Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis
详细信息 查看全文
- 作者：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
- 刊名：ACS Infectious Diseases
- 出版年：2016
- 出版时间：August 12, 2016
- 年：2016
- 卷：2
- 期：8
- 页码：579-591
- 全文大小：750K
- ISSN：2373-8227
文摘
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.