Phosphoinositide biosynthesis (PI -> PI3P/PI4P -> PI(3,5)P2/PI(4,5)P2 kinase network)

Phosphatidylinositol (PI) is phosphorylated on the inositol ring by a conserved set of lipid kinases to give the phosphoinositides that mark eukaryotic membranes and recruit effector proteins. A class III phosphatidylinositol 3-kinase (Vps34), held on membranes by its regulatory protein-kinase subunit, makes PI 3-phosphate (PI3P) on endosomes and autophagic membranes. Phosphatidylinositol 4-kinases make PI 4-phosphate (PI4P) in distinct places: the type III-beta enzyme (Pik1/PI4KB) on the trans-Golgi, the type III-alpha enzyme (Stt4/PI4KA), recruited by an Efr3-Ypp1 scaffold, at the plasma membrane, and a type II enzyme on plasma and vacuolar/endosomal membranes. Two kinds of PIP kinase add a 5-phosphate: the type I PI4P 5-kinase (Mss4/PIP5K1) converts plasma-membrane PI4P to PI(4,5)P2, the precursor of inositol-trisphosphate signalling and a regulator of the cortical actin cytoskeleton, and the FYVE-domain PI3P 5-kinase (Fab1/PIKfyve), acting in a complex with Vac14 and the Fig4 phosphatase, converts PI3P to PI(3,5)P2 on the vacuole/late endosome, where it controls vacuole size and membrane homeostasis. Because each kinase acts in its own compartment, the network produces membrane-specific lipid identities rather than a linear pathway; lipid phosphatases (Sac1, synaptojanins, Fig4) reverse these steps and are outside this module.

NEW (YeastPathways project, 2026-10). Boundary: the four lipid-kinase reactions that make PI3P, PI4P, PI(3,5)P2 and PI(4,5)P2 from PI. PI itself is made by PI synthase in cdp_dag_phospholipid_synthesis; PI(4,5)P2 hydrolysis by phospholipase C begins myo_inositol_and_inositol_phosphate_biosynthesis. The phosphatases that YeastCyc includes in PWY3O-242 (SAC1, INP51/52/53/54, FIG4, YMR1) reverse these steps and are excluded, as are effectors. Scaffold and regulatory subunits that are required in vivo but have no lipid-kinase activity are recorded here rather than as annotons: Vps15 for Vps34 (PMID:8387919), Efr3 and Ypp1 for Stt4 (PomBase model 663d668500002178 gives S. pombe efr3 protein-membrane adaptor activity), and Vac14/Vac7 for Fab1 (PMID:17382260). PI4K is a ONE_OR_MORE variant set because the three PI 4-kinases make separate pools (Golgi Pik1, plasma-membrane Stt4, and a minor type II Lsb6 whose loss has no phosphoinositide phenotype, PMID:12361950). Human orthologs are added as representatives where they share the PANTHER (sub)family (PIK3C3, PI4KB, PI4KA, PIP5K1A). Fab1 and PIKfyve are in different PANTHER families (PTHR45748 and PTHR46715), so the PI3P 5-kinase role carries no family id. MSS4 and S. pombe its3 are in PTHR23086:SF8 and human PIP5K1A in SF54, so the PIP5K role lists the type I PIP5K subfamilies SF8, SF54, SF34 and SF26 of PTHR23086 (not the whole family, which also contains the PI5P 4-kinases). YeastCyc corrections: none for the kinases; STT4 is present in YeastCyc. GO-CAM disagreements: (a) YeastPathways_PWY3O-242 places all kinases in cytosol rather than on their membranes; (b) the PomBase model 663d668500002178 gives S. pombe its3 the MF GO:0052811 (1-phosphatidylinositol-3-phosphate 4-kinase activity), whereas UniProt (O13853) names its3 a PI4P 5-kinase (EC 2.7.1.68), the activity of its S. cerevisiae ortholog MSS4 (PMID:9624178); this module uses GO:0016308 for the role; (c) the PomBase model also includes myo-inositol import (itr2), PI synthase (pis1) and the inositol-phosphate kinases plc1/arg82/ipk1/kcs1/asp1, which are modelled in the neighbouring modules, and it lacks the Vps34, Pik1 and Fab1 steps.