A universal pocket in fatty acyl-AMP ligases ensures redirection of fatty acid pool away from coenzyme A-based activation
| Autor: | Ketan D. Patel, Rajan Sankaranarayanan, Subhash Narasimhan, Murali Krishna Madduri, Surabhi Pramanik, Sudipta Mondal, Biswajit Pal, Priyadarshan Kinatukara, Sakshi Shambhavi, Noopur Dubey, Rajesh S. Gokhale, Gajanan S. Patil |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Universal distribution Protein Conformation polyketide synthases QH301-705.5 Coenzyme A nonribosomal peptide synthetases Science Chemical biology acyl carrier protein coenzyme A fatty acids General Biochemistry Genetics and Molecular Biology Cofactor Ligases Structure-Activity Relationship chemistry.chemical_compound Bacterial Proteins Biosynthesis Binding site Biology (General) chemistry.chemical_classification Binding Sites General Immunology and Microbiology biology General Neuroscience Fatty acid SUPERFAMILY General Medicine Adenosine Monophosphate Acyl carrier protein chemistry Biochemistry Mutation biology.protein Medicine fatty acyl-AMP ligases Acyl Coenzyme A Phosphopantetheine Protein Binding |
| Zdroj: | eLife, Vol 10 (2021) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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