Galactose

Galactose (Gal) is metabolized to glucose-1-phosphate through the Leloir pathway for glycolysis, this pathway maintains the pools of UDP-sugars for the biosynthesis of glycoconjugates.

From: Molecular Nutrition: Carbohydrates , 2019

GALACTOSE

C.A. Williams , in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003

Occurrence

Galactose is a monosaccharide and has the same chemical formula as glucose, i.e., C 6H12O6. It is similar to glucose in its structure, differing only in the position of one hydroxyl group. This difference, however, gives galactose different chemical and biochemical properties to glucose.

The major dietary source of galactose is lactose, a disaccharide formed from one molecule of glucose plus one of galactose. Lactose is found only in milk; after weaning, significant quantities of dietary lactose are found only in dairy products (Table 1). Lactose levels are lower than expected in some dairy products, where it has been used by the microbes involved in processing the food.

Table 1. Lactose content of milk and dairy products

Food Lactose content (g per 100   g)
Cows' milk 4.7
Goats' milk 4.6
Human milk 7.2
Butter Trace
Cream 2.0–3.2
Cheese (most types) Trace
Cottage cheese 1.4
Yogurt 3.2–4.8

From Paul AA and Southgate DAT (1978) McCance and Widdowson's The Composition of Foods, 4th edn. London: Her Majesty's Stationery Office.

Lactose, a byproduct of the dairy industry, can be hydrolyzed to produce lactose hydrolysate syrup, which contains lactose, galactose, and glucose. This syrup is used as a sweetener in biscuits, confectionery, and some dairy desserts. Thus, small amounts of lactose and galactose can appear in nondairy foods. (See Lactose.)

Apart from its presence in lactose hydrolysate syrup, the monosaccharide galactose is seldom found in the diet, although it has been identified as a trace component of some seeds and pulses.

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Volume 5

Albert Flynn , in Encyclopedia of Dairy Sciences (Third Edition), 2022

Introduction

Galactose is an energy-providing nutrient and also a necessary basic substrate for the biosynthesis of many macromolecules in the body. Galactose is an important constituent of the complex polysaccharides, which are part of cell glycoconjugates, key elements of immunological determinants, hormones, cell membrane structures, endogenous lectins, and numerous other glycoproteins. In addition, galactose is incorporated into galactolipids, which are important structural elements of the central nervous system.

Metabolic pathways for galactose are important not only for the provision of these macromolecules but also to prevent the accumulation of galactose and galactose metabolites. Problems with galactose metabolism that result in galactosemia can cause a variety of clinical manifestations in humans.

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Disorders of Galactose Metabolism

Gerard T. Berry , in Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015

Diagnostic Tests

GALE deficiency should be suspected when red cell galactose-1-phosphate is increased while GALT is normal. Newborn screening will give an abnormal result if defined by a raised total blood galactose level with normal GALT activity. Diagnosis is confirmed by the assay of epimerase in erythrocytes. Heterozygous parents have reduced epimerase activity, a finding that can help in the evaluation. Further studies of GALE activity in transformed lymphoblasts and red cell galactose-1-phosphate while on and off dietary galactose may help characterize the disorder further. 97 In those families with the severe form of GALE deficiency, GALE gene sequencing has been the most rapid method of determining whether infants at risk are affected or not.

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Biosynthesis of Vitamins in Plants Part B

Nicholas Smirnoff , in Advances in Botanical Research, 2011

G l-Galactose Dehydrogenase

l-GalDH catalyses NAD+-dependent oxidation of l-Gal at C1 to produce l-galactono-1,4-lactone (Gatzek et al., 2002). The capacity of the enzyme seems to be relatively high, as exogenously supplied l-Gal and its reaction product l-galactonolactone (l-GalL) are very rapidly converted to ascorbate resulting in a large increase in ascorbate pool size (Davey et al., 1999; Wheeler et al., 1998). Arabidopsis l-GalDH activity is encoded by At4g33670. Evidence for its role in ascorbate biosynthesis is derived from decreased ascorbate in plants where l-GalDH expression was decreased by antisense suppression. The enzyme has high specificity for l-Gal (Arabidopsis K m 0.4   mM, Spinach K m 0.1   mM) and much lower V max and lower affinity for l-gulose (K m 4   mM) and l-fucose (K m 56   mM) (Gatzek et al., 2002; Mieda et al., 2004). Purified spinach l-GalDH is competitively inhibited by ascorbate (Mieda et al., 2004). The K i value of 0.1   mM is well above the inferred ascorbate concentration in the cytosol (Table I), suggesting that the enzyme could be regulated by feedback inhibition.

