A universal pocket in Fatty acyl-AMP ligases ensures redirection of fatty acid pool away from Coenzyme A-based activation
- CSIR-Centre for Cellular and Molecular Biology, India
- National Institute of Immunology, India
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
Priyadarshan Kinatukara
Rajan Sankaranarayanan
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
- Frank Raushel, Texas A&M University, United States
Publication history
- Preprint posted: May 4, 2021 (view preprint)
- Received: May 5, 2021
- Accepted: September 6, 2021
- Accepted Manuscript published: September 7, 2021 (version 1)
- 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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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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