Sweet and sour: an update on classic galactosemia

Abstract

Classic galactosemia is a rare inherited disorder of galactose metabolism caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme of the Leloir pathway. It presents in the newborn period as a life-threatening disease, whose clinical picture can be resolved by a galactose-restricted diet. The dietary treatment proves, however, insufficient in preventing severe long-term complications, such as cognitive, social and reproductive impairments. Classic galactosemia represents a heavy burden on patients' and their families' lives. After its first description in 1908 and despite intense research in the past century, the exact pathogenic mechanisms underlying galactosemia are still not fully understood. Recently, new important insights on molecular and cellular aspects of galactosemia have been gained, and should open new avenues for the development of novel therapeutic strategies. Moreover, an international galactosemia network has been established, which shall act as a platform for expertise and research in galactosemia. Herein are reviewed some of the latest developments in clinical practice and research findings on classic galactosemia, an enigmatic disorder with many unanswered questions warranting dedicated research.

Fig. 1

Galactose metabolism. In the Leloir pathway, galactose is converted to glucose-1-phosphate (Glc-1-P) by the action of three consecutive enzymes: galactokinase (GALK1), galactose-1-phosphate uridylyltransferase (GALT), and UDP-galactose 4′-epimerase (GALE). Alternatively, galactose can be reduced to galactitol by aldose reductase, oxidized to galactonate, presumably by galactose dehydrogenase, or be converted into UDP-Glc, via the pyrophosphorylase pathway, by the sequential activities of GALK1, UDP-glucose/galactose pyrophosphorylase (UGP), and GALE. GALE is also responsible for the interconversion of UDP-N-acetylgalactosamine to UDP-N-acetylglucosamine (not shown). PPi, pyrophosphate

Fig. 2

Crystallographic structure of human GALT. Cartoon representation of uridylylated human GALT crystallographic structure obtained in complex with galactose-1-phosphate (PDB code 5IN3). Each monomer is colored either in cyan or light orange. Active site residues H184-P185-H186 in red sticks; covalently linked UMP in blue sticks; galactose 1-phosphate in yellow sticks; residue Q188, responsible for UMP stabilization and site of the most common mutation (Q188R) in classic galactosemia in green sticks; zinc (purple sphere) binding ligands in gray sticks

Fig. 3

The catalytic mechanism of GALT. In the first step of the reaction, the Nε2 of His186 attacks the α-phosphate of UDP-Glc, releasing Glc-1-P and forming the covalent uridylyl-enzyme intermediate; in the second step, the intermediate reacts with Gal-1-P to produce UDP-Gal

Fig. 4

The GALT promoter deletion of the Duarte allele. The GALT promoter presents an AP-1 site from −126 to −119 bp (TCAGTCAG) and two E-box motifs from −146 to −141 bp (CAGGTG) and from −117 to −112 bp (CACGTG). The −119 to −116 GTCA deletion removes the first two nucleotides (CA, in bold) of the −117 to −112 bp E-box motif. The middle tetrad GTCA fills the deleted CA of the E-box motif; however, the spacing between the two E-box motifs is reduced, and the terminal G of the AP-1 site is removed. Nucleotide +1 is the A of the ATG-translation initiation codon