Galactose—1-phosphate uridylyltransferase

Galactose-1-phosphate uridylyltransferase (or GALT) is an is_associated_with::enzyme responsible for converting ingested is_associated_with::galactose to is_associated_with::glucose.

Galactose-1-phosphate uridylyltransferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely:
 * is_associated_with::UDP-glucose + is_associated_with::galactose 1-phosphate $$\rightleftharpoons$$ is_associated_with::glucose 1-phosphate + is_associated_with::UDP-galactose

The expression of GALT is controlled by the actions of the is_associated_with::FOXO3 gene. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined.

Mechanism
GALT catalyzes the second reaction of the is_associated_with::Leloir pathway of is_associated_with::galactose metabolism through ping pong bi-bi kinetics with a is_associated_with::double displacement mechanism. This means that the net reaction consists of two reactants and two products (see reaction above), and it proceeds by the following mechanism: the enzyme reacts with one substrate to generate one product and a modified enzyme, which goes on to react with the second substrate to make the second product while regenerating the original enzyme. In the case of GALT, the His166 residue acts as a potent is_associated_with::nucleophile to facilitate transfer of a nucleotide between UDP-hexoses and hexose-1-phosphates.


 * 1) UDP-glucose + E-His Glucose-1-phosphate + E-His-UMP
 * 2) Galactose-1-phosphate + E-His-UMP UDP-galactose + E-His



Structural studies
The three-dimensional structure at 1.8 angstrom resolution (is_associated_with::x-ray crystallography) of GALT was discovered by Wedekind, Frey, and Rayment, and their structural analysis has found key is_associated_with::amino acids essential for GALT function.

The important amino acids that Wedekind et al. found in their structural analysis of GALT, such as Leu4, Phe75, Asn77, Asp78, Phe79, and Val108, are consistent with residues that have been implicated both in point mutation experiments as well as in clinical screening to play a role in human galactosemia.

Clinical significance
Deficiency of GALT causes is_associated_with::classic galactosemia. is_associated_with::Galactosemia is a childhood disease of hereditary nature. The autosomal recessive trait affects approximately 1 in every 40,000-60,000 live-born infants. is_associated_with::Classical galactosemia (G/G) is caused by a deficiency in GALT activity, whereas the more common clinical affliction, is_associated_with::Duarte/Classica (D/G) arises from attenuation of GALT activity. Symptoms include ovarian failure, is_associated_with::developmental coordination disorder (difficulty speaking correctly and consistently), and neurologic deficits. A single mutation in any of several amino acids can lead to attenuation or deficiency in GALT activity. For example, a single mutation from A to G in exon 6 of the GALT gene changes Glu188 to an is_associated_with::arginine, and a mutation from A to G in exon 10 converts Asn314 to an is_associated_with::aspartic acid. These two mutations also add new is_associated_with::restriction enzyme cut sites, which enable detection by and large-scale population screening with PCR (is_associated_with::polymerase chain reaction). Screening has mostly eliminated neonatal death by G/G galactosemia, but the disease, due to GALT’s role in the biochemical is_associated_with::metabolism of ingested is_associated_with::galactose (which is toxic when accumulated) to the energetically useful is_associated_with::glucose, can certainly be fatal. However, those afflicted with galactosemia can live relatively normal lives by avoiding milk products and anything else containing galactose (since it cannot be metabolized), although there is the potential for problems in neurological development, or other complications, even in those who avoid galactose.

Disease Database
Galactosemia (GALT) Mutation Database