ITPK1 mediates the lipid-independent synthesis of inositol phosphates controlled by metabolism
ITPK1 mediates the lipid-independent synthesis of inositol phosphates controlled by metabolism
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DOI：
10.1073/pnas.1911431116
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发表时间：
2019-12-03
影响因子：
11.1
通讯作者：
Saiardi, Adolfo
中科院分区：
文献类型：
--
作者：
Desfougeres, Yann;Wilson, Miranda S. C.;Saiardi, Adolfo
肌醇磷酸(IP)是一个由磷酸化分子组成的网络，在真核生物中起着多种信号转导作用。IPS的合成被认为起源于磷脂酶C(PLC)由PIP2生成的IP3。在这里，我们报告了在哺乳动物细胞中，PLC产生的IP被迅速循环为肌醇，并揭示了另一条合成IP的“可溶”路线背后的酶学。肌醇四氢磷酸盐1-激酶1(ITPK1)-发现于阿斯加德古生菌、社会阿米巴、植物和动物中-使源于葡萄糖-6-磷酸的I(3)P-1和来自鞘磷脂的I(1)P-1磷酸化，以使IP6的合成成为可能。我们还利用PAGE质量分析发现，磷酸盐饥饿引起的代谢阻断以ITPK1依赖的方式意外地增加了IP6的水平，建立了一条由细胞代谢状态控制的IP6的途径，这是传统的[H-3]-肌醇标记无法检测到的。ITPK1在被认为定义真核发生的古菌分支中的存在表明，在真核生物出现之前，IP具有功能作用。
Inositol phosphates (IPs) comprise a network of phosphorylated molecules that play multiple signaling roles in eukaryotes. IPs synthesis is believed to originate with IP3 generated from PIP2 by phospholipase C (PLC). Here, we report that in mammalian cells PLC-generated IPs are rapidly recycled to inositol, and uncover the enzymology behind an alternative "soluble" route to synthesis of IPs. Inositol tetrakisphosphate 1-kinase 1 (ITPK1)-found in Asgard archaea, social amoeba, plants, and animals-phosphorylates I(3)P-1 originating from glucose-6-phosphate, and I(1)P-1 generated from sphingolipids, to enable synthesis of IP6. We also found using PAGE mass assay that metabolic blockage by phosphate starvation surprisingly increased IP6 levels in a ITPK1-dependent manner, establishing a route to IP6 controlled by cellular metabolic status, that is not detectable by traditional [H-3]-inositol labeling. The presence of ITPK1 in archaeal clades thought to define eukaryogenesis indicates that IPs had functional roles before the appearance of the eukaryote.