Α-Lactalbumin Explained

α-Lactalbumin, also known as LALBA, is a protein that in humans is encoded by the LALBA gene.^{[1] [2] [3]}

Overview

α-Lactalbumin is a protein that regulates the production of lactose in the milk of almost all mammalian species.^[4] In primates, α-lactalbumin expression is upregulated in response to the hormone prolactin and increases the production of lactose.^[5]

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, α-lactalbumin strongly binds calcium and zinc ions and may possess bactericidal or antitumor activity. A folding variant of human α-lactalbumin that may form in acidic environments such as the stomach, called HAMLET, probably induces apoptosis in tumor and immature cells.^[1] The corresponding folding dynamics of α-lactalbumin is thus highly unusual.^[6]

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.

Physical properties

The structure of α-lactalbumin is well known and is composed of 123 amino acids and 4 disulfide bridges. The molecular weight is 14178 Da, and the isoelectric point is between 4.2 and 4.5. α-Lactalbumin has two prominent forms: holo-state and apo-state. The holo-state is the natural form--folded and bound by calcium. The apo-state occurs in acidic conditions and is associated with the release of calcium ions and beta-sheet unfolding.^[7] 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. α-Lactalbumin is a Ca²⁺ binding protein with a single strong calcium binding spot seen below. The calcium binds to the carboxylic groups of three aspartate residues (Asp 82, 87, 88), seen in blue and to the carbonyl groups from lysine 79 and aspartate 84, seen in purple. This binding is coordinated by two water molecules (red). These residue binding sites are conserved among most species containing α-lactalbumin.

Evolution

The sequence comparison of α-lactalbumin shows a strong similarity to that of lysozymes, specifically the Ca²⁺-binding c-lysozyme.^[8] These two proteins share much of their physical structure but contain less than half of the same amino acid sequence and therefore vary in function drastically. So, the expected evolutionary history is that gene duplication of the c-lysozyme was followed by mutation, resulting in the loss of lysozyme catalytic activity in α-lactalbumin.^{[4] [9]} This gene predates the last common ancestor of mammals and birds, which probably puts its origin at about 300 Ma.^[10]

Functions

Current research is finding new application of α-lactalbumin outside the physiological lactose production.

Nutrition: α-Lactalbumin is essential for newborn nutrition. This protein provides essential amino acids and bioactive compounds necessary for optimal growth, development, and health. α-Lactalbumin is the most abundant whey protein in human milk and its properties have been researched to include in infant formulas to replicate mammary milk compounds. This protein is a strong source of branched amino acids, cysteine, and tryptophan residues, each with correlated health benefits.^[11]

Clinical Uses: α-Lactalbumin has been researched in conjunction with many different medical conditions and is thought to correlate with positive outcomes. Many of these benefits are due to the bioactive compounds it is made of and the protein’s ability to bind complexes.

PCOS: Polycystic Ovary Syndrome (PCOS) is one disease that higher levels of α-lactalbumin have been linked with relieving symptoms. This condition is closely linked with gut dysbiosis caused by inflammation of the intestinal lining and a microbiota imbalance. α-Lactalbumin promotes healthy bacterial strains such as Lactobacillus acidophilus, Bifidobacterium short, and Bifidobacterium longum. These bacteria produce short chain fatty acids (SCFA) which improve the gut biome. In a controlled study, the group that ate a diet higher in α-lactalbumin experienced a decrease in symptoms associated with PCOS, and higher levels of healthy bacteria. While there isn’t a cure for this condition, this could be a short-term remedy.^[12]

Mental health: α-Lactalbumin is a source of amino acids which are connected to improved mental health. This protein is rich in Tryptophan residues which are a precursor to serotonin, a neurotransmitter associated with positive moods. The protein also increases the plasma concentration for other large neutral amino acids (LNAAs) which help balance hormones. The cysteine residues aid in glutathione synthesis which is an important antioxidant.

Cancer: There has been extensive research on apoptotic effects that α-lactalbumin potentially has when it forms a complex with oleic acid called HAMLET (Human alpha-lactalbumin made lethal to tumor cells). This HAMLET complex disrupts the structure of the membrane when bound, promoting cell death to protect the integrity of the organism. This complex can translocate into the nuclei of cancerous cells, but not of healthy cells. When in cancer cells, this protein-OA complex has been shown to slow the progression of tumors in numerous studies. α-Lactalbumin's native state does not show these same anti-cancer functions, so it is likely that the oleic acid expresses the apoptotic functions while the α-lactalbumin is responsible for targeting the specific cells lines such as colon, bladder, and glioblastoma cancer cells.

