The mycolic acid reductase Rv2509 has distinct structural motifs and is essential for growth in slow-growing mycobacteria.
The mycolic acid reductase Rv2509 has distinct structural motifs and is essential for growth in slow-growing mycobacteria.
复制标题
分枝菌酸还原酶 Rv2509 具有独特的结构基序，对于缓慢生长的分枝杆菌的生长至关重要。
DOI：
10.1111/mmi.14437
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发表时间：
2020
影响因子：
3.6
通讯作者：
Javid A
中科院分区：
文献类型：
--
作者：
Javid A
结核分枝杆菌霉酚酸生物合成的最后一步，由Rv2509基因编码的霉酚酸还原酶催化。序列分析和同源模建表明，Rv2509属于短链脂肪酸脱氢酶/还原酶(SDR)家族，但具有一些明显的特征，因此它属于一个新的短链脱氢酶家族。特别是，预测的结构揭示了一个独特的α-螺旋C-末端区域，我们证明了该区域对于Rv2509的功能是必不可少的，尽管该区域似乎在蛋白质稳定或寡聚方面没有任何作用。我们也证明了这一点与他们不同。耻垢同源基因Rv2509是生长缓慢的分枝杆菌的必需基因。BCG2529基因的敲除菌株，BCG分枝杆菌中的Rv2509同源物，在BCG2529的条件耗尽后不能生长。这种有条件的消耗还导致成熟霉酚酸的产生减少，并导致3-氧代-霉酚酸酯前体中间体的积累。我们的研究展示了真菌还原酶Rv2509的新特征，并概述了它在分枝杆菌生长中的作用，突出了它作为新治疗靶点的潜力。
The final step in mycolic acid biosynthesis inMycobacterium tuberculosisis catalysed by mycolyl reductase encoded by theRv2509gene. 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 theM. smegmatishomologue which was not essential for growth,Rv2509was an essential gene in slow‐growing mycobacteria. A knockdown strain of theBCG2529gene, theRv2509homologue inMycobacterium bovisBCG, 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 reductaseRv2509and outline its role in mycobacterial growth, highlighting its potential as a new target for therapies.