Mechanistic and functional insights into fatty acid activation in Mycobacterium tuberculosis

Abstract

The recent discovery of fatty acyl-AMP ligases (FAALs) in Mycobacterium tuberculosis (Mtb) provided a new perspective to fatty acid activation dogma. These proteins convert fatty acids to corresponding adenylates, which is an intermediate of acyl-CoA-synthesizing fatty acyl-CoA ligases (FACLs). Presently, it is not evident how obligate pathogens like Mtb have evolved such new themes of functional versatility and whether the activation of fatty acids to acyl-adenylates could indeed be a general mechanism. Here, based on elucidation of the first structure of a FAAL protein and by generating loss- as well as gain-of-function mutants that interconvert FAAL and FACL activities, we demonstrate that an insertion motif dictates formation of acyl-adenylate. Since FAALs in Mtb are crucial nodes in biosynthetic network of virulent lipids, inhibitors directed against these proteins provide a unique multi-pronged approach of simultaneously disrupting several pathways.

Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32

“…FadD32 is a member of the long chain fatty acyl-AMP ligase (FAAL) family in M. tuberculosis that functions to adenylate a long-chain fatty acid and then transfer this activated intermediate to the polyketide synthase PKS13. Transfer of the activated fatty acid to a PKS is a novel function for FAAL proteins recently described for a subfamily of these enzymes found in M. tuberculosis (30,35), as most members of this family form acyl-CoA thioesters. The mechanistic basis for the different enzymatic activity of FadD32 and related family members is as yet incompletely understood.…”

Detection of Delta-like 1 ligand for the diagnosis of tuberculous meningitis: An effective and rapid diagnostic method

“…Research findings have indicated that mycolic acid and fatty acid metabolism are closely related to M. tuberculosis survival, virulence and avoidance of attacks by the immune system. [16][17][18][19][20] These factors demonstrate the importance of M. tuberculosis to host-fat metabolism. [20][21][22][23] Delta-like 1 ligand (DLL1) is an L-type transmembrane protein consisting of 723 amino acids.…”

The Crystal Structure of the Adenylation Enzyme VinN Reveals a Unique β-Amino Acid Recognition Mechanism

“…Crystallization of these enzymes containing flexible C-terminal parts is challenging. Hence, there are some examples of crystal structures in which only the N-terminal part has been used for crystallization (26,38,39). Therefore, we constructed the heterologous expression system of the VinNN protein containing only the N-terminal domain (Met 1 -Arg 426 ) and then attempted to crystallize the VinNN protein.…”