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UDP-galactopyranose mutase has a novel structure and mechanism

D A Sanders1, A G Staines, S A McMahon

  • 1The Centre for Biomolecular Sciences, The University, St. Andrews, Scotland KY16 9ST, UK.

Nature Structural Biology
|September 27, 2001
PubMed

Insights

UDP-galactopyranose mutase (mutase) is essential for pathogens like Mycobacterium tuberculosis and is a potential therapeutic target. This study reveals its structure and suggests a mechanism involving transient substrate reduction.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Microbiology

Background:

  • Uridine diphosphogalactofuranose (UDP-Galf) is crucial for bacterial and parasitic cell walls, including pathogens like Mycobacterium tuberculosis.
  • UDP-galactopyranose mutase (mutase) synthesizes UDP-Galf from UDP-galactopyranose (UDP-Galp).
  • Mutase is essential for mycobacterial viability and absent in humans, presenting a therapeutic target.

Purpose of the Study:

  • To elucidate the structural basis and catalytic mechanism of UDP-galactopyranose mutase.
  • To investigate the role of the flavin cofactor in mutase activity.
  • To provide insights for the development of novel anti-infective agents.

Main Methods:

  • X-ray crystallography to determine the 3D structure of E. coli mutase at 2.4 A resolution.
  • Site-directed mutagenesis to identify active site residues.
  • Enzyme activity assays to assess the role of flavin reduction.

Main Results:

  • The crystal structure revealed a novel cleft containing conserved residues and the flavin adenine dinucleotide (FAD) cofactor.
  • Site-directed mutagenesis confirmed the active site location within this cleft, with substrate proximity to FAD.
  • Enzyme activity was dependent on the reduced state of the flavin cofactor.

Conclusions:

  • UDP-galactopyranose mutase likely functions via transient reduction of its substrate.
  • The structural and mechanistic insights advance our understanding of essential microbial pathways.
  • This research supports the development of mutase inhibitors as potential therapeutics against pathogens.

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