A Comparative Review of the Cell Biology, Biochemistry, and Genetics of Lactose Synthesis

Abstract

Lactose is the primary carbohydrate in the milk of most mammals and is unique in that it is only synthesized by epithelial cells in the mammary glands. Lactose is also essential for the development and nutrition of infants. Across species, the concentration of lactose in milk holds a strong positive correlation with overall milk volume. Additionally, there is a range of examples where the onset of lactose synthesis as well as the content of lactose in milk varies between species and throughout a lactation. Despite this diversity, the precursors, genes, proteins and ions that regulate lactose synthesis have not received the depth of study they likely deserve relative to the significance of this simple and abundant molecule. Through this review, our objective is to highlight the requirements for lactose synthesis at the biochemical, cellular and temporal levels through a comparative approach. This overview also serves as the prelude to a companion review describing the dietary, hormonal, molecular, and genetic factors that regulate lactose synthesis.

Keywords: Alpha-lactalbumin; Beta-1,4-galactosyl transferase; Lactation; Lactose synthase complex; Mammary epithelial cells; Oligosaccharide.

Fig. 1

The relationship between lactose and fat content in the mature milk of different species. A more comprehensive graphical presentations of the association between milk lactose and fat concentration have been presented elsewhere [1]. Data for fat and lactose content in the milk of the human, cow, goat, mouse, rat, dog, minipig are presented as the mean of published ranges. Tammar wallaby: Fat (40 mg/ml) was measured at 26 weeks of lactation and lactose (39 mg/ml) between 13 and 34 weeks of lactation [25, 140]; Florida manatee: Fat (190 mg/ml) and lactose (not detected) at 30 weeks and at 2 years of lactation [9]; Human: fat (28–44 mg/ml) and lactose (61–79 mg/ml) between 40 and 180 days postpartum [5]; Lemur: fat (18 mg/ml) and lactose (81 mg/ml) at 72 days postpartum [5]; Cow: fat (33–54 mg/ml) and lactose (44–56 mg/ml) during mid-lactation [6]; Horse: fat (12.1 mg/ml, range 50–200) and lactose (63.7 mg/ml, range 58–70) during mid-lactation [141]; Goat: fat (40 mg/ml) and lactose (32–50 mg/ml) during mid-lactation [6]; Mouse: fat (190–220 mg/ml) and lactose (24–28 mg/ml) in mature milk samples [7]; Rat: fat (140–159 mg/ml) and lactose (11–41 mg/ml) in mature milk samples [7]; Rabbit: fat (152 mg/ml) and lactose (18 mg/ml) in mature milk samples [7]; Dog: fat (24–134 mg/ml) and lactose (29–40 mg/ml) in mature milk samples [7]; (mini)Pig: fat (77–100 mg/ml) and lactose (43–56 mg/ml) in mature milk samples [7]; Subantarctic fur seal: fat (510 mg/ml) and lactose (not detected) in mid-lactation samples [12]; Polar bear: fat (278 mg/ml) and carbohydrate (26 mg/ml) in yearlings mid-lactation sample [142]

Fig. 2

A schematic representation of the biochemical and cellular requirements for lactose synthesis. Glucose and non-glucose precursors are taken up by the mammary epithelial cell at its basolateral surface. Some glucose is shuttled directly to the Golgi while other glucose and non-glucose precursors are converted to UDP-galactose through a series of enzymatic reactions. The 3.9 kilobase B4GALT1 mRNA is preferentially and abundantly transcribed and translated during lactation relative to the 4.1 kilobase B4GALT1 mRNA. Some LALBA is glycosylated in the smooth endoplasmic reticulum. The lactose synthase complex is formed by B4GALT1 and LALBA in the Golgi, which then joins glucose and UDP-galactose to form lactose while the UMP moiety is recycled. Lactose, LALBA, and B4GALT1 within vesicles are secreted by exocytosis, and are guided and supported by microtubules and microfilaments. Abbreviations: Aquaporin 3 (AQP3), α-lactalbumin (LALBA), β-1,4-galactosyltransferase-1 gene (B4GALT1), calcium (Ca), dihydroxyacetone phosphate (DAP), endoplasmic reticulum (ER), galactose (Gal), glucose (Glc), glucose transporter 1 (GLUT1), glycerol (glyc), glycerol kinase (GK), glyceraldehyde-3-phosphate dehydrogenase (G3PD), hexokinase (HK), kilobases (kb), manganese (Mn), messenger ribonucleic acid (mRNA), pentose phosphate pathway (PPP), phosphoglucomutase (PGM), UDP-glucose-pyrophosphorylase 2 (UGP2), phosphate (P), solute carrier family 35 A2 (SLC35A2), uridine diphosphate (UDP), uridyl monophosphate (UDP), UDP-glucose 4-epimerase (GALE)

Fig. 3

A graphical representation of the biomolecular process of lactose synthesis. (1) First, B4GALT1 resides in the Golgi in its inactive conformation. (2) Then, UDP-gal binds the N-terminus of B4GALT1. The enzyme shifts its conformation from an inactive to an active state, revealing the LALBA binding site. (3) Next, LALBA can bind B4GALT1, increasing the preference of B4GALT1 for glucose by 1000-fold. (4) Lactose synthase transfers D-galactose (derived from UDP-gal) to the OH-4 position of glucose to create lactose. (5) Lactose and LALBA dissociate and B4GALT1 returns to its inactive conformation. Abbreviations: α-lactalbumin (LALBA), β-1,4-galactosyltransferase-1 gene (B4GALT1), galactose (Gal), glucose (Flc), uridine diphosphate (UDP)