Pharmacology of Galactose
As a monosaccharide, galactose is present in only very small quantities in animals and plants. Traces of free galactose are found in milk, semen, and urine. Without an exogenic source, no galactose is found in the blood. Significant quantities of galactose are detected in blood or urine only during certain pathological processes (see below). Like glucose, galactose is a hexose, as are mannose, glucosamine, and galactosamine (both the N-acetylated or sulfated forms). A monosaccharide related to D-galactose is L-fucose, an L-galactose-configured methylpentose that occurs in blood group substances and in membrane components, frequently in the Lewis structures. In no animal or plant organism is galactose consumed in quantities similar to glucose. Galactose in human or plant organisms is usually present in glycosidic linkages to other monosaccharides, where it is a commonly found hexose. Primarily, it is an essential component of glycolipids, such as the gangliosides, and glycoproteins. Galactose significantly influences the structure and function of these complex compounds.
Sources of Galactose in Animal Organisms:
In nursing young, galactose comes from lactose, which is split into equimolar amounts of glucose and galactose by disaccharidase lactase in mucosa cells. After weaning, the intake of milk products is sharply reduced. Galactose is then primarily made from glucose. However, this can only happen if the glucose is present in an activated, or energy-rich, form -- the uridine diphosphate (UDP)-glucose discovered by the Nobel Prize winner Leloir. This is transformed into the activated form of galactose, UDP-galactose. UDP-glucose is the precursor for the biosynthesis of UDP-glucuronic acid and UDP-xylose. These activated monosaccharides are used to make macromolecules like heteroglycans, glycoproteins and glycolipids. UDP-glucuronic acid, UDP-xylose and sulfated hexosamines are components of glycoseaminoglycans (chondroitins, heparins). The interrelation between the glucose and galactose metabolisms is echoed in the following: A critical step is the conversion (epimerization) of UDP-glucose to UDP-galactose. First, the biosynthesis of UDP-glucose occurs in three steps: phosphorylation of glucose to glucose-6-phosphate with consumption of ATP, mutation to glucose-1-phosphate and activation with uridine triphosphate (UTP) as coenzyme to form UDP-glucose. By way of the reduced coenzyme nicotinamide adenine nucleotide (NADH), UDP-glucose is epimerized at C-atom 4 to make UDP-galactose. In this energy-rich form, the galactose can be used for all synthetic tasks. This interconversion of glucose and galactose occurs in all organs, but most effectively in the liver.
The synthesis of milk sugar, lactose, in lactating mothers is simple in concept, but its regulation is a finely tuned, hormonally complex process. Lactose synthase is a heterodimeric protein containing subunits A and B. Protein A is galactosyltransferase; protein B is the modifying protein a-lactalbumin. It lowers the Km value of the galactosyltransferase so that glucose is not accepted as a substrate and glucosamine is. The resulting lactosamine is a typical product of non-lactating mothers and inhibits galactosyltransferase. At the same time, progesterone inhibits the biosynthesis of a-lactalbumin. During pregnancy the hormones estrogen, insulin, cortisol and prolactin convert the cells of the milk ducts to secretory cells and simultaneously induce the synthesis of galactosyltransferase. The fall in the progesterone concentration after birth allows a-lactalbumin to be synthesized, which raises the Km value of the galactosyltransferase so that glucose can be accepted as a substrate. This stops production of the inhibitory lactosamine and produces lactose instead.
Significance of Galactose in Glycoproteins:
As their name suggests, glycoproteins have one protein component and one glycan or oligosaccharide component. The linkage of the two pieces can occur in two ways, either O-glycosidically by way of serine or threonine, or N-glycosidically by way of asparagine in the consensus sequence Asn-xxx-Ser/Thr-. The O-glycans are generally components of mucus and secretions, the N-glycans are in membranes, where they are used for building the structure, and can perform enzyme functions or specific receptor functions. Without glycoproteins, the organized construction of a membrane structure is thus not possible. As soluble compounds, glycoprotiens are the most prevalent proteins in serum, with the exception of albumin. Without the involvement of glycoprotein receptors, regulatory signals from hormones or growth factors cannot enter cells. Without their N-glycan component, several enzymes cannot carry out their specific catalytic functions. Glycoproteins thus have a central role in the formation and maintenance of the structure and the performance of important functions in all plasma membranes in cells of the body. Galactose performs a key function in these components. It is located in the second-to-last position of glycoproteins and is the docking site for N-acetylneuraminic acid (or sialic acid) in the completion of glycoprotein synthesis. N-acetylneuraminic acid is a very unusual sugar acid; it is made of nine C atoms, is the only monosaccharide to carry a negative charge, and contains an N-acetyl side chain and a glycerol side chain. Each of these individual components is linked to a defined biological function. This unusual nine-carbon sugar is always in the terminal position of glycoproteins (unless it is linked to a further neuraminic acid, as is the case in polysialic acids). Sialic acids determine the biological stability, structure, surface charge, and some receptor functions of cells. For the anchorage of sialic acid to glycans, the presence of the subterminal galactose is necessary, because only through this component can it become part of the cell surface.