Table I. Ascorbate Concentrations (mM) in Leaf Cell Intracellular Compartments from Plants Grown Under Low or High Irradiance (Units: μmol   photons   m−   2  s−   1)

Irradiance Ascorbate concentration (mM)
Cytosol Chloroplasts Mitochondria Peroxisomes Nuclei Vacuoles
Arabidopsis 250 21 10 10 23 16 2
700 29 20 13 16 21 12
Barley 100 35 2 n.d. n.d. n.d. 0.6
500 61 10 n.d. n.d. n.d. 3

Arabidopsis concentrations were estimated from immunogold localisation with ascorbate antibodies using data in Zechmann et al. (2010). Barley data were obtained by non-aqueous fractionation (Rautenkranz et al., 1994). n.d., not determined.

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GALACTOSE*

A. Abi-Hanna , J.M. Saavedra , in Encyclopedia of Human Nutrition (Second Edition), 1998

Management

A galactose-free diet is the current treatment for galactosemia. It is important to know that galactose is present not only in milk but in other sources of food. A strict galactose-free diet in galactosemic patients with transferase deficiency is not harmful. The quality of the galactose-free diet and patient compliance are usually monitored by measuring free galactose in plasma and galactose 1-phosphate in erythrocytes.

Growth retardation, cognitive impairment, speech impediment, tremor, ataxia, and ovarian failure are frequent complications in spite of a strict galactose-free diet. Elevated galactose phosphate levels may occur in erythrocytes of even well-treated galactosemic patients. This elevation is attributed to endogenous production of the metabolite. A galactose-free diet is recommended from birth. It is recommended to restrict galactose in the diet of pregnant mothers diagnosed perinatally with transferase deficiency; a galactose-free diet should be started as soon as the diagnosis is made in the infant regardless of any preexisting manifestation of toxicity. The strict galactose-free diet will cause regression of symptoms and findings. It is important for the families to be aware of the high incidence of verbal dyspraxia even on a very strict diet. The speech intervention program and language stimulation are recommended as early as the first year of life. Many patients with normal IQ values who were treated from birth have learning disabilities, speech and language deficit, and psychological problems. Neurological sequelae have been described also in patients on strict galactose-free diets. These sequelae include cerebellar ataxia, tremor, choreoathetosis, and encephalopathy. Gonadal dysfunction in female galactosemic patients is an almost universal finding, even with a strict galactose-free diet. There is no current therapy for ovarian dysfunction except palliative replacement of oestrogen and progesterone. This is suggested in galactosemic females to develop secondary sexual characters and establish regular menses. There is no universal recommendation for the management of newborns screened positive nor for galactosemic heterozygotic patients.

In patients with epimerase deficiency, UDP-glucose cannot be converted to UDP-galactose. Thus a complete absence of galactose from the diet and the lack of formation of UDP-galactose via transferase would have serious consequences. There would be an inability to form complex polysaccharides and an inability to provide an adequate galactose component for brain cerebrosides. The treatment of epimerase deficiency relies on providing a small amount of dietary galactose.

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Fly Models of Human Diseases

J.M.I. Daenzer , J.L. Fridovich-Keil , in Current Topics in Developmental Biology, 2017

3.3 Using Drosophila to Dissect the Differential Roles of GALE in Development

The work described in this section is from Daenzer, Sanders, Hang, and Fridovich-Keil (2012) unless otherwise noted.

3.3.1 Uncoupling the Two Activities of GALE in Drosophila

GALE from both humans and Drosophila interconverts two sets of substrates: UDPgal/UDPglc and UDPgalNAc/UDPglcNAc (Fig. 1). To uncouple and test the developmental roles of these activities individually, Daenzer and colleagues created flies with activity toward only one or the other substrate set. This substrate specificity was achieved by effectively replacing dGALE expression with expression of either of two prokaryotic epimerase genes, each encoding a product capable of interconverting only one substrate pair: eGALE, which interconverts only UDPgal/UDPglc, and wbgU, which interconverts only UDPgalNAc/UDPglcNAc. Expressing these microbial transgenes in dGALE-deficient Drosophila resulted in animals with only one or the other GALE activity.

