Functional characterization and evolution of the isotuberculosinol operon in Mycobacterium tuberculosis and related Mycobacteria.
Functional characterization and evolution of the isotuberculosinol operon in Mycobacterium tuberculosis and related Mycobacteria.
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DOI：
10.3389/fmicb.2012.00368
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发表时间：
2012
影响因子：
5.2
通讯作者：
Peters RJ
中科院分区：
文献类型：
--
作者：
Mann FM;Xu M;Davenport EK;Peters RJ
萜类代谢产物对人类特有的结核分枝杆菌(Mtb)的细胞功能、结构完整性和致病机制具有重要作用。遗传和生化研究表明，二萜类异结核菌醇(IsoTb)在感染过程的早期起到了作用。只有两个基因(Rv3377c和Rv3378c)需要生产等Tb，但这两个基因似乎是在一个由五个基因组成的类萜/类异戊二烯生物合成操纵子中发现的。在剩下的三个基因(Rv3379c、Rv3382c和Rv3383c)中，先前的工作表明Rv3379c是一个失活的假基因。在这里，我们证明了Rv3382c和Rv3383c编码了异戊二烯代谢的生化冗余机制，分别编码了功能上的4-羟基-3-甲基但2-烯基二磷酸还原酶(LytB)和香叶基香叶基二磷酸(GGPP)合成酶，Mtb基因组包含其他功能的同工酶(分别为Rv1110和Rv0562)。这些结果完成了等Tb生物合成操纵子的表征，并进一步阐明了Mtb中的异戊二烯代谢。此外，我们还研究了这个操纵子的进化起源，揭示了负责等Tb生物合成的二萜合成酶基因的Mtb特异性保守，这支持了我们之前提出的假设，即IsoTb作为人类特有的致病代谢物，与Mtb的人类宿主特异性一致。有趣的是，我们的结果显示，许多分枝杆菌都含有Rv3383c和Rv0562的同源基因，这表明这些功能冗余的GGPP合成酶在分枝杆菌中萜类/类异戊二烯代谢的进化中具有潜在的重要作用。
Terpenoid metabolites are important to the cellular function, structural integrity, and pathogenesis of the human-specific pathogen Mycobacterium tuberculosis (Mtb). Genetic and biochemical investigations have indicated a role for the diterpenoid isotuberculosinol (isoTb) early in the infection process. There are only two genes (Rv3377c and Rv3378c) required for production of isoTb, yet these are found in what appears to be a five-gene terpenoid/isoprenoid biosynthetic operon. Of the three remaining genes (Rv3379c, Rv3382c, and Rv3383c), previous work has indicated that Rv3379c is an inactive pseudo-gene. Here we demonstrate that Rv3382c and Rv3383c encode biochemically redundant machinery for isoprenoid metabolism, encoding a functional 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (LytB) for isoprenoid precursor production and a geranylgeranyl diphosphate (GGPP) synthase, respectively, for which the Mtb genome contains other functional isozymes (Rv1110 and Rv0562, respectively). These results complete the characterization of the isoTb biosynthetic operon, as well as further elucidating isoprenoid metabolism in Mtb. In addition, we have investigated the evolutionary origin of this operon, revealing Mtb-specific conservation of the diterpene synthase genes responsible for isoTb biosynthesis, which supports our previously advanced hypothesis that isoTb acts as a human-specific pathogenic metabolite and is consistent with the human host specificity of Mtb. Intriguingly, our results revealed that many mycobacteria contain orthologs for both Rv3383c and Rv0562, suggesting a potentially important role for these functionally redundant GGPP synthases in the evolution of terpenoid/isoprenoid metabolism in the mycobacteria.
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影响因子：
6.5
作者：
Dhiman, RK;Schulbach, MC;Crick, DC
通讯作者：
Crick, DC
影响因子：
4.8
作者：
Burke, C;Croteau, R
通讯作者：
Croteau, R
影响因子：
15
作者：
Mann FM;Xu M;Chen X;Fulton DB;Russell DG;Peters RJ
通讯作者：
Peters RJ
DOI：
10.1073/pnas.0504922102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Fortune, SM;Jaeger, A;Rubin, EJ
通讯作者：
Rubin, EJ
DOI：
10.1073/pnas.182412599
发表时间：
2002-09-17
影响因子：
11.1
作者：
Adam, P;Hecht, S;Rohdich, F
通讯作者：
Rohdich, F