Structure, biochemistry, and inhibition of essential 4'-phosphopantetheinyl transferases from two species of Mycobacteria.

Abstract

4'-Phosphopantetheinyl transferases (PPTase) post-translationally modify carrier proteins with a phosphopantetheine moiety, an essential reaction in all three domains of life. In the bacterial genus Mycobacteria, the Sfp-type PPTase activates pathways necessary for the biosynthesis of cell wall components and small molecule virulence factors. We solved the X-ray crystal structures and biochemically characterized the Sfp-type PPTases from two of the most prevalent Mycobacterial pathogens, PptT of M. tuberculosis and MuPPT of M. ulcerans. Structural analyses reveal significant differences in cofactor binding and active site composition when compared to previously characterized Sfp-type PPTases. Functional analyses including the efficacy of Sfp-type PPTase-specific inhibitors also suggest that the Mycobacterial Sfp-type PPTases can serve as therapeutic targets against Mycobacterial infections.

• Authors: Christopher R Vickery, Nicolas M Kosa, Ellen P Casavant, Shiteng Duan, Joseph P Noel, Michael D Burkart
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 9 Issue 9 Pg. 1939-44 (Sep 19 2014) ISSN: 1554-8937 [Electronic] United States
• PMID: 24963544 (Publication Type: Letter, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Bacterial Proteins
• Enzyme Inhibitors
• Small Molecule Libraries
• phosphopantetheinyl transferase
• Transferases (Other Substituted Phosphate Groups)

Topics

• Anti-Bacterial Agents (pharmacology)
• Bacterial Proteins (antagonists & inhibitors, chemistry, genetics, metabolism)
• Catalytic Domain
• Crystallography, X-Ray
• Enzyme Inhibitors (pharmacology)
• Fluorescence Polarization
• Models, Molecular
• Mutation
• Mycobacterium tuberculosis (enzymology)
• Mycobacterium ulcerans (enzymology)
• Protein Conformation
• Small Molecule Libraries (pharmacology)
• Transferases (Other Substituted Phosphate Groups) (antagonists & inhibitors, chemistry, genetics, metabolism)