title: Unsaturated Lipid Assimilation by Mycobacteria Requires Auxiliary cis-trans Enoyl CoA Isomerase.
abstract: Mycobacterium tuberculosis (Mtb) can survive in hypoxic necrotic tissue by assimilating energy from host-derived fatty acids. While the expanded repertoire of β-oxidation auxiliary enzymes is considered crucial for Mtb adaptability, delineating their functional relevance has been challenging. Here, we show that the Mtb fatty acid degradation (FadAB) complex cannot selectively break down cis fatty acyl substrates. We demonstrate that the stereoselective binding of fatty acyl substrates in the Mtb FadB pocket is due to the steric hindrance from Phe287 residue. By developing a functional screen, we classify the family of Mtb Ech proteins as monofunctional or bifunctional enzymes, three of which complement the FadAB complex to degrade cis fatty acids. Crystal structure determination of two cis-trans enoyl coenzyme A (CoA) isomerases reveals distinct placement of active-site residue in Ech enzymes. Our studies thus reveal versatility of Mtb lipid-remodeling enzymes and identify an essential role of stand-alone cis-trans enoyl CoA isomerases in mycobacterial biology.
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India; Academy of Scientific and Innovative Research, Rafi Marg, New Delhi 110001, India.
authors.forename: Sonali
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India.
authors.forename: Sarika
authors.initials: S
authors.lastname: Chaudhary
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India.
authors.forename: Lipi
authors.initials: L
authors.lastname: Thukral
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ce
authors.initials: C
authors.lastname: Shi
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India.
authors.forename: Rinkoo D
authors.initials: RD
authors.lastname: Gupta
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India; Academy of Scientific and Innovative Research, Rafi Marg, New Delhi 110001, India.
authors.forename: Radhika
authors.initials: R
authors.lastname: Gupta
authors.affiliation: CSIR-Center for Cellular and Molecular Biology, Hyderabad 500007, India.
authors.forename: K
authors.initials: K
authors.lastname: Priyadarshan
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Vats
authors.affiliation: CSIR-Center for Cellular and Molecular Biology, Hyderabad 500007, India.
authors.forename: Asfarul S
authors.initials: AS
authors.lastname: Haque
authors.affiliation: CSIR-Center for Cellular and Molecular Biology, Hyderabad 500007, India.
authors.forename: Rajan
authors.initials: R
authors.lastname: Sankaranarayanan
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India; Academy of Scientific and Innovative Research, Rafi Marg, New Delhi 110001, India.
authors.forename: Vivek T
authors.initials: VT
authors.lastname: Natarajan
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India; Academy of Scientific and Innovative Research, Rafi Marg, New Delhi 110001, India; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Electronic address: rsg@igib.res.in.
authors.forename: Rajesh S
authors.initials: RS
authors.lastname: Gokhale
mesh_terms: D001665:Binding Sites; D064006:Dodecenoyl-CoA Isomerase / Q000737:chemistry / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D009161:Mycobacterium / Q000201:enzymology*
chemical_list: D005231:Fatty Acids, Unsaturated; D008055:Lipids; D064006:Dodecenoyl-CoA Isomerase