Metabolism of Galactose and the Galactosemias



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Galactose Metabolism

 

 

 

 

 

 

 

 

 

 

 

Galactose, which is metabolized from the milk sugar, lactose (a disaccharide of glucose and galactose), enters glycolysis by its conversion to glucose-1-phosphate (G1P). This occurs through a series of steps that is referred to as the Leloir pathway, named after Luis Federico Leloir who determined the overall process of galactose utilization.

Galactose can exist in two different stereoisomeric forms; α-D-galactose and β-D-galactose. The α-form is that which is metabolized in the Leloir pathway. Conversion of the β-form of galactose to the α-form requires the enzyme galactose mutarotase encoded by the GALM gene (also known as aldose 1-epimerase). The first reaction of the Leloir pathway is the phosphorylation of α-D-galactose by galactokinase to yield galactose-1-phosphate. The galactokinase protein is encoded by the GALK1 gene located on chromosome 17q25.1. The GALK1 gene spans 7.3 kbp and contains 8 exons that encode a 392 amino acid protein. There is another gene identified as GALK2 that was originally thought to be a second galactokinse gene but was subsequently shown to be an N-acetylgalactosamine kinase.

Epimerization of galactose-1-phosphate to glucose-1-phosphate (G1P) requires the transfer of UDP from UDP-glucose catalyzed by galactose-1-phosphate uridylyltransferase (GALT). The GALT gene is located on chromosome 9p13.3 and is composed of 11 exons that generate two alternatively spliced mRNAs that encode two distinct isoforms of the enzyme. GALT isoform 1 is a protein of 379 amino acids and GALT isoform 2 is a protein of 270 amino acids. The GALT catalyzed reaction generates UDP-galactose and G1P.

The UDP-galactose is epimerized to UDP-glucose by UDP-galactose-4 epimerase (GALE). The UDP portion is exchanged for phosphate generating glucose-1-phosphate which then is converted to glucose-6-phosphate (G6P) by phosphoglucose mutase. The GALE gene is located on chromosome 1p36.11 and is composed of 13 exons that generate three alternatively spliced mRNAs all of which encode the same 348 amino acid protein. GALE catalyzes two distinct but analogous epimerization reactions, the epimerization of UDP-galactose to UDP-glucose and the epimerization of UDP-N-acetylgalactosamine to UDP-N-acetylglucosamine.

Reactions of galactose metabolism

Entry of galactose carbon atoms into the glycolytic pathway. Metabolism of galactose via the glycolytic pathway requires a continuous supply of UDP-glucose generated from glucose-1-phosphate via the action of UDP-glucose pyrophosphorylase 2 (encoded by the UGP2 gene). The three enzymes that convert galactose to glucose-6-phosphate are encoded by the GALK, GALT, and PGM1 genes. Humans express four phosphoglucomutase (PGM) genes with the PGM1 gene being expressed in most tissues. The interconversion of UDP-galactose and UDP-glucose requires the enzyme encoded by the GALE gene. The UGP2 and PGM1 genes are discussed in more detail in the Glycogen Metabolism page.


There are additional minor pathways of galactose metabolism in humans that do not involve all three of the enzymes of the classical Leloir pathway. Galactose can be converted to UDP-glucose by the sequential activities of GALK, UDP-glucose pyrophosphorylase 2 (UGP2), and GALE. Galactose can also be reduced to galactitol by NADPH-dependent aldose reductase. This latter reaction becomes significant in the context of GALT and GALK1 deficiencies that result in galactosemias (see below). Finally, galactose can be oxidized to galactonate by galactose dehydrogenase. Under normal conditions, these alternative pathways are responsible for the metabolism of only trace quantities of galactose.

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Classic Galactosemia: Type 1

Classic galactosemia refers to a disorder arising from profound deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) and is termed type 1 galactosemia. There are also classified clinical and biochemical variant forms of GALT deficient galactosemia. Classic galactosemia is inherited as an autosomal recessive disorder and almost all afflicted individuals will present with symptoms in the neonatal period if undiagnosed. Type 1 galactosemia occurs with a frequency of between 1:40,000 to 1:60,000 live births in Western countries. When the frequency of galactosemia inheritance is assessed by anyone with erythrocyte GALT activity <5% of normal and erythrocyte galactose-1-phosphate concentration >2mg/dL then the frequency reaches 1:10,000. Certain countries have higher levels of classic galactosemia inheritance than Western countries such as in Ireland where the frequency is close to 1:16,000 live births.

Classic galactosemia manifests by poor feeding behavior, a failure of neonates to thrive, bleeding problems, and E. coli-associated sepsis in untreated infants. In classic glactosemia, infants will exhibit vomiting and diarrhea rapidly following ingestion of lactose from breast milk or from lactose-containing formula. Due to the rapid progression of the symptoms, infants are sometimes erroneously termed lactose intolerant. However, the clinical distinction between classic lactose intolerance and classic galactosemia is quite profound. Newborn screening for classic galactosemia occurs in most states in the US and thus, the risks to newborns with this disease are drastically reduced. The typical prenatal test for galactosemia involves measurements of both erythrocyte GALT activity and erythrocyte levels of galactose-1-phosphate, the former being significantly reduced or absent, and the latter being elevated. Some prenatal tests only measure total blood galactose levels and in infants afflicted with a clinical or biochemical variant type 1 galactosemia, this assay may not be sufficient to detect any abnormality. In some cases of clinical or biochemical variant type 1 galactosemia a genetic test for GALT variant mutations may be necessary to confirm a diagnosis.

