Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria

Valérie Guillet (1) , Ségolène Galandrin (1) , Laurent Maveyraud (1) , Simon Ladevèze (1) , Vincent Mariaule (1) , Cécile Bon (1) , Nathalie Eynard (1) , Mamadou Daffé (1) , Hedia Marrakchi (1) , Lionel Mourey (1)

1 IPBS - Institut de pharmacologie et de biologie structurale

Mycolic acids are essential components of the mycobacterial cell envelope, and their biosynthetic pathway is one of the targets of first-line antituberculous drugs. This pathway contains a number of potential targets, including some that have been identified only recently and have yet to be explored. One such target, FadD32, is required for activation of the long meromy-colic chain and is essential for mycobacterial growth. We report here an in-depth biochemical, biophysical, and structural characterization of four FadD32 orthologs, including the very homo-logous enzymes from Mycobacterium tuberculosis and Myco-bacterium marinum. Determination of the structures of two complexes with alkyl adenylate inhibitors has provided direct information, with unprecedented detail, about the active site of the enzyme and the associated hydrophobic tunnel, shedding new light on structure-function relationships and inhibition mechanisms by alkyl adenylates and diarylated coumarins. This work should pave the way for the rational design of inhibitors of FadD32, a highly promising drug target.

Domaines: Biochimie [q-bio.BM]; Biologie structurale [q-bio.BM]; Bactériologie

Valérie Guillet, Ségolène Galandrin, Laurent Maveyraud, Simon Ladevèze, Vincent Mariaule, et al.. Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria. Journal of Biological Chemistry, 2016, 291 (15), pp.7973-7989. ⟨10.1074/jbc.M115.712612⟩. ⟨hal-03002148⟩