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.

Novel mRNA therapy restores GALT protein and enzyme activity in a zebrafish model of classic galactosemia

“…Several disease-causing variants negatively affect protein folding and stability of the GALT protein 19,20 and pharmacological/chemical chaperones have been shown to rescue variant proteins. [21][22][23] However, a pilot study evaluating the effect of arginine, a chemical chaperone, was not beneficial in CG patients homozygous for c.563A>G (p.Gln188Arg). 24 Another therapeutic approach currently being investigated is gene therapy using adeno-associated virus (AAV) vectors which has shown to rescue GALT activity levels and decrease galactose metabolites.…”

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

“…UDP-Glc is essential for the enzymatic activity of GALT. GALE is also responsible for the interconversion of UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc), required for the galactosylation of complex molecules and the synthesis of different glycoproteins/glycolipids [ 5 ].…”

“…As at least two binding sites (i.e., active site and binding site for allosteric modulators) in the GALT exist [ 64 ], a combination of in silico screening of predicted ligands, screening of chemical libraries, and rational screening of substrate is expected to identify novel drug candidates in the future. Yet, definition of the safety profile, appropriate (age-dependent) dosing, and specific indications (i.e., GALT variants) remain major challenges [ 5 ].…”

β‐Galactosidase therapy can mitigate blood galactose elevation after an oral lactose load in galactose mutarotase deficiency

“…1 This pathway includes four enzymes: galactose-1-phosphate uridylyltransferase (EC 2.7.7.12), galactokinase (GALK; EC 2.7.1.6), UDPgalactose-4-prime-epimerase (EC 5.1.3.2), and galactose mutarotase (GALM; EC 5.1.3.3). 2,3 GALM catalyzes interconversion between αand β-anomers of monosaccharides, and human GALM is likely to choose galactose over glucose as its substrate. 4 Physiologically, GALM appears to convert β-D-galactose produced from lactose to α-D-galactose, which is used as the substrate for GALK at the next step in the Leloir pathway.…”

“…It is metabolized to glucose‐6‐phosphate or utilized for glycosylation via the Leloir pathway 1 . This pathway includes four enzymes: galactose‐1‐phosphate uridylyltransferase (EC 2.7.7.12), galactokinase (GALK; EC 2.7.1.6), UDP‐galactose‐4‐prime‐epimerase (EC 5.1.3.2), and galactose mutarotase (GALM; EC 5.1.3.3) 2,3 . GALM catalyzes interconversion between α‐ and β‐anomers of monosaccharides, and human GALM is likely to choose galactose over glucose as its substrate 4 .…”