– Acts as an anticarcinogenic and anti-inflammatory agent

– It is a protective agent against microbial infections

– Works as a transcription factor

– It is involved in the inhibition of proteases

– It is an antiviral, antifungal and antiparasitic protein

– It also works as a procoagulant and has ribonuclease activity

– It is a bone growth factor.

Regarding the fight against microbial infections, lactoferrin acts in two ways:

– Sequestering iron at infection sites (which causes a nutritional deficiency in infectious microorganisms, acting as a bacteriostatic) or

– Interacting directly with the infectious agent, which can cause cell lysis.

Pharmacological uses

Lactoferrin can be obtained directly by being purified from cow’s milk, but other modern systems are based on its production as a recombinant protein in different organisms with easy, fast and economic growth.

As an active compound in some drugs, this protein is used for the treatment of stomach and intestinal ulcers, as well as diarrhea and hepatitis C.

It is used against infections of bacterial and viral origin and, in addition, it is used as a stimulant of the immune system for the prevention of some pathologies such as cancer.

Sources of lactoferrin in the human body

The expression of this protein can be detected initially in the two and four cell stages of embryonic development and then in the blastocyst stage, until the moment of implantation.

Later it is evidenced in neutrophils and in the epithelial cells of the digestive and reproductive systems in formation.

The synthesis of this protein is carried out in the myeloid and secretory epithelia. In an adult human being, the highest levels of lactoferrin expression are detected in human milk and colostrum.

It can also be found in many mucous secretions such as uterine, seminal, and vaginal fluids, saliva, bile, pancreatic juice, secretions from the small intestine, nasal secretions, and tears. Levels of this protein have been found to change during pregnancy and during the menstrual cycle in women.

In the year 2000, the production of lactoferrin in the kidneys was determined, where it is expressed and secreted through the collecting tubules and can be reabsorbed in the distal portion of the same.

Most of the plasma lactoferrin in adult humans comes from neutrophils, where it is stored in specific secondary granules and in tertiary granules (although in lower concentrations).

References

  1. Adlerova, L., Bartoskova, A., & Faldyna, M. (2008). Lactoferrin: a review. Veterinarni Medicina, 53 (9), 457-468.
  2. Berlutti, F., Pantanella, F., Natalizi, T., Frioni, A., Paesano, R., Polimeni, A., & Valenti, P. (2011). Antiviral properties of lactoferrin — a natural immunity molecule. Molecules, 16 (8), 6992-7018.
  3. Brock, J. (1995). Lactoferrin: a multifunctional immunoregulatory protein? Immunology today, 16 (9), 417-419.
  4. Brock, JH (2002). The physiology of lactoferrin. Biochemistry and Cell Biology, 80 (1), 1-6.
  5. González-Chávez, SA, Arévalo-Gallegos, S., & Rascón-Cruz, Q. (2009). Lactoferrin: structure, function and applications. International journal of antimicrobial agents, 33 (4), 301-e1.
  6. Levay, PF, & Viljoen, M. (1995). Lactoferrin: a general review. Haematologica, 80 (3), 252-267.
  7. Naot, D., Gray, A., Reid, IR, & Cornish, J. (2005). Lactoferrin – a novel bone growth factor. Clinical Medicine & Research, 3 (2), 93-101.
  8. Sanchez, L., Calvo, M., & Brock, JH (1992). Biological role of lactoferrin. Archives of disease in childhood, 67 (5), 657.

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