Clinical findings in infants with classic galactosemia who consume lactose or galactose containing meals include impaired liver function (which if left untreated leads to severe cirrhosis), hypoglycemia, hyperbilirubinemia, elevated blood galactose, hypergalactosemia, hyperchloremic metabolic acidosis, urinary galactitol excretion and hyperaminoaciduria. Unless controlled by exclusion of galactose from the diet, these galactosemias can go on to result in fatal liver failure, brain damage, and blindness. Blindness is due to the conversion of circulating galactose to the sugar alcohol galacitol, by an NADPH-dependent aldose reductase that is present in neural tissue and in the lens of the eye. At normal circulating levels of galactose this enzyme activity causes no pathological effects. However, a high concentration of galacitol in the lens causes osmotic swelling, with the resultant formation of cataracts and other negative symptoms within the eye.

Over 230 different mutations have been described in the gene encoding human GALT resulting in the three main forms (classic, clinical variant, biochemical variant) of type 1 galactosemia. The most commonly detected mutation in Caucasians results in the Q188R allele defined by the substitution of arginine (R) for glutamine (Q) at amino acid 188 which lies close to the active site of the enzyme. Homozygotes for the Q188R allele show very little to no GALT activity in their erythrocytes. The majority of homozygotes are found to have no GALT activity, while others exhibit a low level of enzyme activity generally no more than 20% of the wild type. Whereas the Q188R allele is most common in Caucasians, the most commonly detected mutations in European populations are K285N, S135L, and N314D. The K285N mutation is associated with 0% and 50% GALT activity in homozygous and heterozygous individuals, respectively.

The N314D mutation in the GALT gene is associated with two biochemical variants of type 1 galactosemia. The Los Angeles variant (designated D1) results solely from the N314D mutation. The Duarte variant (designated D2) is the result of both the N314D mutation in the coding region of the GALT gene as well as a GTCA deletion (-119 to -116) in the promoter region of the gene. The loss of those four nucleotides results in impairment of a positive regulatory domain in the GALT promoter. Very often a Duarte variant infant arises through the inheritance of a D2 allele from one parent and another pathogenic GALT mutation from the other parent. Patients with the Duarte variant form of type 1 galactosemia have erythrocyte GALT activity that is typically 14%–25% of that seen in non-affected individuals. Duarte variant infants can often be asymptomatic when given breast milk or lactose-containing formula. Any hyperbilirubinemia (evidenced as jaundice) in these Duarte infants will rapidly resolve when the lactose is removed from their diets.

The principal treatment for infants with classic galactosemia, whose erythrocyte GALT activity is <10% of normal, is elimination of lactose from the diet. This lactose elimination regimen includes breast milk and all other milk products. Even on a galactose-restricted diet, GALT-deficient individuals exhibit urinary galacitol excretion and persistently elevated erythrocyte galactose-1-phosphate levels. In addition, even with life-long restriction of dietary galactose, many patients with classic galactosemia can develop serious long-term complications including speech defects, cognitive impairment, and in female patients the potential for premature follicular atresia resulting in ovarian insufficiency and sterility. Due to these persistent clinical complications, it is recommended that individuals with classic galactosemia undergo routine testing for the accumulation of erythrocyte galactose-1-phosphate, increased urinary galactose output, developmental delay, speech problems, and the formation of cataracts.

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Type 2 Galactosemia

The second form of galactosemia, termed type 2, results from deficiency of galactokinase (GALK1). This form of galactosemia is quite rare with a frequency of <1:100,000 live births. Infants with GALK deficiency, who continue to consume a milk-based diet, accumulate abnormally high levels of galactose in their blood and tissues, similar to infants with classic galactosemia. Like classic galactosemia patients GALK deficiency often presents with cataracts that will resolve upon dietary restriction of galactose. However, unlike patients with classic galactosemia, patients with GALK deficiency who keep to a galactose restricted diet experience no known long-term complications. This difference is biochemically and clinically quite significant because it provides compelling evidence that it is not the accumulation of galactose, but rather galactose-1-phosphate (Gal-1P), or possibly some metabolic derivative Gal-1P, that is the primary cause of the complications, in addition to cataracts, that are observed in classic galactosemia patients and the more rare severe form of GALE deficiency.

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Type 3 Galactosemia

The third disorder of galactose metabolism, termed type 3 galactosemia, results from a deficiency of UDP-galactose-4-epimerase (GALE). Two different forms of this deficiency have been found. The more commonly occurring deficiency affects only red and white blood cells and is relatively benign. The other form of GALE deficiency is extremely rare (only 8 known cases) and is characterized by profound enzyme impairment affecting multiple tissues and manifesting with symptoms similar to those seen with GALT deficiency (classic galactosemia).

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Michael W King, PhD | © 1996–2016 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: February 4, 2015