LpxC                                                 "The future of antibiotic chemistry"

 

 

The cell wall of gram-negative bacteria is surrounded by an outer membrane that is comprised of charged lipopolysaccharide (LPS) molecules. (See Figure)  The highly charged outer membrane serves to prevent entry of hydrophobic molecules into the bacteria.  Lipid A is the hydrophobic anchor of LPS and is essential for bacterial survival.  As a consequence, the enzymes in the Lipid A biosynthetic pathway are obvious targets for the development of antimicrobial agents.  The enzyme LpxC catalyzes the deacetylation of UDP-3-O-(R-3-hydroxymyristoyl)GlcNAc, the committed step in the biosynthesis of Lipid A.  Inhibitors of the bacterial enzyme LpxC have been demonstrated to have antimicrobial activity, validating LpxC as a drug target.  The resistance to available antibiotics creates a need for new antibiotics with activity against novel targets.  The development of highly potent and specific inhibitors of LpxC will require a full understanding of the enzyme's catalytic mechanism.  LpxC has been demonstrated to be a zinc-dependent deacetylase.  The focus of our research in this area is on further elucidating the catalytic mechanism of this bacterial enzyme using classical biochemical as well as novel chemical biology methods.

 

 

Bacterial Biosynthesis of the Cell wall component Kdo2-Lipid A

Raetz, C.R.H., and Whitfield, C.  Lipopolysaccharides endotoxins.  Annu. Rev. Biochem. (2002) 71: p. 635-700

 

Two zinc bound active site of LpxC

Whittington DA, Rusche KM, Shin H, Fierke CA, Christianson DW..  Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis.  PNAS. (2003) 100: p. 8146 -8150

 

Recent Publications     

  1. Whittington DA, Rusche KM, Shin H, Fierke CA, Christianson DW..  Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis.  PNAS. (2003) 100: p. 8146 -8150
  2. McClure CP, Rusche KM, Peariso K, Jackman JE, Fierke CA, Penner-Hahn JE.  EXAFS studies of the zinc sites of UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC).  J Inorg Biochem. (2003) 94(1-2), 78-85.
  3. Jackman JE, Fierke CA, Tumey LN, Pirrung M, Uchiyama T, Tahir SH, Hindsgaul O, Raetz CR.  Antibacterial agents that target lipid A biosynthesis in gram-negative bacteria. Inhibition of diverse UDP-3-O-(r-3-hydroxymyristoyl)-n-acetylglucosamine deacetylases by substrate analogs containing zinc binding motifs. J Biol Chem. (2000) 275, 11002-9.
  4. Jackman JE, Raetz CR, Fierke CA. Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site. Biochemistry. (2001) 40, 514-23.

PubMed Search (most recent publications)

Project Researchers
Graduate Students
Sam Gattis

Questions about this project? Email Sam: sgattis at umich.edu

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