Further reading

• Heine WE, Klein PD, Reeds PJ . The importance of alpha-lactalbumin in infant nutrition . The Journal of Nutrition . 121 . 3 . 277–283 . March 1991 . 2002399 . 10.1093/jn/121.3.277 . free .
• Permyakov EA, Berliner LJ . alpha-Lactalbumin: structure and function . FEBS Letters . 473 . 3 . 269–274 . May 2000 . 10818224 . 10.1016/S0014-5793(00)01546-5 . 83964232 .
• Hall L, Emery DC, Davies MS, Parker D, Craig RK . Organization and sequence of the human alpha-lactalbumin gene . The Biochemical Journal . 242 . 3 . 735–742 . March 1987 . 2954544 . 1147772 . 10.1042/bj2420735 .
• Davies MS, West LF, Davis MB, Povey S, Craig RK . The gene for human alpha-lactalbumin is assigned to chromosome 12q13 . Annals of Human Genetics . 51 . 3 . 183–188 . July 1987 . 3479943 . 10.1111/j.1469-1809.1987.tb00869.x . 37901087 .
• Findlay JB, Brew K . The complete amino-acid sequence of human -lactalbumin . European Journal of Biochemistry . 27 . 1 . 65–86 . May 1972 . 5049057 . 10.1111/j.1432-1033.1972.tb01812.x . free .
• Hall L, Craig RK, Edbrooke MR, Campbell PN . Comparison of the nucleotide sequence of cloned human and guinea-pig pre-alpha-lactalbumin cDNA with that of chick pre-lysozyme cDNA suggests evolution from a common ancestral gene . Nucleic Acids Research . 10 . 11 . 3503–3515 . June 1982 . 6285305 . 320727 . 10.1093/nar/10.11.3503 .
• Håkansson A, Zhivotovsky B, Orrenius S, Sabharwal H, Svanborg C . Apoptosis induced by a human milk protein . Proceedings of the National Academy of Sciences of the United States of America . 92 . 17 . 8064–8068 . August 1995 . 7644538 . 41287 . 10.1073/pnas.92.17.8064 . free . 1995PNAS...92.8064H .
• Stacey A, Schnieke A, Kerr M, Scott A, McKee C, Cottingham I, Binas B, Wilde C, Colman A . 6 . Lactation is disrupted by alpha-lactalbumin deficiency and can be restored by human alpha-lactalbumin gene replacement in mice . Proceedings of the National Academy of Sciences of the United States of America . 92 . 7 . 2835–2839 . March 1995 . 7708733 . 42313 . 10.1073/pnas.92.7.2835 . free . 1995PNAS...92.2835S .
• Fujiwara Y, Miwa M, Takahashi R, Hirabayashi M, Suzuki T, Ueda M . Position-independent and high-level expression of human alpha-lactalbumin in the milk of transgenic rats carrying a 210-kb YAC DNA . Molecular Reproduction and Development . 47 . 2 . 157–163 . June 1997 . 9136116 . 10.1002/(SICI)1098-2795(199706)47:2<157::AID-MRD5>3.0.CO;2-L . 43232515 .
• Lindner RA, Kapur A, Carver JA . The interaction of the molecular chaperone, alpha-crystallin, with molten globule states of bovine alpha-lactalbumin . The Journal of Biological Chemistry . 272 . 44 . 27722–27729 . October 1997 . 9346914 . 10.1074/jbc.272.44.27722 . free .
• Giuffrida MG, Cavaletto M, Giunta C, Neuteboom B, Cantisani A, Napolitano L, Calderone V, Godovac-Zimmermann J, Conti A . 6 . The unusual amino acid triplet Asn-Ile-Cys is a glycosylation consensus site in human alpha-lactalbumin . Journal of Protein Chemistry . 16 . 8 . 747–753 . November 1997 . 9365923 . 10.1023/A:1026359715821 . 42107172 .
• Chandra N, Brew K, Acharya KR . Structural evidence for the presence of a secondary calcium binding site in human alpha-lactalbumin . Biochemistry . 37 . 14 . 4767–4772 . April 1998 . 9537992 . 10.1021/bi973000t .
• Håkansson A, Andréasson J, Zhivotovsky B, Karpman D, Orrenius S, Svanborg C . Multimeric alpha-lactalbumin from human milk induces apoptosis through a direct effect on cell nuclei . Experimental Cell Research . 246 . 2 . 451–460 . February 1999 . 9925761 . 10.1006/excr.1998.4265 .
• Svensson M, Sabharwal H, Håkansson A, Mossberg AK, Lipniunas P, Leffler H, Svanborg C, Linse S . 6 . Molecular characterization of alpha-lactalbumin folding variants that induce apoptosis in tumor cells . The Journal of Biological Chemistry . 274 . 10 . 6388–6396 . March 1999 . 10037730 . 10.1074/jbc.274.10.6388 . free .
• Harata K, Abe Y, Muraki M . Crystallographic evaluation of internal motion of human alpha-lactalbumin refined by full-matrix least-squares method . Journal of Molecular Biology . 287 . 2 . 347–358 . March 1999 . 10080897 . 10.1006/jmbi.1999.2598 .
• Last AM, Schulman BA, Robinson CV, Redfield C . Probing subtle differences in the hydrogen exchange behavior of variants of the human alpha-lactalbumin molten globule using mass spectrometry . Journal of Molecular Biology . 311 . 4 . 909–919 . August 2001 . 11518539 . 10.1006/jmbi.2001.4911 .
• Bai P, Peng Z . Cooperative folding of the isolated alpha-helical domain of hen egg-white lysozyme . Journal of Molecular Biology . 314 . 2 . 321–329 . November 2001 . 11718563 . 10.1006/jmbi.2001.5122 .
• Andrews P . Purification of lactose synthetase a protein from human milk and demonstration of its interaction with alpha-lactalbumin . FEBS Letters . 9 . 5 . 297–300 . August 1970 . 11947697 . 10.1016/0014-5793(70)80382-9 . 23041445 .

