Chapter 6: The Galactosemias

INTRODUCTION

Galactose Metabolism

Galactose is a naturally occurring hexose, an epimer of glucose at C-4, and generally derived in the diet from intestinal hydrolysis of lactose (Figure 6-1). Although galactose contributes to the formation of glycogen through epimerization to glucose in liver, its chief role in metabolism is in the formation of glycoproteins, complex glycolipids, and glycosaminoglycans. These complex molecules are found in cell membranes and are vital components of cell-surface receptors, the extracellular matrix, as well as in myelin of the central nervous system of which galactosylceramide is a major constituent. Thus, although galactose is not considered to be an essential dietary molecule, there is plainly an absolute biosynthetic requirement for galactose. As with many similar biologic requirements, there is a pathway that normally supplies galactose for biosynthesis,¹ even in the absence of dietary intake.

The major dietary source of galactose comes from ingestion of mammalian milk. Lactose, the carbohydrate of milk, is a disaccharide comprising glucose and galactose (Figure 6-1); mammary gland synthesis of lactose requires glucose, UDP-galactose, and mammary gland UDP-galactose galactosyltransferase. After ingestion of milk, hydrolysis of the constituent lactose monosaccharides takes place in the gut. The absorbed galactose flows to the liver in the portal vein, is trapped as a phosphorylated derivative which normally undergoes metabolic conversion to UDPGal for synthesis of complex molecules, glucose, or glycogen; however, this conversion is interrupted in each of the galactosemias, and results in metabolite accumulation and disease.²

The normal metabolism of galactose to glucose occurs in a series of three reactions known as the Leloir pathway^3,4 (Figure 6-2). At the initial step, the enzyme galactokinase (GALK) adds a phosphate to the galactose to generate galactose-1-phosphate (Gal-1-P) in the process expending adenosine triphosphate (ATP). In a second step catalyzed by the enzyme galactose-1-phosphate uridyltransferase (GALT), uridyl diphosphoglucose (UDPG) exchanges its glucose molecule for a galactose from Gal-1-P, thus producing glucose-1-phosphate (Gluc-1-P) and UDPGal. Finally, in a reaction mediated by UDP-galactose-4-epimerase (GALE) in the presence of nicotinamide adenine dinucleotide, the galactose moiety is converted to glucose, allowing the cycle to continue.