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α-Lactalbumin

From Wikipedia, the free encyclopedia
LALBA
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLALBA, entrez:3906, LYZG, lactalbumin alpha, HAMLET
External IDsOMIM: 149750; MGI: 96742; HomoloGene: 1720; GeneCards: LALBA; OMA:LALBA - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3906

16770

Ensembl

ENSG00000167531

ENSMUSG00000022991

UniProt

P00709

P29752

RefSeq (mRNA)

NM_002289
NM_001384350

NM_010679

RefSeq (protein)

NP_002280

NP_034809

Location (UCSC)Chr 12: 48.57 – 48.57 MbChr 15: 98.38 – 98.38 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

α-Lactalbumin, also known as LALBA, is a protein that in humans is encoded by the LALBA gene.[5][6][7]

Overview

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α-Lactalbumin is a protein that regulates the production of lactose in the milk of almost all mammalian species.[8] In primates, α-lactalbumin expression is upregulated in response to the hormone prolactin and increases the production of lactose.[9]

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.[5] The corresponding folding dynamics of α-lactalbumin is thus highly unusual.[10]

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

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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.[11] 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.[11]

This is the calcium binding site for LALBA. The calcium ion, shown in green, is surrounded by two water molecules (red). The purple residues are the carbonyl binding sites of Lys79 and Asp84. The blue shows the carboxylic groups of Asp82, Asp87, Asp 88.

Evolution

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The sequence comparison of α-lactalbumin shows a strong similarity to that of lysozymes, specifically the Ca2+-binding c-lysozyme.[12] 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.[11] 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.[8][13] This gene predates the last common ancestor of mammals and birds, which probably puts its origin at about 300 Ma.[14]

Functions

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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.[15]

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.[13]

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.[16]

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.[15][16]

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.[13]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000167531 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022991 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: LALBA lactalbumin, alpha-".
  6. ^ Hall L, Davies MS, Craig RK (January 1981). "The construction, identification and characterisation of plasmids containing human alpha-lactalbumin cDNA sequences". Nucleic Acids Research. 9 (1): 65–84. doi:10.1093/nar/9.1.65. PMC 326669. PMID 6163135.
  7. ^ Hall L, Emery DC, Davies MS, Parker D, Craig RK (March 1987). "Organization and sequence of the human alpha-lactalbumin gene". The Biochemical Journal. 242 (3): 735–742. doi:10.1042/bj2420735. PMC 1147772. PMID 2954544.
  8. ^ a b Qasba PK, Kumar S (1997). "Molecular divergence of lysozymes and alpha-lactalbumin". Critical Reviews in Biochemistry and Molecular Biology. 32 (4): 255–306. doi:10.3109/10409239709082574. PMID 9307874.
  9. ^ Kleinberg DL, Todd J, Babitsky G (July 1983). "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. Bibcode:1983PNAS...80.4144K. doi:10.1073/pnas.80.13.4144. PMC 394217. PMID 6575400.
  10. ^ Bu Z, Cook J, Callaway DJ (September 2001). "Dynamic regimes and correlated structural dynamics in native and denatured alpha-lactalbumin". Journal of Molecular Biology. 312 (4): 865–873. doi:10.1006/jmbi.2001.5006. PMID 11575938.
  11. ^ a b c Permyakov EA (August 2020). "α-Lactalbumin, Amazing Calcium-Binding Protein". Biomolecules. 10 (9): 1210. doi:10.3390/biom10091210. PMC 7565966. PMID 32825311.
  12. ^ Acharya KR, Stuart DI, Walker NP, Lewis M, Phillips DC (July 1989). "Refined structure of baboon alpha-lactalbumin at 1.7 A resolution. Comparison with C-type lysozyme". Journal of Molecular Biology. 208 (1): 99–127. doi:10.1016/0022-2836(89)90091-0. PMID 2769757.
  13. ^ a b c El-Fakharany EM, Redwan EM (November 2019). "Protein-lipid complexes: molecular structure, current scenarios and mechanisms of cytotoxicity". RSC Advances. 9 (63): 36890–36906. Bibcode:2019RSCAd...936890E. doi:10.1039/C9RA07127J. PMC 9075609. PMID 35539089.
  14. ^ Prager EM, Wilson AC (1988). "Ancient origin of lactalbumin from lysozyme: analysis of DNA and amino acid sequences". Journal of Molecular Evolution. 27 (4): 326–335. Bibcode:1988JMolE..27..326P. doi:10.1007/BF02101195. PMID 3146643. S2CID 10039589.
  15. ^ a b Almeida CC, Mendonça Pereira BF, Leandro KC, Costa MP, Spisso BF, Conte-Junior CA (2021-05-14). Spigno G (ed.). "Bioactive Compounds in Infant Formula and Their Effects on Infant Nutrition and Health: A Systematic Literature Review". International Journal of Food Science. 2021: 8850080. doi:10.1155/2021/8850080. PMC 8140835. PMID 34095293.
  16. ^ a b Cardinale V, Lepore E, Basciani S, Artale S, Nordio M, Bizzarri M, Unfer V (August 2022). "Positive Effects of α-Lactalbumin in the Management of Symptoms of Polycystic Ovary Syndrome". Nutrients. 14 (15): 3220. doi:10.3390/nu14153220. PMC 9370664. PMID 35956395.

Further reading

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