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.
Bibliographical noteFunding 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).
- Mycobacterium tuberculosis
- fatty acyl-AMP ligase
- mycolic acid biosynthesis