A universal pocket in Fatty acyl-AMP ligases ensures redirection of fatty acid pool away from Coenzyme A-based activation

Abstract

Fatty acyl-AMP ligases (FAALs) channelize fatty acids towards biosynthesis of virulent lipids in mycobacteria and other pharmaceutically or ecologically important polyketides and lipopeptides in other microbes. They do so by bypassing the ubiquitous coenzyme A-dependent activation and rely on the acyl carrier protein-tethered 4'-phosphopantetheine (holo-ACP). The molecular basis of how FAALs strictly reject chemically identical and abundant acceptors like coenzyme A (CoA) and accept holo-ACP unlike other members of the ANL superfamily remains elusive. We show FAALs have plugged the promiscuous canonical CoA-binding pockets and utilize highly selective alternative binding sites. These alternative pockets can distinguish adenosine 3', 5'-bisphosphate-containing CoA from holo-ACP and thus FAALs can distinguish between CoA and holo-ACP. These exclusive features helped identify the omnipresence of FAAL-like proteins and their emergence in plants, fungi, and animals with unconventional domain organisations. The universal distribution of FAALs suggests they are parallelly evolved with FACLs for ensuring a CoA-independent activation and redirection of fatty acids towards lipidic metabolites.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, Figure 4, Figure supplement 5b and Figure supplement 6.

Article and author information

Author details

  1. Gajanan Shrikant Patil

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  2. Priyadarshan Kinatukara

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2210-2369
  3. Sudipta Mondal

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3923-7449
  4. Sakshi Shambhavi

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8852-1542
  5. Ketan D Patel

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4254-3145
  6. Surabhi Pramanik

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  7. Noopur Dubey

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  8. Subhash Narasimhan

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  9. Murali Krishna Madduri

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  10. Biswajit Pal

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  11. Rajesh S Gokhale

    National Institute of Immunology, New Delhi, India
    Competing interests
    No competing interests declared.
  12. Rajan Sankaranarayanan

    CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    For correspondence
    sankar@ccmb.res.in
    Competing interests
    Rajan Sankaranarayanan, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4524-9953

Funding

Department of Biotechnology, Ministry of Science and Technology, India

  • Gajanan Shrikant Patil

Council of Scientific and Industrial Research, Ministry of Science and Technology, India

  • Sudipta Mondal

University Grants Commission

  • Sakshi Shambhavi

Council of Scientific and Industrial Research, Ministry of Science and Technology, India

  • Rajan Sankaranarayanan

Science and Engineering Research Board, India

  • Rajan Sankaranarayanan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Frank Raushel, Texas A&M University, United States

Version history

  1. Preprint posted: May 4, 2021 (view preprint)
  2. Received: May 5, 2021
  3. Accepted: September 6, 2021
  4. Accepted Manuscript published: September 7, 2021 (version 1)
  5. Version of Record published: September 23, 2021 (version 2)

Copyright

© 2021, Patil et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Gajanan Shrikant Patil
  2. Priyadarshan Kinatukara
  3. Sudipta Mondal
  4. Sakshi Shambhavi
  5. Ketan D Patel
  6. Surabhi Pramanik
  7. Noopur Dubey
  8. Subhash Narasimhan
  9. Murali Krishna Madduri
  10. Biswajit Pal
  11. Rajesh S Gokhale
  12. Rajan Sankaranarayanan
(2021)
A universal pocket in Fatty acyl-AMP ligases ensures redirection of fatty acid pool away from Coenzyme A-based activation
eLife 10:e70067.
https://doi.org/10.7554/eLife.70067

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https://doi.org/10.7554/eLife.70067

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