Galactose 1-phosphate cannot enter the glycolytic pathway unless it is first converted to uridine diphosphate (UDP)-galactose (Fig. 12.6). This occurs in an exchange reaction, in which UDP-glucose reacts with galactose 1phosphate, producing UDP-galactose and glucose 1-phosphate (see Fig. 12.5). The reaction is catalyzed by galactose 1-phosphate uridylyltransferase (GALT). [Note: The glucose 1-phosphate product can be isomerized to glucose 6-phosphate, which can enter glycolysis or be dephosphorylated.]
C. UDP-galactose conversion to UDP-glucose
For UDP-galactose to enter the mainstream of glucose metabolism, it must first be isomerized to its C-4 epimer, UDP-glucose, by UDP-hexose 4epimerase. This “new” UDP-glucose (produced from the original UDPgalactose) can participate in biosynthetic reactions (for example, glycogenesis) as well as in the GALT reaction. [Note: See Fig. 12.5 for a summary of the interconversions.]
D. UDP-galactose in biosynthetic reactions
UDP-galactose can serve as the donor of galactose units in a number of synthetic pathways, including synthesis of lactose (see IV. below), glycoproteins (see p. 166), glycolipids (see p. 210), and glycosaminoglycans (see p. 158). [Note: If galactose is not provided by the diet (for example, when it cannot be released from lactose owing to a lack of β-galactosidase in people who are lactose intolerant), all tissue requirements for UDP-galactose can be met by the action of UDP-hexose 4-epimerase on UDP-glucose, which is efficiently produced from glucose 1-phosphate and uridine triphosphate (see Fig. 12.5).]
E. Disorders
GALT is severely deficient in individuals with classic galactosemia (see Fig. 12.5). In this disorder, galactose 1-phosphate and, therefore, galactose accumulate. Physiologic consequences are similar to those found in HFI (see p. 138), but a broader spectrum of tissues is affected. The accumulated galactose is shunted into side pathways such as that of galactitol production. This reaction is catalyzed by aldose reductase, the same enzyme that reduces glucose to sorbitol (see p. 139). GALT deficiency is part of the newborn screening panel. Treatment of galactosemia requires removal of galactose and lactose from the diet. [Note: Deficiencies in galactokinase and the epimerase result in less severe disorders of galactose metabolism, although cataracts are common (see Fig. 12.5).]
IV. LACTOSE SYNTHESIS