The structural and molecular biology of type i galactosemia: Enzymology of galactose 1-phosphate uridylyltransferase

Thomas J. McCorvie, David J. Timson

Research output: Contribution to journalArticlepeer-review

Abstract

Reduced galactose 1-phosphate uridylyltransferase (GALT) activity is associated with the genetic disease type I galactosemia. This results in an increase in the cellular concentration of galactose 1-phosphate. The accumulation of this toxic metabolite, combined with aberrant glycoprotein and glycolipid biosynthesis, is likely to be the major factor in molecular pathology. The mechanism of GALT was established through classical enzymological methods to be a substituted enzyme in which the reaction with UDP-glucose results in the formation of a covalent, UMP-histidine adduct in the active site. The uridylated enzyme can then react with galactose 1-phosphate to form UDP-galactose. The structure of the enzyme from Escherichia coli reveals a homodimer containing one zinc (II) and one iron (II) ion per subunit. This enzymological and structural knowledge provides the basis for understanding the biochemistry of this critical step in the Leloir pathway. However, a high-resolution crystal structure of human GALT is required to assist greater understanding of the effects of disease-associated mutations.

Original languageEnglish
Pages (from-to)694-700
Number of pages7
JournalIUBMB Life
Volume63
Issue number9
DOIs
Publication statusPublished - 1 Sep 2011

Keywords

  • disease-associated mutation
  • galactose 1-phosphate uridylyltransferase
  • galactose metabolism
  • GALT
  • histidine triad transferase
  • UMP-histidine

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