Notes and References

1. Web site: Entrez Gene: LALBA lactalbumin, alpha-.
2. Hall L, Davies MS, Craig RK . The construction, identification and characterisation of plasmids containing human alpha-lactalbumin cDNA sequences . Nucleic Acids Research . 9 . 1 . 65–84 . January 1981 . 6163135 . 326669 . 10.1093/nar/9.1.65 .
3. Hall L, Emery DC, Davies MS, Parker D, Craig RK . Organization and sequence of the human alpha-lactalbumin gene . The Biochemical Journal . 242 . 3 . 735–742 . March 1987 . 2954544 . 1147772 . 10.1042/bj2420735 .
4. Qasba PK, Kumar S . Molecular divergence of lysozymes and alpha-lactalbumin . Critical Reviews in Biochemistry and Molecular Biology . 32 . 4 . 255–306 . 1997 . 9307874 . 10.3109/10409239709082574 .
5. Kleinberg DL, Todd J, Babitsky G . Inhibition by estradiol of the lactogenic effect of prolactin in primate mammary tissue: reversal by antiestrogens LY 156758 and tamoxifen . Proceedings of the National Academy of Sciences of the United States of America . 80 . 13 . 4144–4148 . July 1983 . 6575400 . 394217 . 10.1073/pnas.80.13.4144 . free . 1983PNAS...80.4144K .
6. Bu Z, Cook J, Callaway DJ . Dynamic regimes and correlated structural dynamics in native and denatured alpha-lactalbumin . Journal of Molecular Biology . 312 . 4 . 865–873 . September 2001 . 11575938 . 10.1006/jmbi.2001.5006 .
7. Permyakov EA . α-Lactalbumin, Amazing Calcium-Binding Protein . Biomolecules . 10 . 9 . 1210 . August 2020 . 32825311 . 7565966 . 10.3390/biom10091210 . free .
8. Acharya KR, Stuart DI, Walker NP, Lewis M, Phillips DC . Refined structure of baboon alpha-lactalbumin at 1.7 A resolution. Comparison with C-type lysozyme . Journal of Molecular Biology . 208 . 1 . 99–127 . July 1989 . 2769757 . 10.1016/0022-2836(89)90091-0 .
9. El-Fakharany EM, Redwan EM . Protein-lipid complexes: molecular structure, current scenarios and mechanisms of cytotoxicity . RSC Advances . 9 . 63 . 36890–36906 . November 2019 . 35539089 . 9075609 . 10.1039/C9RA07127J . 2019RSCAd...936890E .
10. Prager EM, Wilson AC . Ancient origin of lactalbumin from lysozyme: analysis of DNA and amino acid sequences . Journal of Molecular Evolution . 27 . 4 . 326–335 . 1988 . 3146643 . 10.1007/BF02101195 . 10039589 . 1988JMolE..27..326P .
11. Almeida CC, Mendonça Pereira BF, Leandro KC, Costa MP, Spisso BF, Conte-Junior CA . Bioactive Compounds in Infant Formula and Their Effects on Infant Nutrition and Health: A Systematic Literature Review . International Journal of Food Science . 2021 . 8850080 . 2021-05-14 . 34095293 . 8140835 . 10.1155/2021/8850080 . Spigno G . free .
12. Cardinale V, Lepore E, Basciani S, Artale S, Nordio M, Bizzarri M, Unfer V . Positive Effects of α-Lactalbumin in the Management of Symptoms of Polycystic Ovary Syndrome . Nutrients . 14 . 15 . 3220 . August 2022 . 35956395 . 9370664 . 10.3390/nu14153220 . free .