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

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 ac...

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Autores principales:	Gajanan S Patil, Priyadarshan Kinatukara, Sudipta Mondal, Sakshi Shambhavi, Ketan D Patel, Surabhi Pramanik, Noopur Dubey, Subhash Narasimhan, Murali Krishna Madduri, Biswajit Pal, Rajesh S Gokhale, Rajan Sankaranarayanan
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	fatty acyl-AMP ligases polyketide synthases nonribosomal peptide synthetases coenzyme A fatty acids acyl carrier protein Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c2652a9c2f7b4d7a89a1c081a858f05a
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spelling	oai:doaj.org-article:c2652a9c2f7b4d7a89a1c081a858f05a2021-12-01T10:56:00ZA universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation10.7554/eLife.700672050-084Xe70067https://doaj.org/article/c2652a9c2f7b4d7a89a1c081a858f05a2021-09-01T00:00:00Zhttps://elifesciences.org/articles/70067https://doaj.org/toc/2050-084XFatty 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 that 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 organizations. The universal distribution of FAALs suggests that they are parallelly evolved with FACLs for ensuring a CoA-independent activation and redirection of fatty acids towards lipidic metabolites.Gajanan S PatilPriyadarshan KinatukaraSudipta MondalSakshi ShambhaviKetan D PatelSurabhi PramanikNoopur DubeySubhash NarasimhanMurali Krishna MadduriBiswajit PalRajesh S GokhaleRajan SankaranarayananeLife Sciences Publications Ltdarticlefatty acyl-AMP ligasespolyketide synthasesnonribosomal peptide synthetasescoenzyme Afatty acidsacyl carrier proteinMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	fatty acyl-AMP ligases polyketide synthases nonribosomal peptide synthetases coenzyme A fatty acids acyl carrier protein Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	fatty acyl-AMP ligases polyketide synthases nonribosomal peptide synthetases coenzyme A fatty acids acyl carrier protein Medicine R Science Q Biology (General) QH301-705.5 Gajanan S Patil Priyadarshan Kinatukara Sudipta Mondal Sakshi Shambhavi Ketan D Patel Surabhi Pramanik Noopur Dubey Subhash Narasimhan Murali Krishna Madduri Biswajit Pal Rajesh S Gokhale Rajan Sankaranarayanan A universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation
description	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 that 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 organizations. The universal distribution of FAALs suggests that they are parallelly evolved with FACLs for ensuring a CoA-independent activation and redirection of fatty acids towards lipidic metabolites.
format	article
author	Gajanan S Patil Priyadarshan Kinatukara Sudipta Mondal Sakshi Shambhavi Ketan D Patel Surabhi Pramanik Noopur Dubey Subhash Narasimhan Murali Krishna Madduri Biswajit Pal Rajesh S Gokhale Rajan Sankaranarayanan
author_facet	Gajanan S Patil Priyadarshan Kinatukara Sudipta Mondal Sakshi Shambhavi Ketan D Patel Surabhi Pramanik Noopur Dubey Subhash Narasimhan Murali Krishna Madduri Biswajit Pal Rajesh S Gokhale Rajan Sankaranarayanan
author_sort	Gajanan S Patil
title	A universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation
title_short	A universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation
title_full	A universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation
title_fullStr	A universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation
title_full_unstemmed	A universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation
title_sort	universal pocket in fatty acyl-amp ligases ensures redirection of fatty acid pool away from coenzyme a-based activation
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/c2652a9c2f7b4d7a89a1c081a858f05a
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A universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation

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