Galactose catabolism (Leloir pathway)

The Leloir pathway, the main route by which dietary D-galactose (chiefly from the milk sugar lactose) is converted to glucose-1-phosphate and thereby fed into glycolysis and general carbohydrate metabolism. It is a short cytosolic pathway of four enzymes. Galactose mutarotase (GALM/aldose 1-epimerase) first equilibrates the β- and α-anomers of D-galactose, supplying the α-anomer; galactokinase (GALK1) then phosphorylates α-D-galactose with ATP to α-D-galactose 1-phosphate; galactose-1-phosphate uridylyltransferase (GALT) transfers a UMP group from UDP-glucose to galactose-1-phosphate, producing glucose-1-phosphate (which enters glycolysis/glycogen metabolism via phosphoglucomutase) and UDP-galactose; and UDP-galactose-4-epimerase (GALE) interconverts UDP-galactose and UDP-glucose, regenerating the UDP-glucose that GALT consumes and balancing the UDP-galactose pool used for glycoconjugate synthesis. Because GALT both consumes UDP-glucose and (via GALE) regenerates it, the pathway is catalytic in UDP-sugars: only a trace pool is needed to turn over large amounts of galactose. Each enzyme has a corresponding inherited galactosemia: GALT deficiency causes classic galactosemia (type I, severe neonatal toxicity); GALK1 deficiency causes type II (predominantly cataracts, from galactitol); GALE deficiency causes type III (epimerase deficiency, peripheral to generalized); and GALM deficiency causes type IV. The shared toxic intermediates are galactose-1-phosphate and, via aldose reductase, galactitol.