Galactosemia: Towards Pharmacological Chaperones

Abstract

Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive disability. The phenotype varies from almost asymptomatic to life-threatening disability. The fundamental biochemical cause of the disease is a decrease in enzymatic activity due to failure of the affected protein to fold and/or function correctly. Many novel therapies have been proposed for the treatment of galactosemia. Often, these are designed to treat the symptoms and not the fundamental cause. Pharmacological chaperones (PC) (small molecules which correct the folding of misfolded proteins) represent an exciting potential therapy for galactosemia. In theory, they would restore enzyme function, thus preventing downstream pathological consequences. In practice, no PCs have been identified for potential application in galactosemia. Here, we review the biochemical basis of the disease, identify opportunities for the application of PCs and describe how these might be discovered. We will conclude by considering some of the clinical issues which will affect the future use of PCs in the treatment of galactosemia.

Keywords: UDP-galactose 4′-epimerase; drug screening; enzyme; galactokinase; galactose 1-phosphate uridylyltransferase; galactose metabolism; galactose mutarotase; ligand binding; protein degradation; protein misfolding.

Figure 1

The Leloir pathway and associated reactions. Protein names are shown in red. GALM, galactose mutarotase; GALK1, galactokinase; GALT, galactose 1-phosphate uridylyltransferase; PGM, Phosphoglucomutase; GALE, UDP -galactose 4′-epimerase; Gal, galactose; Glc, glucose.

Figure 2

Beulter test: this test detects the fluorescence produced by the NADPH. NADPH is made by the action of galactose 6-phosphate dehydrogenase on glucose 6-phosphate [34]. The absence of fluorescence, which would occur in GALT deficiency, is a positive test. Protein names are shown in redGALT, galactose 1-phosphate uridylyltransferase; PGM, Phosphoglucomutase; G6PDH, glucose-6-phosphate dehydrogenase; Gal, galactose; Glc, glucose.

Figure 3

A flow chart showing a possible route for pharmacological chaperones for galactosemia. This represents an idealised view, in reality some steps may need to be repeated and others performed in parallel.