ITPK1 mediates the lipid-independent synthesis of inositol phosphates controlled by metabolism.
basic_science · Level V
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- Record sourced from PubMed, PMID 31754032.
- Also identified by DOI 10.1073/pnas.1911431116 and PMC identifier 6900528.
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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<sub>3</sub> generated from PIP<sub>2</sub> 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<sub>1</sub> originating from glucose-6-phosphate, and I(1)P<sub>1</sub> generated from sphingolipids, to enable synthesis of IP<sub>6</sub> We also found using PAGE mass assay that metabolic blockage by phosphate starvation surprisingly increased IP<sub>6</sub> levels in a ITPK1-dependent manner, establishing a route to IP<sub>6</sub> controlled by cellular metabolic status, that is not detectable by traditional [<sup>3</sup>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.
Medical subject headings
- Inositol Phosphates
- Phosphotransferases (Alcohol Group Acceptor)