Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis

Misty L. Kuhn, Evan Alexander, George Minasov, Holland J. Page, Zdzislaw Warwrzak, Ludmilla Shuvalova, Kristin J. Flores, Daniel J. Wilson, Ce Shi, Courtney C. Aldrich, Wayne F. Anderson

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Mycolic acids are indispensible lipids of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. FadD32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (FAS) and polyketide synthase (PKS) biosynthetic pathways. FadD32, a fatty acyl-AMP ligase (FAAL), represents one of the best genetically and chemically validated new TB drug targets. We have determined the three-dimensional crystal structure of Mtb FadD32 in complex with a ligand specifically designed to stabilize the catalytically active adenylate-conformation, which provides a foundation for structure-based drug design efforts against this essential protein. The structure also captures the unique interactions of a FAAL-specific insertion sequence and provides insight into the specificity and mechanism of fatty acid transfer.

Original languageEnglish (US)
Pages (from-to)579-591
Number of pages13
JournalACS Infectious Diseases
Volume2
Issue number8
DOIs
StatePublished - Aug 12 2016

Bibliographical note

Funding Information:
This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health a n d Human S e r v i c e s , u n d e r c o n t r a c t n o s . HHSN272200700058C and HHSN272201200026C (to W.F.A.). C.C.A. acknowledges support from the NIH (1- U54-AI-057153, AI070291). Some support was also provided as a subgrantee of the SGC under a Bill and Melinda Gates Foundation grant for the Structure-Guided Drug Discovery Coalition (SDDC). Additional funding for this project includes San Francisco State University Startup funds (to M.L.K.). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817).

Keywords

  • FadD32
  • Mycobacterium tuberculosis
  • fatty acyl-AMP ligase
  • mycolic acid biosynthesis

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