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

Anna Marabotti, Angelo M. Facchiano

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)773-779
Number of pages7
JournalJournal of Medicinal Chemistry
Volume48
Issue number3
DOIs
Publication statusPublished - Feb 10 2005

ASJC Scopus subject areas

  • Organic Chemistry

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