Galactose ( D-tr-galactose. cerebrose: molecular weight 1X0) is a six-carbon aldose (aldohexose).
GalNAc Gal N-acetylglucosamme
GLUT! glucose transporter 1 (SLC2A1)
SGLT1 sodium/glucose cocransporrer 1 (SLC5A1)
Function: Galactose (Gal) is used as an energy fuel and for the synthesis of glycoproteins and gtyeolipkls.
Food sources: Most Gal is consumed with dairy products.
Requirements: No dietary Gal is needed since the required amounts are modest and can easily be produced endogenously from glucose.
Deficiency: There are no health effects associated with low intake.
Excessive intake: Lactose intolerance is the most common complaint related to higher than minimal intakes. Much higher Gal intake than likely to ever occur in humans induces lens deposits (cataracts) in animal models, most likely due to oxidative damage.
Phosphogluco-mutase y^OH 0.
°H ¿H Glucose 1-phosphate
UDP-gtucosc L- UTP pytophos- f phorylase JVt pp,
0H ¿H U DP-galactose tigurr 7.11 Galactose is iynthcsiied from glucose
Enough Gal for ail functional requirements is endogenous!) produced I'rom D-glucose (Glc). First. Glc is activated by conjugation with I DP (UTP-glucosc-1-phosphate uridylv(transferase; EC22.214.171.124; there are two genetically distinct isoforms). UDP-glucose-4'-epimerase (GALF.: EC126.96.36.199) can then generate UDP-galactose in a reversible reaction. UDP-galactose is the direct precursor for lactose synthesis and for guiactosyl-transter for glycoprotein and glycolipid synthesis.
Lactose, the tt-D-galaeiopyranosyl-f I >4) D-glucose dimer, provides most of the carbohydrate in milk (including human milk). infant formula, and dairy products. Lactose pro\ ides about 40% of the energy for infants, and about 2".. in a mixed diet of American adults (Perisse et ui. 1969). Small amounts of Gal are 3lso present in a wide variety of foods including legumes and meats (Acosta and Gross, 1995), The Gal content of peas (boiled ready to eat) can be as high as mg/g (Pcterhauer el a/., 2002). Lactose is used as an extender (bulking agent) in some medications.
The hydrolysis of lactose by brush border lactase (EC3.2.I.I0X) generates Glc and Gal. Intestinal lactase expression persists to a considerable degree beyond childhood in most humans. Persistent expression is least prevalent in Asian populations, and most common in Northern Europeans (Harvey cl al.. 1995). One particular haplotype from a set of 7 polymorphisms is associated with persistence and is more common in Northern Europeans than in Asians (Harvey ¿7 til.. 1998).
An additional locus more than 2 Mb from the lactase gene is responsible for some severe forms of congenital lactase deficiency, indicating that lactase expression and or activity is under the control of an additional factor (Jarvela et a!.. I99X).
Pyridoxitie-beta-D-glueoside hydrolase (no EC number assigned) in jejunum enterocyte cytosol also cleaves lactose (McMahon el til.. 1997).
Gal is taken up into enterocyles by active transport via sodium/glucose cotransporter 1 (SGLTI. SLC5AI). and to a much lesser extent by SGLT2 (SLC5A2: Helliwell et <*/., 2000),
Some of the absorbed Gal is used to provide energy or precursors for the enlero-cyte's own needs, or is lost into the intestinal lumen when the enterocyte is shed. Most Gal leaves the enterocyte via GLUT2 (SLC5A2) and diffuses into portal blood.
The plant oligosaccharides rafhnose (Cial oM I >6) tile «-(I >(52) Fru), stachyose (Gal cr-i I >6) Gal «-(I >6) Glc «-(1 >02) Fru I. and verbascose (Gal «-(l>6) Gal a-(I >6) Gal «-( 1 >6) Glc «-(I >¡32) Fru) in beans, peas, and other plant foods are not well absorbed, because (he Ga! in alpha-position blocks digestion. Alpha-galactosi-dnsc is active in the lysosomes of most cells, but not in digestive secretions or the luminal ".ide of the human intestine. It is not known to what extent Gal is released by galactose
Brush border membrane
Figure 7.13 Intestinal absorption of galactose
Brush border membrane
Figure 7.13 Intestinal absorption of galactose unspecitic digestive or bacterial enzyme action and how much of the released Gal is absorbed (particularly from the terminal ileum and colon I. Ingestion of manufactured alpha-galactosidase (F.t'3,2,1.22, Beano) along with legumes promotes digestion and may decrease oligosaccharide utilization by gas-forratng intestinal bacteria (Ganiats el at., 1994).
