The New Insight of Alfa Lactalbumin
Lactalbumin, alpha-, also known as LALBA, is a protein that in humans is encoded by the LALBA gene. α-Lactalbumin is an important whey protein in cow’s milk (~1 g/l), and is also present in the milk of many other mammalian species. Lactalbumin is the albumin contained in milk and obtained from whey. Lactalbumin is found in the milk of many mammals. There are alpha and beta lactalbumins; both contained in milk. In primates, alpha-lactalbumin expression is upregulated in response to the hormone prolactin and increases the production of lactose.
α-Lactalbumin forms the regulatory subunit of the lactose synthase (LS) heterodimer and β-1,4-galactosyltransferase (beta4Gal-T1) forms the catalytic component. Together, these proteins enable LS to produce lactose by transferring galactose moieties to glucose. As a multimer, alpha-lactalbumin strongly binds calcium and zinc ions and may possess bactericidal or antitumor activity. A folding variant of human alpha-lactalbumin that may form in acidic environments such as the stomach, called HAMLET, probably induces apoptosis in tumor and immature cells.
Alpha-lactalbumin (LALBA) is the major protein found in breast milk. It is one of the reasons that human milk is superior to cow’s milk in feeding infants. It is found in the milk of many mammals, however. This protein helps to synthesize the milk sugar lactose. Alpha-lactalbumin is added to some infant formula mixtures to make them more nutritious.
Lactose is the major carbohydrate found in milk. It is a combination of the two sugars glucose and galactose. Alpha-lactalbumin acts as a regulatory unit for the enzyme that synthesizes lactose, by combining these two sugars. This protein complex stimulates lactose production and is itself stimulated by a hormone known as prolactin. When an infant sucks on a nipple, this stimulates prolactin production, which also causes the breast to fill with milk.
A major component of human breast milk is alpha-lactalbumin, which is itself a nutrient for the infant. The presence of it contributes to the nutritional benefits of breastfeeding. LALBA is known as a whey protein. Whey is a term often used in conjunction with cow’s milk. It indicates the soluble fraction of milk left over when cheese is made. Many bodybuilders take whey, from cows, as a supplement after workouts, so their bodies will use the protein fragments to increase muscle mass.
There are four main protein fractions in whey from cows, with the protein present in the greatest amounts being beta-lactoglobulin. This is not generally found in human breast milk. It can cause allergies in some children who are given cow’s milk. About one quarter of the whey protein is comprised of alpha-lactalbumin.
In contrast, alpha-lactalbumin makes up approximately 60% of the proteins in human whey protein. Additionally, breast milk has a much greater concentration of whey proteins than cow’s milk. Thus, the effective amount of LALBA is much greater in human milk.
Alpha-lactalbumin has high quantities of several types of amino acids that make it a particularly noteworthy protein to ingest. It has a large amount of tryptophan, which can induce sleep. This amino acid is converted, in the body, to the neurotransmitter serotonin, which can boost moods and lower stress levels. This is why a class of antidepressant drugs acts by increasing serotonin in people suffering from mood disorders.
Also present in this protein is a large quantity of the amino acid cysteine. This compound is thought to help boost the immune system. LALBA also contains branched-chain amino acids, which are essential for people. These types of amino acids are required by the body, but cannot be synthesized by it.
In humans, the gene for alpha-lactalbumin is known as the LALBA gene. The sequence of this gene shows a strong similarity to that of lysozyme. This is an antibacterial protein that is found in saliva and tears. Its evolution is thought to predate that for LALBA, which is also thought to have antibacterial properties.
Research by a Dr. Vincent Tuohy at the Cleveland Clinic is using α-Lactalbumin as the basis for a potential breast cancer vaccine. Breast cancer usually develops later in life, well after the typical child-bearing age. This protein is normally expressed only during late pregnancy and lactation, but Tuohy notes that expression is also common in newly formed tumours: “One of the things they do is make inappropriate proteins like α-lactalbumin”. Dr. Tuohy’s group has developed a vaccine that targets α-Lactalbumin, tricking the patients own immune system to attack breast tissue that expresses the α-Lactalbumin genes and thus killing a high percentage of the cancerous cells. In fact, vaccinated mice achieved 100% protection against breast cancer, provided they were dosed before tumours began to develop. Tissue damage and inflammation were limited to the breast tissue of nursing animals. This should not be a problem for humans, as the highest risk breast cancer patients are generally past childbearing age.
