Probing UDP-galactopyranose mutase binding pocket: a dramatic effect on substitution of the 6-position of UDP-galactofuranose

Bioorg Med Chem Lett. 2009 Feb 1;19(3):814-6. doi: 10.1016/j.bmcl.2008.12.014. Epub 2008 Dec 7.

Abstract

UDP-galactopyranose mutase (UGM) catalyzes the isomerization of UDP-galactopyranose (UDP-Galp) into UDP-galactofuranose (UDP-Galf), an essential step of the mycobacterial cell wall biosynthesis. UDP-(6-deoxy-6-fluoro)-D-galactofuranose 1 was tested as substrate of UGM. Turnover could be observed by HPLC. The k(cat) (7.4s(-1)) and the K(m) (24 mM) of 1 were thus measured and compared with those of UDP-Galf and other fluorinated analogs. The presence of the fluorine atom at the 6-position had a moderate effect on the rate of the reaction but a huge one on the interactions between the enzyme and its substrate. This result demonstrated that key interactions occur at the vicinity of the 6-position of UDP-galactose in the Michaelis complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbohydrates / chemistry
  • Catalysis
  • Cell Wall / metabolism
  • Chemistry, Pharmaceutical / methods
  • Chromatography, High Pressure Liquid
  • Drug Design
  • Fluorine / chemistry
  • Furans / chemistry
  • Galactose / analogs & derivatives*
  • Galactose / chemistry
  • Intramolecular Transferases / chemistry*
  • Kinetics
  • Molecular Conformation
  • Mycobacterium / metabolism
  • Protein Binding
  • Uridine Diphosphate / analogs & derivatives*
  • Uridine Diphosphate / chemistry

Substances

  • Carbohydrates
  • Furans
  • uridine diphosphate galactofuranose
  • Fluorine
  • Uridine Diphosphate
  • Intramolecular Transferases
  • UDP-galactopyranose mutase
  • Galactose