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Introduction
Lactoferrin is part of the transferrin family of proteins. The protein is present in cow and human milk with a molecular mass of 80KDa. Lactoferrin is responsible for transferring irons to different types of cells in the body. It controls or regulates the irons that are present in the blood. pH as a factor can resist or inhibit the activities of other proteins, but lactoferrin can interact with iron at a certain pH range. Lactoferrin can bind to iron at 4.5 pH, but it cannot interact with iron to perform its function when pH is very low, for example, in the stomach of humans. It stops the regulation when the pH is about 2-3 in the stomach (i.e., the stomach becomes too acidic). The protein is also present in tears, white blood cells, seminal fluid, and saliva. It belongs to the innate immune system and helps fight viruses and bacteria that may enter the body of humans. Most biologists think of the human and bovine lactoferrin when they hear of lactoferrin. Bovine lactoferrin is highly mannose-containing with high N-glycan composition, while human lactoferrin is associated with low mannose and N-glycan composition when compared to bovine lactoferrin (Nwosu et al., 2012). Lactoferrin has a high binding affinity for iron (III) ions. Although it comes from the transferrin protein family, the iron-binding affinity of lactoferrin is higher than transferrin proteins.
Functions
Recent studies have shown that lactoferrin can help reduce or fight the disorders caused by bacteria and viruses. It works by counteracting the iron homeostasis and some inflammatory that rises in the body of the affected humans. There is a high homology of sequence between the human and the bovine lactoferrin. Bovine lactoferrin, to be specific, is used in the treatment of in vitro and in vivo studies and had been approved by the United States FDA (Campione et al., 2021). Bovine lactoferrin helps fight viral infections at the early stage (i.e., the attachment period). It hinders the formation of some oxygenic species that leads to bacterial and viral replication by chelating two ferric ions per molecule. It also destroys receptors that may be present for the viruses and bacteria to attach (Kell, Heyden, & Pretorious, 2020). Lactoferrin helps in the treatment of Anemia in pregnant women. It can supply iron to epithelium cells of the intestine when released in the gut or when received from a diet. In adults, for example, lactoferrin receptors located on gut epithelium bind to lactoferrin molecules saturated with iron (III) ions (Artym, Zimecki, & Kruzel, 2021). When the receptors are bound, the lactoferrin now releases the irons into the body of the pregnant woman. This means that, for Anemia to be reduced in the body of a pregnant woman, there must be more receptors for the lactoferrin molecules.
Structural highlights
The two main hemispheres of lactoferrin are the N and the C terminals connected by the alpha helix. Each terminal has two parts, the upper and the lower lobes. The middle of the lobes of each terminal is located as the binding site where the iron activities occur. A unique feature of lactoferrin to transferrin proteins is the helix linker or interconnecting helix. (Libretexts, 2019). The binding of iron at the binding site does not complete the activities of the lactoferrin. The entire structure of the lactoferrin must undergo some conformational changes to ensure iron regulation in the body of humans. The flexible beta nature of the alpha helix contributes to the structural changes that happen to the protein (lactoferrin). The two lobes and the amino acids present at the binding site indicate that the protein is part of the transferrin protein family (i.e., specific to transferrin proteins) (Baker et al., 2002). Amino acids present at the binding site are aspartic acid, two tyrosine, and histidine arranged to help bind iron (III) ions. Iron binding at the binding site of lactoferrin is different from what happens in other proteins. The positive charge carried by the iron (III) ion gets balanced or canceled with the negative charge on the arginine-bound carbonate ion (Baker & Lindley, 1992). The binding abilities of the two lobes of the lactoferrin are not the same. There are some similarities, but there is a clear difference between the two lobes (i.e., the N-and-C terminal halves). They also have differences in pH dependence (Bezwoda & Mansoor, 1989). Lactoferrin can undergo conformational changes under crystallography. A study was performed on lactoferrin crystal structures (i.e., Apo lactoferrin and Iron-saturated lactoferrin). The comparison between the two crystal structures explained how lactoferrin structures react to iron. The C-terminal binding cleft of both lactoferrin structures appeared closed when the crystal lactoferrin structures were liganded and unliganded. The N-terminal binding cleft appeared opened when the crystal lactoferrin structures were unliganded but closed when liganded (Anderson et al., 1990) The lobes of lactoferrin, for example, carry the binding sites and help contribute to the main function of lactoferrin as it helps prevent viral and bacterial infections. The structure of lactoferrin and how iron (III) binds lead to the explanation of some scientific concepts. The protein structure helps to explain the Chelate effect and Hard-Soft Acid-Base theory. Iron (III) ion present in lactoferrin binds to seven different molecules, but when the irons are free in the body of humans, they only bind to six different molecules. The chelate theory states that an increase in the number of molecules in a particular system increases the stability of that system. It is the reason why lactoferrin has a higher affinity for iron (III) ions than transferrin proteins. The irons present in lactoferrin are more stable than the free irons in the body. The hard-soft acid-base theory can also be explained as the hard iron (III) ion (the acid) binds to the hard base except for the histidine. Not all lactoferrin is specific to the binding of iron. There are three different isoforms of lactoferrin. Two of the isoforms bind to the same substrate, and one binds to iron. The Iron binding one is the most popular isoform of lactoferrin. The three main isoforms of lactoferrin are lactoferrin-alpha, lactoferrin-beta, and lactoferrin-gamma. Lactoferrins beta and gamma are the isoforms with ribonuclease activity, and they do not bind with iron at the binding site (Karav et al., 2017). Lactoferrin-alpha is the only isoform that has an iron-binding activity. The ability of lactoferrin to withstand heat is another good characteristic. If the iron at the binding site of lactoferrin is not in place, especially for lactoferrin-alpha, the function of the lactoferrin alpha will be disturbed or altered. A heat resistant study was performed to study the amount of heat that lactoferrin can withstand and maintain its iron at the binding site. From Abe et al., lactoferrin at 72 degrees Celsius for 15 seconds of pasteurization was unaffected and the iron at the binding site was still in place, but when the same lactoferrin was placed at a temperature (heat) of 135 degrees Celsius for four seconds, the lactoferrin was not able to bind with iron at its binding site. The protein (lactoferrin) loses its antimicrobial characteristics.
Conclusion
Lactoferrin, as a protein, helps the human body to function well with its unique iron-binding properties and must be consumed in the right amount to maintain the immune health of humans
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