ITPK1 mediates the lipid-independent synthesis of inositol phosphates controlled by metabolism

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.