3.3.2 Both GALE Activities Play Essential Roles During Development

As explained earlier, Sanders et al. (2010) showed that GALE is essential for Drosophila development, and that dGALE-deficient animals die in embryogenesis. By expressing eGALE only, wbgU only, or both eGALE and wbgU together in dGALE-deficient embryos, Daenzer and colleagues confirmed that GALE activity toward both substrate pairs is essential for survival of Drosophila. Specifically, neither microbial transgene alone enabled survival, but together they did, and further, hGALE, which like dGALE recognizes both substrate pairs, was also sufficient.

Using a modified version of the conditional knockdown technique described in Sanders et al. (2010), Daenzer et al. (2012) created a time course series of Drosophila that experienced dGALE knockdown with concurrent induction of either hGALE, eGALE, wbgU, or both eGALE and wbgU at successive stages of development. As expected, RNAi knockdown of dGALE during both embryonic and larval stages of development was lethal, but was rescued by expression of either hGALE or eGALE   +   wbgU. Surprisingly, expression of either eGALE or wbgU alone was also sufficient for survival when dGALE knockdown was initiated during the early stages of development, though to a lesser extent. This result suggested that residual dGALE activity remaining after knockdown, or existing substrate and product pools already accumulated in the animals, may have reduced the requirement for transgene activity. However, animals experiencing dGALE knockdown with replacement by either eGALE only or wbgU only, at any stage prior to late pupation, exhibited marked fecundity defects. Interestingly, the fecundity defects differed between males and females, and were dependent on which GALE activity was missing. Specifically, dGALE knockdown during early to mid-pupation resulted in fecundity defects in both male and female flies. GALE activity toward UDPgal/UDPglc alone, but not UDPgalNAc/UDPglcNAc alone, was sufficient to rescue the male defect. However, both GALE activities were required to rescue female fecundity.

3.3.3 GALE Activity Toward UDPgal/UDPglc Is Required for Normal Life Span of Adult Drosophila Exposed to Dietary Galactose

Sanders et al. (2010) demonstrated that dGALE hypomorphs developing in the presence of environmental galactose displayed a reduction in viability. Daenzer et al. (2012) extended from that finding by measuring the life spans of dGALE-knockdown animals expressing neither, only one, or both GALE activities. Specifically, flies experiencing dGALE knockdown during early to mid-pupal stages were allowed to develop on a standard molasses food diet and, upon eclosion, were moved to food containing either 555   mM glucose or 555   mM glucose plus 175   mM galactose. The life span of dGALE-knockdown animals eating glucose-only food did not differ significantly from that of control animals. However, when exposed to galactose as adults, the dGALE-knockdown animals displayed a dramatic reduction in life span such that in the absence of knockdown close to 50% of animals remained viable at 35 days, but in the presence of knockdown close to half the animals had died by 10 days and almost no animals remained alive at 35 days. Expression of GALE activity toward UDPgalNAc/UDPglcNAc alone (wbgU transgene) was not sufficient to overcome the galactose-dependent reduction in life span. In contrast, dGALE-knockdown animals in which GALE activity toward UDPgal/UDPglc was restored (eGALE transgene) survived equally well in the presence and absence of dietary galactose. These data confirmed that loss of activity toward UDPgal/UDPglc was responsible for the galactose-induced reduction of life span in dGALE-knockdown animals.

3.3.4 The Two GALE Activities Impact Galactose Metabolite Levels Differently

While it is clear that dGALE-impaired Drosophila experience a variety of acute and long-term outcomes, the pathophysiology of these outcomes remains unclear. Daenzer and colleagues gained some insights into pathophysiology from studying the galactose metabolite levels in their differentially impaired animals. For example, Drosophila in which dGALE knockdown occurred early in development accumulated very high levels of Gal-1P when exposed to galactose as larvae. These larvae also accumulated very high levels of UDPgal. Similarly, larvae deficient only in activity toward UDPgal/UDPglc accumulated very high levels of both Gal-1P and UDPgal when they developed in the presence, but not in the absence, of high dietary galactose. In contrast, animals deficient only in GALE activity toward UDPgalNAc/UDPglcNAc did not accumulate abnormal levels of either Gal-1P or UDPgal. Nonetheless, these animals were not viable. Clearly, elevated Gal-1P and UDPgal cannot be the only cause of pathophysiology in GALE deficiency.

