Unsaturated Lipid Assimilation by Mycobacteria Requires Auxiliary cis-trans Enoyl CoA Isomerase

Sonali Srivastava; Sarika Chaudhary; Lipi Thukral; Ce Shi; Rinkoo D. Gupta; Radhika Gupta; K. Priyadarshan; Archana Vats; Asfarul S. Haque; Rajan Sankaranarayanan; Vivek T. Natarajan; Rakesh Sharma; Courtney C. Aldrich; Rajesh S. Gokhale

doi:10.1016/j.chembiol.2015.10.009

Unsaturated Lipid Assimilation by Mycobacteria Requires Auxiliary cis-trans Enoyl CoA Isomerase

Sonali Srivastava, Sarika Chaudhary, Lipi Thukral, Ce Shi, Rinkoo D. Gupta, Radhika Gupta, K. Priyadarshan, Archana Vats, Asfarul S. Haque, Rajan Sankaranarayanan, Vivek T. Natarajan, Rakesh Sharma, Courtney C. Aldrich, Rajesh S. Gokhale

Medicinal Chemistry

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22 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1577-1587
Number of pages	11
Journal	Chemistry and Biology
Volume	22
Issue number	12
DOIs	https://doi.org/10.1016/j.chembiol.2015.10.009
State	Published - Dec 17 2015

Bibliographical note

Funding Information:
R.S.G. acknowledges the support from CSIR grant (GENCODE BSC0123 ). S.C. acknowledges Department of Science and Technology-Ramanujan fellowship (SB/S2/RJN-14/2013). L.T. is thankful to the Department of Science and Technology, INSPIRE faculty fellowship. C.C.A. acknowledges support from the National Institutes of Health ( AI070219 ). We also acknowledge DBT for institutional support to NII.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

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Srivastava, S., Chaudhary, S., Thukral, L., Shi, C., Gupta, R. D., Gupta, R., Priyadarshan, K., Vats, A., Haque, A. S., Sankaranarayanan, R., Natarajan, V. T., Sharma, R., Aldrich, C. C., & Gokhale, R. S. (2015). Unsaturated Lipid Assimilation by Mycobacteria Requires Auxiliary cis-trans Enoyl CoA Isomerase. Chemistry and Biology, 22(12), 1577-1587. https://doi.org/10.1016/j.chembiol.2015.10.009

Srivastava, S, Chaudhary, S, Thukral, L, Shi, C, Gupta, RD, Gupta, R, Priyadarshan, K, Vats, A, Haque, AS, Sankaranarayanan, R, Natarajan, VT, Sharma, R, Aldrich, CC & Gokhale, RS 2015, 'Unsaturated Lipid Assimilation by Mycobacteria Requires Auxiliary cis-trans Enoyl CoA Isomerase', Chemistry and Biology, vol. 22, no. 12, pp. 1577-1587. https://doi.org/10.1016/j.chembiol.2015.10.009

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Unsaturated Lipid Assimilation by Mycobacteria Requires Auxiliary cis-trans Enoyl CoA Isomerase

Abstract

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