Abstract
The final step in mycolic acid biosynthesis in Mycobacterium tuberculosis is catalysed by mycolyl reductase encoded by the Rv2509 gene. Sequence analysis and homology modelling indicate 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 gene, the Rv2509 homologue in Mycobacterium bovis BCG, was unable to grow following the 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.
Highlights
The cell walls of mycobacteria including the tuberculosis-causing Mycobacterium tuberculosis contain distinct long chain fatty acids termed mycolic acids
Summary 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
Summary
The cell walls of mycobacteria including the tuberculosis-causing Mycobacterium tuberculosis contain distinct long chain fatty acids termed mycolic acids. While the precise knowledge of the substrate for Rv2509 is lacking, functional analysis of the preceding enzyme in the biosynthetic pathway, Pks, indicated that while this polyketide synthase primarily catalyses the formation of the -alkyl, -keto fatty acyl precursor, it contains enzymatic motifs that facilitate the release of the nascent fatty acyl chain and its subsequent transfer to a trehalose residue to produce a trehalose residue esterified with the alkyl, -keto fatty acyl precursor of mycolic acid (Gavalda et al, 2014). We probed the essentiality of Rv2509 for growth and viability of the slow growing M. tuberculosis complex using Mycobacterium bovis BCG
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