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Facts About: Lactose and Milk Sugars

April 01, 2024

By: Richard D. Cummings

The disaccharide lactose, Galβ1-4Glc, is found only in the milk of mammals, and so far, it and extended milk oligosaccharides derived from it, are found nowhere else in nature (1-4).  All mammals make milk, of course, but the assortment of oligosaccharides beyond lactose is very different in different mammalian milk sources.  

Interestingly, the reverse sequence Glc-Gal is found in collagen, where it is linked to hydroxylysine residues in collagen as Glcα1-2Galβ1-O-hydroxyLys. This sequence in collagen is universal, and found in sponge collagen (5) and all animal collagens (6).

Lactose is made by a novel pathway unique in all respects.  It is synthesized in the lactating mammary gland by the enzyme UDPGal:β-D-GlcNAcβ1,4galactosyltransferase (β4GalT-1), encoded by B4GAL-T1 (7).  However, this β4GalT-1 is unique among the seven known human β4GalTs, in that it can galactosylate two different types of acceptors; it can use free glucose as an acceptor to generate lactose, and use terminal GlcNAc residues in glycoconjugates to synthesize the N-acetyllactosamine sequence.

The history of this discovery is one of the most unusual in glycoscience and considered a milestone in mammalian biology.  Early studies had shown that the glucose residue in lactose was derived from blood glucose, based on experiments in which 14C-glucose was intravenously injected into a lactating goat (8).  Studies in the late 1960s indicated that milk contains an enzyme designated lactose synthetase, UDPGal:D-glucose β-4-galactosyltransferase, which can catalyze transfer of galactose from UDP-Gal to D-glucose, but it can also transfer galactose to D-N-acetylglucosamine to generate N-acetyllactosamine-type termini (9).  [See reactions below.]

UDP-D-Galactose + D-glucose à Galβ1-4Glc (lactose) + UDP
(requires the presence of α-lactalbumin)

UDP-D-Galactose + D-GlcNAc-R à Galβ1-4GlcNAc-R (N-acetyllactosamine-type) + UDP

In its function as lactose synthetase, studies from Robert Hill’s laboratory showed that the enzyme is actually comprised of two components, labeled the A and B proteins.  These two proteins together in the presence of manganese can produce lactose using Glc as the acceptor and UDP-Gal as the donor, but neither can function separately to promote this reaction (10).  The A protein was determined to be the β4GalT, and the B protein was discovered to be α-lactalbumin, with sequence homology to egg-white lysosome (11).  α-Lactalbumin is a calcium-binding protein, and was named a "specifier" protein; when present and bound to the β-4-galactosyltransferase, the A protein, it modifies or redirects it to use glucose rather than N-acetylglucosamine as an acceptor (12). α-Lactalbumin is only expressed by epithelial cells in the lactating mammary gland (13).

The sequence and structure of β4GalT-1 and how it functions in this regard with α-lactalbumin was worked out by Qasba’s laboratory (7,14).  The complex of the β4GalT-1 and α-lactalbumin is unique in nature.   Interestingly, β4GalT-1 like many other glycosyltransferases, is synthesized as a type II transmembrane protein and functions in the Golgi apparatus.  However, it is susceptible to proteolytic cleavage in its stem domain (15), as is seen in many other glycosyltransferases (16), and can be secreted from cells into fluids (including milk) as a soluble and functional enzyme.

The history of lactose itself is interesting.  Pasteur is famous for many discoveries, but one of the most important discoveries was of the sugar galactose in milk. Oddly, in 1856 Pasteur purified a sugar from milk that he named lactose1. Berthelot in 1860 found, however, that Pasteur had purified the sugar galactose, which Berthelot named as galactose ("glucose lactique") and preserved the name lactose for the disaccharide we know as lactose2. The American Chemical Society website notes that “F. Bartolletti discovered lactose in milk in 1619; C. W. Scheele identified it as a sugar in 1780.” https://www.acs.org/molecule-of-the-week/archive/l/d-lactose.html

Footnotes:  

1 Pasteur L (1856). "Note sur le sucre de lait" [Note on milk sugar]. Comptes rendus (in French). 42: 347–351
2 Berthelot M (1860). "Chimie organique fondée sur la synthèse" [Organic chemistry based on synthesis]. Mallet-Bachelier (in French). Paris, France. 2: 248–249.

References:

  1. Atkinson, R. L., Kratzer, F. H., and Stewart, G. F. (1957) Lactose in Animal and Human Feeding:  A Review. Journal of Dairy Science 40, 1114-1132
  2. Bode, L. (2012) Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology 22, 1147-1162
  3. Kobata, A. (2010) Structures and application of oligosaccharides in human milk. Proc Jpn Acad Ser B Phys Biol Sci 86, 731-747
  4. Thomes, L., Karlsson, V., Lundstrom, J., and Bojar, D. (2023) Mammalian milk glycomes: Connecting the dots between evolutionary conservation and biosynthetic pathways. Cell Rep 42, 112710
  5. Katzman, R. L., Halford, M. H., Reinhold, V. N., and Jeanloz, R. W. (1972) Isolation and structure determination of glucosylgalactosylhydroxylysine from sponge and sea anemone collagen. Biochemistry 11, 1161-1167
  6. Hennet, T. (2019) Collagen glycosylation. Curr Opin Struct Biol 56, 131-138
  7. Qasba, P. K., Ramakrishnan, B., and Boeggeman, E. (2008) Structure and function of beta -1,4-galactosyltransferase. Curr Drug Targets 9, 292-309
  8. Reiss, O. K., and Barry, J. M. (1953) The synthesis of lactose from glucose in the mammary gland. Biochem J 55, 783-785
  9. Babad, H., and Hassid, W. Z. (1966) Soluble uridine diphosphate D-galactose: D-glucose beta-4-D-galactosyltransferase from bovine milk. J Biol Chem 241, 2672-2678
  10. Brew, K., Vanaman, T. C., and Hill, R. L. (1968) The role of alpha-lactalbumin and the A protein in lactose synthetase: a unique mechanism for the control of a biological reaction. Proc Natl Acad Sci U S A 59, 491-497
  11. Brew, K., Vanaman, T. C., and Hill, R. L. (1967) Comparison of the amino acid sequence of bovine alpha-lactalbumin and hens egg white lysozyme. J Biol Chem 242, 3747-3749
  12. Bell, J. E., Beyer, T. A., and Hill, R. L. (1976) The kinetic mechansim of bovine milk galactosyltransferase. The role of alpha-lactalbumin. J Biol Chem 251, 3003-3013
  13. Permyakov, E. A. (2020) alpha-Lactalbumin, Amazing Calcium-Binding Protein. Biomolecules 10
  14. Ramakrishnan, B., Boeggeman, E., Ramasamy, V., and Qasba, P. K. (2004) Structure and catalytic cycle of beta-1,4-galactosyltransferase. Curr Opin Struct Biol 14, 593-600
  15. Masri, K. A., Appert, H. E., and Fukuda, M. N. (1988) Identification of the full-length coding sequence for human galactosyltransferase (beta-N-acetylglucosaminide: beta 1,4-galactosyltransferase). Biochem Biophys Res Commun 157, 657-663
  16. Kitazume-Kawaguchi, S., Dohmae, N., Takio, K., Tsuji, S., and Colley, K. J. (1999) The relationship between ST6Gal I Golgi retention and its cleavage-secretion. Glycobiology 9, 1397-1406

 

 

See also: Interesting Facts About Glycans