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Carbohydrates, Alcohols, and Organic Acids

Martin Kohlmeier , in Nutrient Metabolism (Second Edition), 2015

Metabolism

Gal is mainly converted to glucose l-phosphate and then to glucose 6-phosphate in the liver (Figure 6.14). A minor alternate pathway exists but remains to be characterized (Berry et al., 2001). The initial critical step is phosphorylation by galactokinase (EC2.7.1.6). There are two genetically distinct isoforms of the enzyme with different tissue distribution. Galactitol accumulation in the lenses of individuals with defective galactokinase 1 can cause cataracts in childhood or early adulthood. The next step of Gal metabolism is the transfer of UDP by UDP-glucose-hexose-i-phosphate uridylyltransferase (EC2.7.7.12). UDP-glucose-4′-epimerase (EC5.1.3.2) epimerizes UDPGal to UDP-glucose. Since UDP-glucose provides the UDP again for the next Gal 1-phosphate molecule, this works like an autocatalytic mechanism with a net conversion of Gal 1-phosphate to glucose 1-phosphate. Magnesium-dependent phosphoglucomutase (EC5.4.2.2; two isoforms, PGM1 and PGM2) converts glucose 1-phosphate into the readily metabolizable intermediate glucose 6-phosphate. Gal can alternatively be reduced to galactitol by NADPH-dependent aldehyde reductase (aldose reductase, EC1.1.1.21), especially in the presence of Gal excess.

Figure 6.14. Metabolism of Gal.

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Disorders of Carbohydrate Metabolism

Priya S. Kishnani , Yuan-Tsong Chen , in Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), 2013

93.4.1 Galactose Metabolism

Galactose, a component of lactose, is an important nutrient for newborn infants and young children. In human breast milk, the lactose content is about 7  g/dL, and in cow's milk the concentration is approximately 5   g/dL. In the newborn infant, lactose may provide as much as 40% of the caloric intake but only 3–4% in the adult due to proportionally lower milk intake. Galactose is also a constituent of many glycoproteins, glycolipids, and mucopolysaccharides.

The principal pathway for the metabolism of galactose has been designated as the Leloir pathway (Figure 93-2). Galactose is phosphorylated to galactose-1-phosphate by the enzyme galactokinase. Galactose-1-phosphate is exchanged for the glucose-1-phosphate moiety of uridine diphosphate glucose (UDPG) to form uridine diphosphate galactose (UDPGal) by galactose-1-phosphate uridyl transferase (transferase or GALT). The glucose-1-phosphate released leads into the glucose pathway. The UDPGal formed is converted to UDPG by the enzyme UDPGal-4-epimerase (epimerase). The sum of these three enzymatic reactions involving galactokinase, transferase, and epimerase is

FIGURE 93-2. Pathways of galactose metabolism.

Galactose   +   adenosine triphosphate (ATP)   =   Glucose-1-phosphate   +   adenosine diphosphate (ADP).

UDPGal is also used for the synthesis of galactose-containing complex carbohydrates. A small amount of galactose is converted to galactitol by aldose reductase and to galactonic acid by galactose dehydrogenase.

These three galactose enzymes in the major pathway are widely distributed in tissues, including erythrocytes, leukocytes, liver, kidney, brain, cultured skin fibroblasts, chorionic villi, and amniotic fluid cells. The gene loci in humans for galactokinase, transferase, and epimerase are on chromosomes 17, 9, and 1, respectively (34–36).

Deficiency in the activity of each of the three enzymes results in metabolic disorders known as galactokinase deficiency, galactose-1-phosphate uridyl transferase deficiency (galactosemia), and UDPgalactose-4-epimerase deficiency. All three disorders can be identified by newborn screening based on increased amounts of galactose or galactose-1-phosphate in the blood spots (Guthrie cards), provided that there is normal amount of lactose intake in the newborn's formula or breast feedings. The identification of the specific defect is based on enzyme assays in erythrocytes, providing that the newborn did not receive a blood transfusion before the collection of the blood sample. Often, the Beutler spot test has been employed by newborn screening laboratories for the detection of the transferase defect (37). Some screening laboratories employ automated transferase activity analysis. As of recently, all three galactose enzymes can now be simultaneously analyzed through a novel multiplex enzyme assay utilizing ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) (38).

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