Blood circulation: Gal is transported in blood as a serum solute. The concentration in blood of healthy people is under 0.22 mmo! I. Gal is taken up into cells \ ia facilitate transporters, including GLUT! (brain). GLUT2 (SLC5A2, liver, kidney), GLUT3 (SLC5A3, many tissues), and several related transporters.
Blood brain barrier: GLUT1, which is present on both sides of the brain capillary epithelial cells, transports galactose as readily as glucose,
Materno fetal transfer: til UTI mediates facilitat e Gal transport across both sides of the syntrophoblast cell layer (lllsley, 2000). The net transfer of Gal lo the fetus is unknown.
Gal is mainly convened to glucose I-phosphate and then to glucosc 6-phosphate in the liver. A minor alternate pathway exists, but remains to be characterized (Berry etui., 2001).
The initial critical step is phosphorylation by galactokinase (EC188.8.131.52). There are two genetically distinct isoforms of the enzyme with different tissue distribution.
Galactitol accumulation in the lenses of individuals with defective galactokinase I can cause cataracts in childhood or early adulthood. The next step of Gal metabolism is the transfer of uridine diphosphate f I UP) by UDP-glucose-hcxose-1 -phosphate uridyly 1-transferase (EC2.7.7.I2), UDP-glucose-4'-epiinerase (EC5..1.3.2) epimen/es UDP-Gal to UDP-gtucose. Since UDP-glucose provides the UDP again for the next Gal I-phosphate molecule, this works like an autocatalytie mechanism w ith a net conversion of Gal I-phosphate to glucose 1-phosphate. Magnesium-dependent phosphoglucomu-tase (EC184.108.40.206. two isoforms PGM1 and PGM2) converts glucose ¡-phosphate into the readily metabolizable intermediate glucose 6-phosphate. Gal can alternatively be reduced to galactitol by NADPH-dependcnt aldehyde reductase (aldose reductase: EC I.I .1,21). especially in the presence of Gal excess.
fOH OH Galactitol fOH OH Galactitol
Asdanyoe / reductase V
Galactokinase atp ^»ADP
0H ¿H UDP-galaclose undïllfantloiase
Glucose 1 -phosphate
Glucose 1 -phosphate
Figm-t? 7.14 Metabolitm of galactose
There is no significant specific accumulation of Gal thai could be mobilized in times of need-
Gal passes into renal primary filtrate owing to its small molecular size and complete water solubility. SGLT1 actively transports Gal into the epithelium of proximal renal tubules from where ii is exported into blood via the high-capacity transporter GLUT2.
The regulation of tissue and whole-body Gal homeostasis is complex and tightly integrated into the regulation of carbohydrate metabolism.
Lactose synthesis; Nursing infants depend on the high lactose content of milk as the main energy fuel. Women produce, after a normal pregnancy, large amounts of lactose in their mammary glands. Human milk contains 60 -XOg 'l lactose and Gal-containing oligosaccharides. Gal and Glc are actively taken up from maternal blood across the basolateral membrane into the mammary epithelial cell by SGLT1 (Obermeier et al.. 2D0()). Transport of Gal into the Golgi system may require a transporter, possibly GLUTl (Nemeth eta!.. 2000). The presence of GLUTl in human mammary glands is. however, in question (Obermeier et a!.. 2000).
UDP-galactose and glucose are linked in the Golgi complex by lactase synthase (EC2.4.I.22), a heterodimer consisting ofthe enzymatically active A-protein (the shortened version of beta-1.4-galaetosyltrans(erase 1. which is transcribed from an alternative initiation site) and alpha-lactalbumin.
Enetg fuel: The complete oxidation of Gal yields about 4 kcal g and requires adequate supplies of thiamin, riboflavin, niacin, lipoatc. ubiquinone, iron, and magnesium. Unspeaficprecursor; Gal can provide carbons for numerous endogenously generated compounds such as amino acids [e.g., glutainate from the Krebs cycle intermediate alpha-kctogiutaratc), cholesterol (from acetyl-eoen/yme A), or the glycerol in triglycerides.
