Laktoferin (atau laktotransferin) adalah protein yang dapat mengikat dan mentransfer ion Fe dan [1] terdapat dalam

jumlah tinggi dalam susu dan kolostrum. Protein ini pertama kali diisolasi dari susu [1] sapi pada tahun 1939 oleh Sorensen dan Sorensen. Laktoferin memiliki berat 82.600 Da dan secara [2] spesifik dapat mengikat dua atom feri per molekulnya. Selain pada susu dan kolostrum, protein ini juga dapat ditemukan pada neutrofil, ginjal, sel epitelial, dan pada cairan mukosa, seperti: saliva, air [1] mata, sekresi usus kecil, sekresi vagina, dan lain-lain. Laktoferin memiliki aktivitas bakteriostatik (anti-bakteri) yang kuat karena kemungkinan disebabkan kemampuannya mengiat ion metal yang [2] vital bagi makhluk hidup, seperti besi . Bakteri dapat mati karena kekurangan ion besi untuk [2] tumbuh.

3+

Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globularglycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, andnasal secretions. Lactoferrin is also present in secondary granules of PMN and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum ("first milk") has the highest concentration, followed by human milk, then cow milk (150 mg/L).
[1]

Lactoferrin is one of the components of the immune system of the body; it has antimicrobial activity (bacteriocide, fungicide) and is part of the innate defense, mainly at mucoses. lactoferrin provides antibacterial activity to human infants.
[2][3] [1]

In particular,

Lactoferrin interacts

withDNA and RNA, polysaccharides and heparin, and shows some of its biological functions in complexes with these ligands.

Molecular structure
Lactoferrin is one of the transferrin proteins that transfer iron to the cells and control the level of free iron in the blood and external secretions. It is present in the milk of humans and other mammals,
[8] [6]

in

the blood plasma and neutrophils and is one of the major proteins of virtually all exocrine secretions of mammals, such as saliva, gall, tears and pancreas. from 7 g/L in thecolostrum to 1 g/L in mature milk. X-ray diffraction reveals that lactoferrin is based on one polypeptide chain that contains about 700 amino acids and forms two homologous globular domains named N-and C-lobes. N-lobe corresponds to amino acid residues 1-333 and C-lobe to 345-692, and the ends of those domains are connected by a short -helix.
[9][10]

Concentration of lactoferrin in the milk varies

Each lobe consists of two subdomains, N1, N2 and C1, C2, and contains one

iron binding site and one glycosylation site. The degree of glycosylation of the protein may be different and therefore the molecular weight of lactoferrin varies between 76 and 80 kDa. The stability of lactoferrin has been associated with the high glycosylation degree.
[11]

Lactoferrin belongs to the basic proteins, its isoelectric point is 8.7. It exists in two forms: iron-rich hololactoferrin and iron-free apolactoferrin. Their tertiary structures are different; apolactoferrin is characterized by "open" conformation of the N-lobe and the "closed" conformation of the C-lobe, and both lobes are closed in the hololactoferrin.
[12]

Each lactoferrin molecule can reversibly bind two ions of iron, zinc, copper or other metals.

[13]

The

binding sites are localized in each of the two protein globules. There, each ion is bonded with six ligands: four from the polypeptide chain (two tyrosine residues, one histidine residue and one aspartic acid residue) and two from carbonate or bicarbonate ions. Lactoferrin forms reddish complex with iron; its affinity for iron is 300 times higher than that of transferrin.
[14]

The affinity increases in weakly acidic medium. This facilitates the transfer of iron
[15]

from transferrin to lactoferrin during inflammations, when the pH of tissues decreases due to accumulation of lactic and other acids. The saturated iron concentration in lactoferrin in human

milk is estimated as 10 to 30% (100% corresponds to all lactoferrin molecules containing 2 iron atoms). It is demonstrated that lactoferrin is involved not only in the transport of iron, zinc and copper, but also in the regulation of their intake.
[16]

Presence of loose ions of zinc and copper does not affect

the iron binding ability of lactoferrin, and might even increase it.

Polymeric forms
Both in blood plasma and in secretory fluids lactoferrin can exist in different polymeric forms ranging from monomers to tetramers. Lactoferrin tends to polymerize both in vitro and in vivo, especially at high concentrations.
5 [17][18][19] [15]

Several authors found that the dominant form of lactoferrin in physiological

conditions is a tetramer, with the monomer:tetramer ratio of 1:4 at the protein concentrations of 10 M.

It is suggested that the oligomer state of lactoferrin is determined by its concentration and that polymerization of lactoferrin is strongly affected by the presence of Ca monomers were dominant at concentrations below 10
10 2+

ions. In particular,
2+

10

11

M in the presence of Ca , but they

9 10

converted into tetramers at lactoferrin concentrations above 10 10

M.

