Galactokinase 1 (GALK1) (GALK1)

Galactokinase 1 (GALK1) is a critical enzyme in the Leloir pathway, responsible for the ATP-dependent phosphorylation of alpha-D-galactose to galactose-1-phosphate (UniProt: P51570). This enzymatic step is the first committed stage in the metabolism of dietary galactose, facilitating its eventual conversion into glucose derivatives for energy production (NCBI Gene: 2584). Mutations in the GALK1 gene lead to Galactosemia type II, a condition primarily characterized by the development of neonatal cataracts caused by the accumulation of galactitol in the lens (StatPearls: Galactosemia). In addition to its role in deficiency-related disease, GALK1 has gained prominence as a therapeutic target for Classic Galactosemia (Type I), which is caused by a deficiency in the downstream enzyme GALT. In Classic Galactosemia, the buildup of galactose-1-phosphate is highly toxic; therefore, pharmacological inhibition of GALK1 serves as a substrate reduction therapy to prevent the formation of this toxic intermediate (PubMed: PMID 20833609). Current drug development efforts focus on identifying small-molecule GALK1 inhibitors to mitigate the long-term neurological and reproductive complications that persist in patients despite adherence to a galactose-restricted diet (PubMed: PMID 29330338).

Other names

Galactose kinase 1GALKGK1Galactokinase

Substrate reduction therapy (SRT) via competitive or non-competitive inhibition of galactose phosphorylation to prevent the accumulation of toxic galactose-1-phosphate in GALT-deficient states (PubMed: PMID 20833609).