The molecular basis of galactosemia - Past, present and future.

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