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Mechanistic and functional insights into fatty acid activation in Mycobacterium tuberculosis

Nature Chemical Biology volume 5, pages 166–173 (2009)Cite this article

Abstract

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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Figure 1: Dichotomy in the metabolic functions of FAALs and FACLs.
Figure 2: Crystal structure of FAAL28 N-terminal domain and structural analysis of the FAAL insertion.
Figure 3: Interconversion of FACL and FAAL activities.
Figure 4: Inhibition of FAAL and FACL enzymes by acylsulfamoyl analogs.
Figure 5: Characterization of FAAL in other actinomycetes.

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Acknowledgements

We thank L. Eltis (University of British Columbia) for Rhodococcus sp. RHA1 strain and S. Cole (Pasteur Research Institute, France) for the M. tuberculosis BAC genomic DNA library. P.A., A.G. and E.R. are Senior Research Fellows of the Council of Scientific and Industrial Research, India. R.S. is supported by a Wellcome Trust International Senior Research Fellowship in India. R.S.G. is supported by a Howard Hughes Medical Institute International Fellowship. This work is also partially supported by a Swarnajayanti Fellowship from the Department of Science and Technology of India and by a Centre of Excellence Grant from the Department of Biotechnology of India.

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  1. Pooja Arora, Aneesh Goyal and Vivek T Natarajan: These authors contributed equally to this work.

Authors and Affiliations

  1. National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110 067, India

    Pooja Arora, Vivek T Natarajan, Priyanka Verma, Omita A Trivedi, Debasisa Mohanty & Rajesh S Gokhale

  2. Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad, 500 007, India

    Aneesh Goyal, Eerappa Rajakumara, Malikmohamed Yousuf & Rajan Sankaranarayanan

  3. Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India

    Radhika Gupta & Anil Tyagi

  4. Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, 560064, India

    Rajesh S Gokhale

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Contributions

P.A., A.G., V.T.N., R.S. and R.S.G. designed the experiments, analyzed the data and wrote the manuscript. E.R. and M.Y. participated in structural studies. P.V., R.G. and O.A.T. participated in biochemical and mechanistic studies. D.M. and A.T. provided valuable advice.

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Correspondence to Rajan Sankaranarayanan or Rajesh S Gokhale.

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Arora, P., Goyal, A., Natarajan, V. et al. Mechanistic and functional insights into fatty acid activation in Mycobacterium tuberculosis. Nat Chem Biol 5, 166–173 (2009). https://doi.org/10.1038/nchembio.143

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