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The inositol-3-phosphate synthase biosynthetic enzyme has distinct catalytic and metabolic roles

Frej, A. D., Clark, J., Le Roy, C., Lilla, S., Thomason, P., Otto, G. P., Churchill, G., Insall, R., Claus, S. P., Hawkins, P., Stephens, L. and Williams, R. S. B. (2016) The inositol-3-phosphate synthase biosynthetic enzyme has distinct catalytic and metabolic roles. Molecular and cellular biology, 36 (10). pp. 1464-1479. ISSN 1098-5549

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To link to this item DOI: 10.1128/MCB.00039-16

Abstract/Summary

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, to demonstrate distinct effects of loss of Ino1 and inositol depletion. We show that loss of Ino1 results in inositol auxotrophy that can only be partially rescued by exogenous inositol. Removal of inositol supplementation from the ino1- mutant results in a rapid 56% reduction in inositol levels, triggering the induction of autophagy, reduced cytokinesis and substrate adhesion. Inositol depletion also caused a dramatic generalised 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 independent of inositol biosynthesis. To characterise this role, an Ino1 binding partner containing SEL1L1 domains (Q54IX5) was identified with homology to mammalian macromolecular complex adaptor proteins. Our findings therefore identify a new role for Ino1, independent of inositol biosynthesis, with broad effects on cell metabolism.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) > NMR (CAF)
Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Food and Nutritional Sciences > Food Microbial Sciences Research Group
ID Code:57784
Publisher:American Society for Microbiology

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