Medical Research Council Laboratory for Molecular Cell Biology, University College London, WC1E 6BT London, United Kingdom.
Department of Chemistry, The Catholic University of America, Washington, DC 20064.
Proc Natl Acad Sci U S A. 2019 Dec 3;116(49):24551-24561. doi: 10.1073/pnas.1911431116. Epub 2019 Nov 21.
Inositol phosphates (IPs) comprise a network of phosphorylated molecules that play multiple signaling roles in eukaryotes. IPs synthesis is believed to originate with IP generated from PIP 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 originating from glucose-6-phosphate, and I(1)P generated from sphingolipids, to enable synthesis of IP We also found using PAGE mass assay that metabolic blockage by phosphate starvation surprisingly increased IP levels in a ITPK1-dependent manner, establishing a route to IP controlled by cellular metabolic status, that is not detectable by traditional [H]-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.
肌醇磷酸盐（inositol phosphates，IPs）是一组磷酸化分子的网络，在真核生物中发挥多种信号作用。人们认为 IPs 的合成始于由磷脂酶 C（PLC）产生的来自 PIP 的 IP。在这里，我们报告说，在哺乳动物细胞中，PLC 产生的 IP 会迅速回收再生成肌醇，并揭示了另一种“可溶性”途径合成 IP 的酶学机制。在古菌、黏菌、植物和动物中发现的肌醇四磷酸 1-激酶 1（inositol tetrakisphosphate 1-kinase 1，ITPK1）可磷酸化来自葡萄糖-6-磷酸的 I(3)P 和来自鞘脂的 I(1)P，从而合成 IP。我们还通过 PAGE 质量分析发现，通过磷酸盐饥饿进行代谢阻断会出人意料地以 ITPK1 依赖的方式增加 IP 水平，从而建立了一种受细胞代谢状态控制的 IP 途径，这是传统的 [H]-肌醇标记无法检测到的。在被认为定义真核生物起源的古菌枝系中存在 ITPK1，表明在真核生物出现之前，IPs 就具有功能作用。
