Structural and molecular biology of type I galactosemia: Disease-associated mutations

Type I galactosemia results from reduced galactose 1-phosphate uridylyltransferase (GALT) activity. Signs of disease include damage to the eyes, brain, liver, and ovaries. However, the exact nature and severity of the pathology depends on the mutation(s) in the patient's genes and his/her environment. Considerable enzymological and structural knowledge has been accumulated and this provides a basis to explain, at a biochemical level, impairment in the enzyme in the more than 230 disease-associated variants, which have been described. The most common variant, Q188R, occurs close to the active site and the dimer interface. The substitution probably disrupts both UDP-sugar binding and homodimer stability. Other alterations, for example K285N, occur close to the surface of the enzyme and most likely affect the folding and stability of the enzyme. There are a number of unanswered questions in the field, which require resolution. These include the possibility that the main enzymes of galactose metabolism form a supramolecular complex and the need for a high resolution crystal structure of human GALT.