Significance of Galactose in Glycolipids:
Like glycoproteins, glycolipids are essential components of intracellular membranes and the plasma membrane. Their concentration in membranes is smaller than that of the glycoproteins. Their biosynthesis is just as complex as that of the glycoproteins. They have pathophysiologically important features for degradation, because the highly specific degradation enzymes can be defective, leading to glycolipid storage disease. Glycolipids also have receptor functions and can regulate the activity of proteins such as enzymes. Most of these membrane-localized glycolipids are gangliosides. They are formed from a glycolipid by attachment of the terminal galactose to N-acetylneuraminic acid; in principle, this is the same process as the formation of glycoproteins, but with different specifications for the responsible sialyltransferases. In this case it is also possible for an additional neuraminic acid molecule to be attached to one already present. However, a neuraminic acid without a galactose docking site can never be linked to the glycolipid or nascent glycoprotein. Galactose thus plays a central, determinant role in the structure and function of both types of glycoconjugate.
Significance of Galactose in Glycogen:
Glycogen is a homopolymer made of 1,4- and 1,6-linked glucose molecules. The starting material for its synthesis is an autoglucosylated glycoprotein primer, to which individual activated glucose molecules (UDP-glucose) are attached one by one by means of glycogensynthase. This branching enzyme results in a space-saving spherical packing of the molecule, whose molecular weight is above 300 million, making it visible with an electron microscope (g and d cluster). When a large pool of UDP-galactose is available, galactose too can be incorporated into glycogen in the form of non-reducing end groups. The degradation of glycogen mainly (90%) takes place by way of the hormone-regulated (glucagon, adrenalin) glycogenphosphorylase, which cleaves off terminal glucose molecules as glucose-1-P through the mediation of the coenzyme pyridoaxal phosphate (phosphorylation without ATP consumption). When there is a large supply of UDP-galactose, galactose gets incorporated into glycogen. If galactose is located in the terminal position of the glycogen molecule, degradation is slowed with the result that the glycogen molecule is retained longer as an energy source. The mechanism of galactose cleavage from the glycogen molecule is not completely understood (relative nonspecificity of the phosphorylase?).
Glycoproteins and glycolipids undergo constant formation and degradation. Membrane glycoproteins are distinguished by the fact that their glycan portion is more rapidly degraded than their protein portion. The half-lives of the individual monosaccharides in the glycan portion are between 10 and 30 hours, and those of the protein portion are between 60 and 80 hours. This demonstrates the high demand for these monosaccharides for maintenance of the structure and function of glycoconjugates, in particular for the renewal of the terminal monosaccharides. States of metabolic deficiency are more rapidly reflected in the reduced biosynthesis of the glycan portion than in the protein portion. Such states of deficiency have a profound influence on the structure and thus the function of glycoproteins and glycolipids.
Disruptions of the Galactose Metabolism
The most common congenital metabolic disorder is hereditary galactosemia. In one out of every 55,000 individuals, there is a lack of uridyltransferase, the enzyme that makes UDP-galactose from galactose-1-phosphate. This enzyme is expressed after galactose intake. Since it appears after the cleavage of lactose in motherâs milk, this defect becomes evident through severe illness in the nursing infant (failure to thrive, aversion to drinking, vomiting, increased newborn jaundice, hypoglycemia, hepatomegaly, splenomegaly, kidney damage in the proximal tubulus, cataract formation, mental retardation). Galactose-1-phosphate and then galactose accumulate and both have toxic effects. In the lens of the eye, galactose is converted to galalctitol (dulcite). Because this reaction requires NADPH as coenzyme, the concentration of NADPH-dependent reduced glutathion falls, the oxidized glutathion forms mixed disulfides with the crystallin in the eye, which results in the cataracts typical of this disease. Galactose-1-phosphate leads to graver toxic effects. It inhibits the activities of various enzymes, such as phosphoglucomutase, glucose-6-phosphatase and glucose-6-phosphatedehydrogenase. The toxic effects are particularly evident in the liver, where often-fatal cirrhosis can develop. However, these complications only arise in cases of this particular incompatibility. In Europe and many other countries, this disorder is tested for on the third day after birth and is thus almost always detected. If an infant or toddler has a hereditary intolerance of milk and simultaneous galactose intolerance (1:55,000) that has not been detected, galactose should only be given after consultation with a physician or therapist. An excellent review about galactosemia can be found here: www.galactosemia.de/stoffwechsel.html
Hereditary Galactokinase Deficiency:
This is a very rare disease in which galactose is not phosphorylated. It causes no damage because no toxic metabolites are formed, nor does a deficiency of UDP-galactose occur; it can be synthesized from UDP-glucose.
Hereditary Deficiency of UDP-Glucose-4-Epimerase:
This genetic defect is also extremely rare and leads to no impairment, because the necessary UDP-galactose is synthesized by way of free galactose, which is formed in the digestion of food.