Article abstract

Nature Chemical Biology 5, 166 - 173 (2009)
Published online: 1 February 2009 | doi:10.1038/nchembio.143

Mechanistic and functional insights into fatty acid activation in Mycobacterium tuberculosis

Pooja Arora1,5, Aneesh Goyal2,5, Vivek T Natarajan1,5, Eerappa Rajakumara2, Priyanka Verma1, Radhika Gupta3, Malikmohamed Yousuf2, Omita A Trivedi1, Debasisa Mohanty1, Anil Tyagi3, Rajan Sankaranarayanan2 & Rajesh S Gokhale1,4

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

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  1. National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
  2. Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad-500 007, India.
  3. Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India.
  4. Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India.
  5. These authors contributed equally to this work.

Correspondence to: Rajesh S Gokhale1,4 e-mail: rsg@nii.res.in

Correspondence to: Rajan Sankaranarayanan2 e-mail: sankar@ccmb.res.in