myo-Inositol and inositol (pyro)phosphate biosynthesis (MIPS/IMPase and the PLC-IPMK-IPK1-IP6K-PPIP5K route)

myo-Inositol is made de novo from glucose 6-phosphate in two cytosolic steps: myo-inositol-3-phosphate synthase (MIPS), an NAD+-dependent isomerase, cyclises glucose 6-phosphate to 1D-myo-inositol 3-phosphate, and a lithium-sensitive inositol monophosphatase (IMPase) removes the phosphate to release free myo-inositol. Free inositol is used to make phosphatidylinositol and, through the phosphoinositides, the higher soluble inositol phosphates. In the lipid-dependent route, phospholipase C cleaves phosphatidylinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate (IP3). An inositol polyphosphate multikinase (IPMK; yeast Arg82/Ipk2) phosphorylates IP3 to inositol 1,4,5,6-tetrakisphosphate and then to inositol 1,3,4,5,6-pentakisphosphate (IP5), and inositol-pentakisphosphate 2-kinase (IPK1) completes inositol hexakisphosphate (IP6, phytate). IP6 is further pyrophosphorylated to the high-energy inositol pyrophosphates by two unrelated kinase families: IP6 kinases (yeast Kcs1, mammalian IP6K) make 5-diphosphoinositol pentakisphosphate (IP7), and the PPIP5K/Vip1/Asp1 kinases add a further diphosphate to make IP8. IP6 and the inositol pyrophosphates act in mRNA export, phosphate homeostasis, vacuole biogenesis and stress responses. Some fungi, including fission yeast, lack the de novo branch and rely on imported inositol.

NEW (YeastPathways project, 2026-10). The module has two sub-pathways joined through lipid intermediates made in other modules: de novo myo-inositol synthesis (MIPS -> IMPase) and the lipid-dependent synthesis of IP6 and inositol pyrophosphates (PLC -> IPMK -> IPMK -> IPK1 -> IP6K -> PPIP5K). Inositol is incorporated into PI by PI synthase (cdp_dag_phospholipid_synthesis) and PI is phosphorylated to PI(4,5)P2 (phosphoinositide_biosynthesis) before PLC releases IP3. The IMPase step uses GO:0052832 (inositol monophosphate 3-phosphatase) because the MIPS product is 1D-myo-inositol 3-phosphate; YeastPathways uses the 1-phosphatase term GO:0008934 for the same reaction (the 1D-3-phosphate is the L-1-phosphate in the older numbering). Arg82/IPMK is modelled as two sequential steps (IP3 6-kinase, then Ins(1,4,5,6)P4 3-kinase); the secondary 3-kinase-first route through Ins(1,3,4,5)P4 and the minor diphosphoinositol-tetrakisphosphate products of Arg82 and Kcs1 (PMID:11311242, PMID:10827188) are recorded here rather than as separate parts. The positional specificities (Kcs1/IP6K at position 5, Vip1/PPIP5K at position 1) are not established in the cached literature, so the generic GO terms GO:0000828 and GO:0000829 are used. DDP1 inositol-pyrophosphate diphosphatase activity (PMID:10419486) is turnover and is excluded, as are the transcriptional and mRNA-export roles of the products. Exemplars: S. cerevisiae for all steps, S. pombe for the IP route (plc1, arg82, ipk1, kcs1/SPCC970.08, asp1) and human orthologs sharing the PANTHER family. S. pombe has no member of the MIPS (PTHR11510) or IMPase (PTHR20854) families in the PANTHER 19.0 classification and no MIPS in UniProt, so the de novo branch has no S. pombe exemplar; the PomBase model 663d668500002178 instead contains the itr2 myo-inositol transporter. YeastCyc corrections: none needed; ARG82, KCS1 and VIP1 are present in PWY3O-402 (contrary to the crosswalk note). The crosswalk lists only the YeastPathways models for this group; the PomBase model 663d668500002178, assigned to phosphoinositide_biosynthesis, is also linked here because it contains plc1, arg82, ipk1, kcs1 and asp1. GO-CAM disagreements: (a) both YeastPathways models place everything in cytosol (the IPMK/IPK1 pathway is largely nuclear in yeast, not addressed in cached sources); (b) YeastPathways_PWY3O-402 gives ARG82 the IP3 6-kinase term GO:0000823 for the Ins(1,4,5,6)P4 3-kinase reaction (RXN-7162), where GO:0000824 is specific; (c) the PomBase model gives asp1 GO:0052723 (IP6 1-kinase) but has no IP7 kinase activity, and gives kcs1 and the other kinases no location.