When formed into a complex with Gal-T1, a galactosyltransferase, α-lactalbumin, enhances the enzyme’s affinity for glucose by about 1000 times, and inhibits the ability to polymerise multiple galactose units. This gives rise to a pathway for forming lactose by converting Gal-TI to Lactose synthase.
The molecular weight is 14178 Da, and the isoelectric point is between 4.2 and 4.5. One of the main structural differences with beta-lactoglobulin is that it does not have any free thiol group that can serve as the starting-point for a covalent aggregation reaction. As a result, pure α-lactalbumin will not form gels upon denaturation and acidification.
The sequence comparison of α-lactalbumin shows a strong similarity to that of lysozymes, specifically the Ca2+-binding c-lysozyme.So the expected evolutionary history is that gene duplication of the c-lysozyme was followed by mutation.This gene predates the last common ancestor of mammals and birds, which probably puts its origin at about 300 Ma
Single nucleotide polymorphism in the human alpha-lactalbumin gene
Variability in the protein composition of breast milk has been observed in many women and is believed to be due to natural variation of the human population. Single nucleotide polymorphisms (SNPs) are present throughout the entire human genome, but the impact of this variation on human milk composition and biological activity and infant nutrition and health is unclear.
A variant form of alpha-lactalbumin was observed in HPLC chromatograms, and the difference in molecular weight was determined by MS (wild type=14,070 Da, variant=14,056 Da). Protein reduction and digestion narrowed the polymorphism between the 33rd and 77th amino acid of the protein. The genetic polymorphism was identified as adenine to guanine, which translates to a substitution from isoleucine to valine at amino acid 46. The frequency of variation was higher in milk from China, Japan and Philippines, which suggests that this polymorphism is most prevalent in Asia. There are SNPs in the genome for human milk proteins and their implications for protein bioactivity and infant nutrition need to be considered.
Bioactivity of α-lactalbumin and interaction with fatty acids
α-Lactalbumin (α-LA) is a whey protein that has been extensively studied for its folding properties and its ability to bind several cations. An interesting property of α-LA is its ability to interact with fatty acids, although this interaction requires the previous unfolding of the protein by removing the Ca(2+) bound. The main function of α-LA is to participate in lactose biosynthesis. However, other biological functions have been attributed to the protein in the last decade. It has been reported that a particular form of human and bovine apo-α-LA induces apoptosis in tumoral and immature cells though spares healthy differentiated cells. The conversion of α-LA to the active apoptotic form requires the unfolding of the protein and the binding of specific fatty acids, mainly unsaturated C18 fatty acids in the cis-conformation. Likewise, it has been shown that a folding variant of α-LA and also some peptidic fragments have a bactericidal activity. The proposed functions for α-LA open new perspectives for its use as a potential ingredient to be added in functional foods or in nutraceutical products.
Cytotoxic complexes formed
α-Lactalbumin is a ubiquitous calcium-binding milk protein with a well-characterized function in regulating the synthesis of lactose. An entirely different activity has been shown to occur when a complex is formed between calcium-free α-lactalbumin and oleic acid. This complex shows strong cytotoxic action against several cancer cells, and several mechanisms have been suggested to account for this cell-killing activity. Most studies have been performed using the human protein, but bovine α-lactalbumin shows similar activity. A new and simple 2-step method for purification of calcium-free α-lactalbumin has been developed, and the resulting highly purified preparation was used to generate a complex with oleic acid. Using 3 different cell lines and 2 types of cell viability assays, the bovine and human α-lactalbumin showed comparable cytotoxic activity. The effect was apparent after 15 min of incubation and was inhibited by the presence of fetal bovine serum or bovine serum albumin. The bovine protein might be a useful alternative to the human protein, but also raises the question whether cytotoxic activity could be generated in different kinds of food containing α-lactalbumin.
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