title: Inositol Pyrophosphate Specificity of the SPX-Dependent Polyphosphate Polymerase VTC.
abstract: The free energy of nucleotide hydrolysis depends on phosphate concentration. Cells regulate cytosolic phosphate levels by orchestrating phosphate acquisition and storage through inositol pyrophosphates (PP-InsP) and SPX domains. Here, we report the synthesis of the novel 5-PPP-InsP5containing a triphosphate subunit. Using this and a series of synthetic PP-InsP, we examined the ligand specificity of the SPX domain in the PP-InsP-controlled yeast polyphosphate polymerase VTC. SPX decodes the relative positioning of the phosphoric anhydrides, their structure (diphosphate vs triphosphate), and the presence of other phosphates on the inositol ring. Despite the higher potency of 1,5-(PP)2-InsP4, 5-PP-InsP5is the primary activator of VTC in cells, indicating that its higher concentration compensates for its lower potency. 1,5-(PP)2-InsP4levels rise and could become relevant under stress conditions. Thus, SPX domains may integrate PP-InsP dependent signaling to adapt cytosolic phosphate concentrations to different metabolic situations.
authors.affiliation: Department of Biochemistry, University of Lausanne , Chemin de Boveresses 155, 1066 Epalinges, Switzerland.
authors.forename: Ruta
authors.initials: R
authors.lastname: Gerasimaite
authors.affiliation: Department of Chemistry, University of Zürich , Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Igor
authors.initials: I
authors.lastname: Pavlovic
authors.affiliation: Department of Chemistry, University of Zürich , Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Samanta
authors.initials: S
authors.lastname: Capolicchio
authors.affiliation: Department of Chemistry, University of Zürich , Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hofer
authors.affiliation: Department of Biochemistry, University of Lausanne , Chemin de Boveresses 155, 1066 Epalinges, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Institute of Organic Chemistry, Albert-Ludwigs University of Freiburg , Albertstrasse 21, 79104 Freiburg, Germany.
authors.forename: Henning J
authors.identifier: 0000-0002-1025-9484
authors.initials: HJ
authors.lastname: Jessen
authors.affiliation: Department of Biochemistry, University of Lausanne , Chemin de Boveresses 155, 1066 Epalinges, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mayer
mesh_terms: D004798:Enzymes / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism*; D011122:Polyphosphates / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004798:Enzymes; D007295:Inositol Phosphates; D011122:Polyphosphates; C013571:inositol pentaphosphate