Plasmodium falciparum sir2:: an unusual sirtuin with dual histone deacetylase and ADP-ribosyltransferase activity
Plasmodium falciparum sir2:: an unusual sirtuin with dual histone deacetylase and ADP-ribosyltransferase activity
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DOI：
10.1128/ec.00114-07
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发表时间：
2007-11-01
期刊：
影响因子：
--
通讯作者：
Duraisingh, Manoj T.
中科院分区：
文献类型：
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作者：
Merrick, Catherine J.;Duraisingh, Manoj T.
在人类疟疾寄生虫恶性疟原虫中，sirtuin家族的一员参与了对疟疾发病机制和持续性至关重要的毒力基因的表观遗传调控。这种真核sirtuin（PfSir 2）的序列与迄今为止表征的序列不同，属于主要包含真细菌和古细菌sirtuin的系统发育类别。PfSir 2与血液期寄生虫中的组蛋白共分馏，并且重组酶有效地使组蛋白H3和H4的N-末端尾部脱乙酰基。此外，PfSir 2可以ADP-核糖基化历史和本身，在大多数具有显著脱乙酰酶活性的sirtuins中最小或不存在的活性。值得注意的是，PfSir 2的脱乙酰酶活性依赖于其ADP-核糖基化。最后，虽然PfSir 2不受已建立的沉默调节蛋白抑制剂的影响，但它可以被沉默调节蛋白反应的天然产物烟酰胺完全抑制。该研究表明PfSir 2具有适当的特性，可以直接调节恶性疟原虫的染色质结构。这也提出了一个重要的可能性，即ADP-核糖基化和组蛋白的去乙酰化可能是沉默调节蛋白调节的染色质结构在这个物种。
In the human malaria parasite Plasmodium falciparum, a member of the sirtuin family has been implicated in the epigenetic regulation of virulence genes that are vital to malaria pathogenesis and persistence. This eukaryotic sirtuin, PfSir2, is divergent in sequence from those characterized thus far and belongs to the phylogenetic class that contains primarily eubacterial and archaeal sirtuins. PfSir2 cofractionates with histones in blood-stage parasites, and the recombinant enzyme efficiently deacetylates the N-terminal tails of histones H3 and H4. In addition, PfSir2 can ADP-ribosylate both histories and itself, an activity that is minimal or absent in most sirtuins with significant deacetylase activity. Strikingly, the deacetylase activity of PfSir2 is dependent on its ADP-ribosylation. Finally, although PfSir2 is not affected by established sirtuin inhibitors, it can be completely inhibited by nicotinamide, a natural product of the sirtuin reaction. This study shows that PfSir2 has the appropriate characteristics to be a direct regulator of chromatin structure in P. falciparum. It also raises the significant possibility that both ADP-ribosylation and deacetylation of histones could be sirtuin-regulated modulators of chromatin structure in this species.