TAILIEUCHUNG - Báo cáo khoa học: Functional analysis of disease-causing mutations in human galactokinase

Galactokinase (EC ) catalyzes the first committed step in the catabolism of galactose. The sugar is phosphor-ylated at position 1 at the expense of ATP. Lack of fully functional galactokinase is one cause of the inherited disease galactosemia, the main clinical manifestation of which is early onset cataracts. Human galactokinase (GALK1) was expressed in and purified fromEscherichia recom-binant enzyme was both soluble and active. Product inhi-bition studies showed that themost likelykineticmechanism of the enzyme was an ordered ternary complex one inwhich ATP is the first substrate to bind. . | Eur. J. Biochem. 270 1767-1774 2003 FEBS 2003 doi Functional analysis of disease-causing mutations in human galactokinase David J. Timson and Richard J. Reece School of Biological Sciences University of Manchester Manchester United Kingdom Galactokinase EC catalyzes the first committed step in the catabolism of galactose. The sugar is phosphorylated at position 1 at the expense of ATP. Lack of fully functional galactokinase is one cause of the inherited disease galactosemia the main clinical manifestation of which is early onset cataracts. Human galactokinase GALK1 was expressed in and purified from Escherichia coli. The recombinant enzyme was both soluble and active. Product inhibition studies showed that the most likely kinetic mechanism of the enzyme was an ordered ternary complex one in which ATP is the first substrate to bind. The lack of a solvent kinetic isotope effect suggests that proton transfer is unlikely to be involved in the rate determining step of catalysis. Ten mutations that are known to cause galactosemia were constructed and expressed in E. coli. Of these five P28T V32M G36R T288M and A384P were insoluble following induction and could not be studied further. Four of the remainder H44Y R68C G346S and G349S were all less active than the wild-type enzyme. One mutant A198V had kinetic properties that were essentially wild-type. These results are discussed both in terms of galactokinase structure-function relationships and how these functional changes may relate to the causes of galactosemia. Keywords galactosemia cataracts GHMP family kinase GALK1. Galactose is metabolized by the enzymes of the Leloir pathway 1 . The sugar is first phosphorylated at position 1 then converted to UDP-galactose and glucose-1-phosphate which can enter the glycolytic pathway by reaction with UDP-glucose. Defects in the enzymes of the Leloir pathway can result in galactosemia in humans 2 3 . The main symptom of this disease is .

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