Desfougères, Y; Wilson, MSC; Laha, D; Miller, GJ; Saiardi, A; (2019) ITPK1 mediates the lipid-independent synthesis of inositol phosphates controlled by metabolism. Proceedings of the National Academy of Sciences of the United States of America , 116 (49) pp. 24551-24561. 10.1073/pnas.1911431116.

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Abstract

Inositol phosphates (IPs) comprise a network of phosphorylated molecules that play multiple signaling roles in eukaryotes. IPs synthesis is believed to originate with IP_{3} generated from PIP_{2} 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 IP_{6}. We also found using PAGE mass assay that metabolic blockage by phosphate starvation surprisingly increased IP_{6} levels in a ITPK1-dependent manner, establishing a route to IP_{6} controlled by cellular metabolic status, that is not detectable by traditional [{3}^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.

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