Homology modeling studies on human galactose-1-Phosphate uridylyltransferase and on its galactosemia-Related mutant q188r provide an explanation of molecular effects of the mutation on homo- And heterodimers.
We have created theoretical models of the three-dimensional dimeric structure of
human galactose-1-phosphate uridylyltransferase as well as of homo- and
heterodimers carrying the Q188R mutation by using comparative modeling
procedures. These mutants are associated to the most frequent form of the
genetic disease galactosemia. We have analyzed the impact of this mutation both
on enzyme-substrate interactions as well as on interchain interactions in the
heterodimers and in the homodimer. We suggest a molecular explanation for the
altered function, caused by different enzyme-substrate interactions, and for the
partial dominant negative effect of the mutant allele that is present in
heterozygotes for this gene, related to a substantial loss of interchain
hydrogen bonds. These results can be considered a starting point for a more
extensive characterization at the molecular level of the other mutations linked
to this genetic disease.
