Abstract
The third step of the catabolism of galactose in mammals is catalyzed by the enzyme galactose-1-phosphate uridylyltransferase (GALT), a homodimeric enzyme with two active sites located in the proximity of the intersubunit interface. Mutations of this enzyme are associated to the rare inborn error of metabolism known as classic galactosemia; in particular, the most common mutation, associated with the most severe phenotype, is the one that replaces Gln188 in the active site of the enzyme with Arg (p.Gln188Arg). In the past, and more recently, the structural effects of this mutation were deduced on the static structure of the wild-type human enzyme; however, we feel that a dynamic view of the proteins is necessary to deeply understand their behavior and obtain tips for possible therapeutic interventions. Thus, we performed molecular dynamics simulations of both wild-type and p.Gln188Arg GALT proteins in the absence or in the presence of the substrates in different conditions of temperature. Our results suggest the importance of the intersubunit interactions for a correct activity of this enzyme and can be used as a starting point for the search of drugs able to rescue the activity of this enzyme in galactosemic patients.
Highlights
Galactose is an aldohexose sugar, C4-epimer of glucose
Galactose metabolism has been named the “Leloir pathway” after the contribution of Luis Leloir to its elucidation [2], and it consists of four different steps in which galactose is converted into glucose-1-phosphate, which subsequently enters the glycolytic pathway [3] (Scheme 1)
Mutations in the gene coding for the third enzyme of this pathway, galactose-1phosphate uridylyltransferase (GALT), which catalyzes the transfer of a uridine monophosphate (UMP) group from uridine diphosphate (UDP)-glucose to galactose 1-phosphate, thereby generating glucose 1-phosphate and UDP-galactose, cause the inborn error of metabolism known as “classic galactosemia” (OMIM: #230400)
Summary
Galactose is an aldohexose sugar, C4-epimer of glucose. As suggested by its name (from the Greek term “galaktos”, which means “milk”), it is present mainly in milk and dairy products, bound to glucose to form the disaccharide sugar lactose, but it is present in free or bound forms in many food plants [1]. Mutations in the gene coding for the third enzyme of this pathway, galactose-1phosphate uridylyltransferase (GALT), which catalyzes the transfer of a uridine monophosphate (UMP) group from uridine diphosphate (UDP)-glucose to galactose 1-phosphate, thereby generating glucose 1-phosphate and UDP-galactose, cause the inborn error of metabolism known as “classic galactosemia” (OMIM: #230400). This disease manifests soon after birth if the newborn is exposed to galactose, with acute symptoms such as jaundice, feeding problems, failure to thrive, hepatocellular damage, bleeding, and possible. No treatments are available to avoid the insurgence of these complications [4]
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