Classic Galactosemia Type 1

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Classic Galactosemia, Type 1, is a complex disorder and the exact pathophysiology has is controversial. However, it is most commonly accepted that the main factor is the accumulation of galactose-1-phosphate, gal-1P, which is due to the impairment of galactose-1-phosphate uridylytransferase, GALT. This reaction uses the GALT enzyme as a part of the Leloir pathway which enables the body to process galactose. The GLAT enzyme itself belongs to the histidine triad super family and is a member of branch III. This enzyme shows specific nucleoside monophosphate activity and is a homodimer with each monomer containing a single domain comprised of 6 α- helices and a β-sheet which is formed by 13 antiparallel and 1 parallel strand. The mechanism of this enzyme is described as having ping-pong kinetics with the following two steps. In the first step the active site histidine attacks R-phosphorus of UDP-glucose which displaces glucose-1-phosphate and forms a covalent intermediate. The second step involves the previously formed intermediate reacting with galactose-1-phosphate to displace the histidine and produce UDP-galactose. (Facchiano, 103-104). A deficiency in the GALT enzyme leads to Galactosemia which can present with the following acute symptoms: “jaundice, cataracts, vomiting, diarrhea, hepatomegaly, sepsis, and neonatal death” (McCorvie, 1) with the possibility of long term problems without treatment. Currently, restriction of galactose is able to help reduce the acute

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