The molecular basis of galactosemia — Past, present and future

Abstract

Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100 years have seen considerable progress in understanding the underlying genetics and biochemistry of this condition. Initial studies concentrated on increasing the understanding of the clinical manifestations of the disease. However, Leloir's discovery of the pathway of galactose catabolism in the 1940s and 1950s enabled other scientists, notably Kalckar, to link the disease to a specific enzymatic step in the pathway. Kalckar's work established that defects in galactose 1-phosphate uridylyltransferase (GALT) were responsible for the majority of cases of galactosemia. However, over the next three decades it became clear that there were two other forms of galactosemia: type II resulting from deficiencies in galactokinase (GALK1) and type III where the affected enzyme is UDP-galactose 4'-epimerase (GALE). From the 1970s, molecular biology approaches were applied to galactosemia. The chromosomal locations and DNA sequences of the three genes were determined. These studies enabled modern biochemical studies.Structures of the proteins have been determined and biochemical studies have shown that enzymatic impairment often results from misfolding and consequent protein instability. Cellular and model organism studies have demonstrated that reduced GALT or GALE activity results in increased oxidative stress. Thus, after a century of progress, it is possible to conceive of improved therapies including drugs to manipulate the pathway to reduce potentially toxic intermediates, antioxidants to reduce the oxidative stress of cells or use of "pharmacological chaperones" to stabilise the affected proteins.

Phosphoglucomutase Is Not the Target for Galactose Toxicity in Plants

“…Lactose uptake in humans leads to high amounts of galactose as result of lactose cleavage. Individuals with a mutation in the galactose utilization pathway develop the disease galactosemia already in newborns (Timson, 2016).…”

Improving the Activity and Stability of Human Galactokinase for Therapeutic and Biotechnological Applications

“…Mutations in the gene encoding human galactokinase are associated with the inherited metabolic disease type II galactosaemia (OMIM #230250) . Compared to types I and III galactosaemia, type II is generally considered relatively mild . The only well‐documented manifestations of this disease are early‐onset cataracts, which can be resolved by eliminating galactose (and its precursors such as lactose) from the diet or by surgery .…”

Galactokinase promiscuity: a question of flexibility?

“…This inherited metabolic disorder presents as a decreased ability to metabolize galactose [14,15]. There are three types of galactosaemia each resulting from a mutation in a gene encoding a different enzyme of galactose metabolism.…”