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The mycolic acid reductase Rv2509 has distinct structural motifs and is essential for growth in slow growing mycobacteria

Javid, Asma and Cooper, Charlotte and Singh, Albel and Schindler, Steffen and Hänisch, Milena and Marshall, Robert and Kalscheuer, Rainer and Bavro, Vassiliy N and Bhatt, Apoorva (2020) 'The mycolic acid reductase Rv2509 has distinct structural motifs and is essential for growth in slow growing mycobacteria.' Molecular Microbiology, 113 (2). pp. 521-533. ISSN 0950-382X

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The final step in mycolic acid biosynthesis in Mycobacterium tuberculosis is catalysed by a mycolyl reductase encoded by the Rv2509 gene. Sequence analysis and homology modelling indicates that Rv2509 belongs to the short‐chain fatty acid dehydrogenase/reductase (SDR) family, but with some distinct features that warrant its classification as belonging to a novel family of short‐chain dehydrogenases. In particular, the predicted structure revealed a unique α‐helical C‐terminal region which we demonstrated to be essential for Rv2509 function, though this region did not seem to play any role in protein stabilisation or oligomerisation. We also show that unlike the M. smegmatis homologue which was not essential for growth, Rv2509 was an essential gene in slow growing mycobacteria. A knockdown strain of the BCG2529, the Rv2509 homologue in Mycobacterium bovis BCG was unable to survive following conditional depletion of BCG2529. This conditional depletion also led to a reduction of mature mycolic acid production and accumulation of intermediates derived from 3‐oxo‐mycolate precursors. Our studies demonstrate novel features of the mycolyl reductase Rv2509 and outline its role in mycobacterial growth, highlighting its potential as a new target for therapies.

Item Type: Article
Uncontrolled Keywords: Mycobacterium, mycolic acid, reductase, dehydrogenase, tuberculosis
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 04 Dec 2019 12:04
Last Modified: 06 Jan 2022 14:08

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