Α-Lactalbumin
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α-lactalbumin, also known as alpha-lactalbumin and LALBA, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''LALBA''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.


Overview

α-lactalbumin is a protein that regulates the production of lactose in the milk of almost all
mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
ian species. In primates, α-lactalbumin expression is upregulated in response to the hormone
prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...
and increases the production of
lactose Lactose is a disaccharide composed of galactose and glucose and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from (Genitive case, gen. ), the Latin word for milk, plus the suffix ''-o ...
. α-lactalbumin forms the regulatory subunit of the
lactose synthase Lactose synthase is an enzyme that generates lactose from glucose and UDP-galactose. It is classified under . It consists of N-acetyllactosamine synthase and alpha-lactalbumin. Alpha-lactalbumin, which is expressed in response to prolactin, i ...
(LS) heterodimer and β-1,4-galactosyltransferase (beta4Gal-T1) forms the catalytic component. Together, these proteins enable LS to produce
lactose Lactose is a disaccharide composed of galactose and glucose and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from (Genitive case, gen. ), the Latin word for milk, plus the suffix ''-o ...
by transferring
galactose Galactose (, ''wikt:galacto-, galacto-'' + ''wikt:-ose#Suffix 2, -ose'', ), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweetness, sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epime ...
moieties to
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
. 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 ''The Tragedy of Hamlet, Prince of Denmark'', often shortened to ''Hamlet'' (), is a Shakespearean tragedy, tragedy written by William Shakespeare sometime between 1599 and 1601. It is Shakespeare's longest play. Set in Denmark, the play (the ...
, probably induces
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
in tumor and immature cells. The corresponding folding dynamics of α-lactalbumin is thus highly unusual. When formed into a complex with Gal-T1, a
galactosyltransferase Galactosyltransferase is a type of glycosyltransferase which catalyzes the transfer of galactose Galactose (, ''wikt:galacto-, galacto-'' + ''wikt:-ose#Suffix 2, -ose'', ), sometimes abbreviated Gal, is a monosaccharide sugar that is about ...
, α-lactalbumin enhances the enzyme's affinity for
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
by about 1000 times and inhibits the ability to polymerise multiple
galactose Galactose (, ''wikt:galacto-, galacto-'' + ''wikt:-ose#Suffix 2, -ose'', ), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweetness, sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epime ...
units. This gives rise to a pathway for forming
lactose Lactose is a disaccharide composed of galactose and glucose and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from (Genitive case, gen. ), the Latin word for milk, plus the suffix ''-o ...
by converting Gal-T1 to
lactose synthase Lactose synthase is an enzyme that generates lactose from glucose and UDP-galactose. It is classified under . It consists of N-acetyllactosamine synthase and alpha-lactalbumin. Alpha-lactalbumin, which is expressed in response to prolactin, i ...
.


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 The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electric charge, electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). Howe ...
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. One of the main structural differences with beta-lactoglobulin is that it does not have any free
thiol group In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...
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
lysozyme Lysozyme (, muramidase, ''N''-acetylmuramide glycanhydrolase; systematic name peptidoglycan ''N''-acetylmuramoylhydrolase) is an antimicrobial enzyme produced by animals that forms part of the innate immune system. It is a glycoside hydrolase ...
s, specifically the Ca2+-binding c-lysozyme. 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. This gene predates the last common ancestor of mammals and birds, which probably puts its origin at about 300 Ma.


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 acid An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life forms ...
s 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 Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
, and
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
residues, each with correlated health benefits.


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 Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...
(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 ''Lactobacillus acidophilus'' (Neo-Latin 'acid-loving milk-bacillus') is a rod-shaped, Gram-positive bacteria, Gram-positive, homofermentative, Anaerobic organism, anaerobic microbe first isolated from infant feces in the year 1900. The species ...
, Bifidobacterium short,'' and ''
Bifidobacterium longum ''Bifidobacterium longum'' is a Gram-positive, catalase-negative, rod-shaped bacterium present in the human gastrointestinal tract and one of the 32 species that belong to the genus ''Bifidobacterium''. It is a microaerotolerant anaerobe and con ...
.'' These bacteria produce
short chain fatty acids Short-chain fatty acids (SCFAs) are fatty acids of two to six carbon atoms. The SCFAs' lower limit is interpreted differently, either with one, two, three or four carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, ...
(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 is not a cure for this condition, this could be a short-term remedy.


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 Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
, 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 Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...
synthesis which is an important antioxidant.


Cancer

There has been extensive research on
apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...
effects that α-lactalbumin potentially has when it forms a complex with oleic acid called
HAMLET ''The Tragedy of Hamlet, Prince of Denmark'', often shortened to ''Hamlet'' (), is a Shakespearean tragedy, tragedy written by William Shakespeare sometime between 1599 and 1601. It is Shakespeare's longest play. Set in Denmark, the play (the ...
(Human alpha-lactalbumin made lethal to tumor cells). This
HAMLET ''The Tragedy of Hamlet, Prince of Denmark'', often shortened to ''Hamlet'' (), is a Shakespearean tragedy, tragedy written by William Shakespeare sometime between 1599 and 1601. It is Shakespeare's longest play. Set in Denmark, the play (the ...
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.


References


Further reading

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External links

* * {{Globulins Milk Mammalian proteins Lactose