[17][20]

Titer of lactoferrin in

the blood corresponds to this particular "transition concentration" and thus lactoferrin in the blood should be presented both as a monomer and tetramer. Many functional properties of lactoferrin depend on its oligomeric state. In particular, monomeric, but not tetrameric lactoferrin can strongly bind to DNA. [edit]Biological

functions

Lactoferrin belongs to the innate immune system. Apart from its main biological function, namely binding and transport of iron ions, lactoferrin also has antibacterial, antiviral, antiparasitic, catalytic, anti-cancer, anti-allergic and radioprotecting functions and properties.
[21]

Antibacterial activity
Antibacterial activity of lactoferrin is best studied; it originates from the iron-binding properties of lactoferrin, which deprive the bacterial flora from an element necessary for its growth.
[22]

Antibacterial

action of lactoferrin is also explained by the presence of specific receptors on the cell surface of microorganisms. Lactoferrin binds to lipopolysaccharide of bacterial walls, and the oxidized iron part

of the lactoferrin oxidizes bacteria via formation of peroxides. This affects the membrane permeability and results in the cell breakdown (lysis).
[22]

Although lactoferrin also has other antibacterial mechanisms not related to iron, such as stimulation of phagocytosis,
[23]

the interaction with the outer bacterial membrane described above is the most
[24]

dominant and most studied.

Lactoferrin not only disrupts the membrane, but even penetrates into

the cell. Its binding to the bacteria wall is associated with the specific peptide lactoferricin, which is located at the N-lobe of lactoferrin and is produced by in vitro cleavage of lactoferrin with another protein, trypsin.
[25][26]

A mechanism of the antimicrobial action of lactoferrin has been reported as

[27]

lactoferrin targets H(+)-ATPase and interferes with proton translocation in the cell membrane, resulting in a lethal effect in vitro. [edit]Antiviral

activity
including the herpes simplex virus 1 and
[31]

Lactoferrin acts, mostly in vitro, on a wide range of human and animal viruses based on DNA and RNA genomes, 2, 1,
[29][30] [35] [28] [30][32] [33][34]

cytomegalovirus,

HIV,

hepatitis C virus,

hantaviruses, rotaviruses, poliovirus type

[26]

human respiratory syncytial virus and murine leukemia viruses.

The most studied mechanism of antiviral activity of lactoferrin is its diversion of virus particles from the target cells. Many viruses tend to bind to the lipoproteins of the cell membranes and then penetrate into the cell.
[34]

Lactoferrin binds to the same lipoproteins thereby repelling the virus particles. Iron-free
[28]

apolactoferrin is more efficient in this function than hololactoferrin; and lactoferricin, which is responsible for antimicrobial properties of lactoferrin, shows almost no antiviral activity.

Beside interacting with the cell walls, lactoferrin also directly binds to viral particles, such as the hepatitis viruses. rotaviruses,
[26] [34]

This mechanism is also confirmed by the antiviral activity of lactoferrin against

which act on different cell types.

[26][32]

Lactoferrin also suppresses virus replication after the virus penetrated into the cell.

Such an

indirect antiviral effect is achieved by affecting natural killer cells, granulocytes and macrophages cells, which play a crucial role in the early stages of viral infections, such assevere acute respiratory syndrome (SARS).
[36]

[edit]Antifungal

activity
[37]

Lactoferrin and lactoferricin inhibit in vitro growth of Trichophyton mentagrophytes, which are responsible for several skin diseases such asringworm.
[38][39]

Lactoferrin also acts against the Candida

albicans a diploid fungus (a form of yeast) that causes opportunistic oral and genitalinfections in humans. Fluconazole has long been used against Candida albicans, which resulted in

emergence of strains resistant to this drug. However, a combination of lactoferrin with fluconazole can act against fluconazole-resistant strains of Candida albicans as well as other types of Candida: C. glabrata, C. krusei, C. parapsilosis and C. tropicalis.
[38]

Antifungal activity is observed for sequential

incubation ofCandida with lactoferrin and then with fluconazole, but not vice versa. The antifungal

activity of lactoferricin exceeds that of lactoferrin. In particular, synthetic peptide 1-11 lactoferricin shows much greater activity against Candida albicans than native lactoferricin.
[38]

Administration of lactoferrin through drinking water to mice with weakened immune systems and symptoms of aphthous ulcer reduced the number of Candida albicans strains in the mouth and the size of the damaged areas in the tongue.
[40]

Oral administration of lactoferrin to animals also reduced

the number of pathogenic organisms in the tissues close to the gastrointestinal tract. Candida albicans could also be completely eradicated with a mixture containing lactoferrin, lysozyme and introakonazol in HIV-positive patients who were resistant to other antifungal drugs.
[41]

Such antifungal action when other drugs deem inefficient is characteristic of lactoferrin and
[42]

is especially valuable for HIV-infected patients.

Contrary to the antiviral and antibacterial actions of

[39]

lactoferrin, very little is known about the mechanism of its antifungal action. Lactoferrin seems to destroy the cell wall and bind the plasma membrane of C. albicans.

Interaction with nucleic acids

One of the important properties of lactoferrin is its ability to bind with nucleic acids. The fraction of protein extracted from milk, contains 3.3% RNA,
[17]

besides, the protein preferably binds to the

double-stranded than to the single-stranded DNA. The ability of lactoferrin to bind DNA is used for the isolation and purification of lactoferrin using affinity chromatography with columns containing immobilized DNA-containingsorbents, such as agarose with the immobilized single-stranded DNA. [edit]Enzymatic
[43]

activity of lactoferrin

Lactoferrin hydrolyzes RNA and exhibits the properties of pyrimidine-specific secretory ribonucleases. In particular, by destroying the RNA genome, milk RNase inhibits reverse transcription of retroviruses that cause breast cancer in mice.
[45] [44]

Parsi women in West India have the milk RNase

level markedly lower than in other groups, and their breast cancer rate is three times higher than average. Thus, ribonucleasesof milk, and lactoferrin in particular, might play an important role

in pathogenesis of diseases caused by various retroviruses.