title: The Inositol-3-Phosphate Synthase Biosynthetic Enzyme Has Distinct Catalytic and Metabolic Roles.
abstract: Inositol levels, maintained by the biosynthetic enzyme inositol-3-phosphate synthase (Ino1), are altered in a range of disorders, including bipolar disorder and Alzheimer's disease. To date, most inositol studies have focused on the molecular and cellular effects of inositol depletion without considering Ino1 levels. Here we employ a simple eukaryote, Dictyostelium discoideum, to demonstrate distinct effects of loss of Ino1 and inositol depletion. We show that loss of Ino1 results in an inositol auxotrophy that can be rescued only partially by exogenous inositol. Removal of inositol supplementation from the ino1(-) mutant resulted in a rapid 56% reduction in inositol levels, triggering the induction of autophagy, reduced cytokinesis, and substrate adhesion. Inositol depletion also caused a dramatic generalized decrease in phosphoinositide levels that was rescued by inositol supplementation. However, loss of Ino1 triggered broad metabolic changes consistent with the induction of a catabolic state that was not rescued by inositol supplementation. These data suggest a metabolic role for Ino1 that is independent of inositol biosynthesis. To characterize this role, an Ino1 binding partner containing SEL1L1 domains (Q54IX5) and having homology to mammalian macromolecular complex adaptor proteins was identified. Our findings therefore identify a new role for Ino1, independent of inositol biosynthesis, with broad effects on cell metabolism.
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, United Kingdom.
authors.forename: Anna D
authors.initials: AD
authors.lastname: Frej
authors.affiliation: The Babraham Institute, Cambridge, Cambridgeshire, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clark
authors.affiliation: Department of Food and Nutritional Sciences, The University of Reading, Reading, Berkshire, United Kingdom.
authors.forename: Caroline I
authors.initials: CI
authors.lastname: Le Roy
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow, United Kingdom.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lilla
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow, United Kingdom.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Thomason
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, United Kingdom.
authors.forename: Grant P
authors.initials: GP
authors.lastname: Otto
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, Oxfordshire, United Kingdom.
authors.forename: Grant
authors.initials: G
authors.lastname: Churchill
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow, United Kingdom.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Insall
authors.affiliation: Department of Food and Nutritional Sciences, The University of Reading, Reading, Berkshire, United Kingdom.
authors.forename: Sandrine P
authors.initials: SP
authors.lastname: Claus
authors.affiliation: The Babraham Institute, Cambridge, Cambridgeshire, United Kingdom.
authors.forename: Phillip
authors.initials: P
authors.lastname: Hawkins
authors.affiliation: The Babraham Institute, Cambridge, Cambridgeshire, United Kingdom.
authors.forename: Len
authors.initials: L
authors.lastname: Stephens
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, United Kingdom robin.williams@rhul.ac.uk.
authors.forename: Robin S B
authors.initials: RS
authors.lastname: Williams
mesh_terms: D001343:Autophagy; D048749:Cytokinesis; D004023:Dictyostelium / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D007294:Inositol / Q000378:metabolism*; D019753:Intramolecular Lyases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008660:Metabolism; D009154:Mutation; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D015800:Protozoan Proteins; D007294:Inositol; D019753:Intramolecular Lyases; C105497:D-myo-inositol-3-phosphate synthase