Glycoprotein synthesis: Cial and galactosamine are attached to numerous proteins. Examples of the presence of Gal in O-glycans are the Gal and Glc-a-2-GaI side chains beta-linked to 5-hydroxylysine in collagens. Gal N-acetylglucosamine (GalNAc) is attached to serine and threonine residues in mucins. Glucosaminoglycans (chondroitin sulfate, dermatan sulfates, keratan sulfates) contain Gal. GalNAc. or both. Glycolipid synthesis: Gal is a structural component of both neutral and acidic cerebro-sides and gangliostdes. The brain and the myelin sheath of nerves contain particularly large amounts of Gal-linked glycol ipids. typically in association with specific proteins. Neutral glycolipids are ofthe types Gal(/31-11 ceramide and Gal(/3 l-4)Gle(01-l)
ccramide. Acidic gtycolipids are of the types Neu5Ac(or2-3)Gal(£l-4l} Glc(/3M) ccrajntde and Neu5Ac(a2-8)Neu5Aci(a2-3)Gal03M)G]ef^M) cenamide (Neu5Ac = N-acctylne u ramin ic acid). The ce ram ides are sphingolipids with long-chain fatty acids.
Acosta PB, Gross KC. Midden sources of galactose in the environment Eur .i Ped 1995; 154:S87 S*>2
Berry GT, Leslie N. Reynolds R. Yager CT. Segal S. Ii\ idence for alternate galactose oxidation in a patient with deletion of the galactose-1 -phosphate uridyl transferase gene. Mot Genet Metab 2001 ;72:316 21 Ganiats TG, Norcross WA, Halverson AL. Burford PA. Palinkas LA. Does Beano prevent gas? A double-blind crossover study of oral alpha-galactosidase to treat dietary oligosaccharide intolerance.,/Family Pruct 1994:39:441 5 Harvey CB. Pratt WS, Islam 1, Whitehouse DB. Swallow DM. DNA polymorphisms in the lactase gene: linkage disequilibrium across the 70-kb region. Eur J Hum Genet 1995: 3:27-41
Harvey CB. Hollost f:J. Poulter M. Wang Y. Rossi M. Auricchto S. Iqbal FFL Cooper BT. Barton R. Sarncr M, Korpela R. Swallow DM. Lactase haplotype frequencies in Caucasians: association with the lactase persistence non-persistence polymorphism. Ann Hum Genet 1948:62: 215-23 Helliwell PA. Richardson M. Affleck J. Relictt GL. Regulation orGLUT5, GLUT2 and intestinal brush border fructose absorption by the extracellular signal-regulated kinase, p38 mitogen-activated kinase and phosphatidyl inositol 3-kinase intracellular signalling pathways: implications for adaptation to diabetes. Biochem J 2000;350:163 4 lllsley NP. Glucose transporters in the human placenta. Placenta 2000:21:14-22 Jarvela I. Sabri Hnattah N. Kokkoncn ,1, Varilo T. Savilahti F.. Peltonen L. Assignment of the locus for congenital laclasc deficiency to 2q21, in the vicinity of but separate from the lactase-phlorizin hydrolase gene. Am J Hum Genet 1948:63:107X 85 McMahon LG. Nakano II, Levy MD, Gregory JF 3rd. Cytosolic pyridoxine-bcta-D-glucoside hydrolase from porcine jejunal mucosa. Purification, properties, and comparison with broad specificity bcta-glucosidase. J Biot Chem 1997:272: 32025-33
Nemeth BA. Tsang SW, Geske RS, Haney I'M. Golgi targeting of the GLUT I glucose transporter in lactating mouse mammary gland. Ped Res 2000:47-144 50 Obermeier S, lluselweh B. Tine! II. Kinne Rll, Kurtz C Lxpression of glucose transporters ui lactating human mammary gland epithelial cells. Eur./ \uu 2000:39: 194-200
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Pcterbauer T, Mucba J, Mach L. Richter A. Cham elongation of rafhnose in pea seeds. Isolation, characterization, and molecular cloning of multifunctional enzyme catalyzing the synthesis of stachyosc and vcrbascosc. J Bird Chem 2002:277: 194-200
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