The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sci Signal. 2011 Aug 23;4(188):re1. doi: 10.1126/scisignal.2001958.
Inositol pyrophosphates are highly energetic inositol polyphosphate molecules present in organisms from slime molds and yeast to mammals. Distinct classes of enzymes generate different forms of inositol pyrophosphates. The biosynthesis of these substances principally involves phosphorylation of inositol hexakisphosphate (IP₆) to generate the pyrophosphate IP₇. Initial insights into functions of these substances derived primarily from yeast, which contain a single isoform of IP₆ kinase (yIP₆K), as well as from the slime mold Dictyostelium. Mammalian functions for inositol pyrophosphates have been investigated by using cell lines to establish roles in various processes, including insulin secretion and apoptosis. More recently, mice with targeted deletion of IP₆K isoforms as well as the related inositol polyphosphate multikinase (IPMK) have substantially enhanced our understanding of inositol polyphosphate physiology. Phenotypic alterations in mice lacking inositol hexakisphosphate kinase 1 (IP₆K1) reveal signaling roles for these molecules in insulin homeostasis, obesity, and immunological functions. Inositol pyrophosphates regulate these processes at least in part by inhibiting activation of the serine-threonine kinase Akt. Similar studies of IP₆K2 establish this enzyme as a cell death inducer acting by stimulating the proapoptotic protein p53. IPMK is responsible for generating the inositol phosphate IP₅ but also has phosphatidylinositol 3-kinase activity--that participates in activation of Akt. Here, we discuss recent advances in understanding the physiological functions of the inositol pyrophosphates based in substantial part on studies in mice with deletion of IP₆K isoforms. These findings highlight the interplay of IPMK and IP₆K in regulating growth factor and nutrient-mediated cell signaling.
肌醇六磷酸是一种高能的多磷酸肌醇分子，存在于从黏菌和酵母到哺乳动物等生物体中。不同类别的酶产生不同形式的肌醇六磷酸。这些物质的生物合成主要涉及肌醇六磷酸（IP₆）的磷酸化，以生成焦磷酸 IP₇。这些物质的功能最初主要是从酵母中得出的，酵母中含有一种同工型的 IP₆激酶（yIP₆K），以及从黏菌 Dictyostelium 中得出的。通过使用细胞系来研究哺乳动物中肌醇六磷酸的功能，以确定其在各种过程中的作用，包括胰岛素分泌和细胞凋亡。最近，靶向缺失 IP₆K 同工型以及相关的肌醇多磷酸激酶（IPMK）的小鼠大大增强了我们对肌醇多磷酸生理学的理解。缺乏肌醇六磷酸激酶 1（IP₆K1）的小鼠的表型改变揭示了这些分子在胰岛素稳态、肥胖和免疫功能中的信号作用。肌醇六磷酸通过抑制丝氨酸-苏氨酸激酶 Akt 的激活来调节这些过程。对 IP₆K2 的类似研究确立了该酶作为通过刺激促凋亡蛋白 p53 发挥作用的细胞死亡诱导剂。IPMK 负责生成肌醇磷酸盐 IP₅，但也具有磷酸肌醇 3-激酶活性——该活性参与 Akt 的激活。在这里，我们讨论了基于对缺失 IP₆K 同工型的小鼠的研究，对肌醇焦磷酸盐生理功能的理解的最新进展。这些发现强调了 IPMK 和 IP₆K 在调节生长因子和营养物质介导的细胞信号转导中的相互作用。
