title: On the contribution of stereochemistry to human ITPK1 specificity: Ins(1,4,5,6)P4 is not a physiologic substrate.
abstract: Ins(1,4,5,6)P4, a biologically active cell constituent, was recently advocated as a substrate of human Ins(3,4,5,6)P4 1-kinase (hITPK1), because stereochemical factors were believed relatively unimportant to specificity [Miller, G.J., Wilson, M.P., Majerus, P.W. and Hurley, J.H. (2005) Specificity determinants in inositol polyphosphate synthesis: crystal structure of inositol 1,3,4-triphosphate 5/6-kinase. Mol. Cell. 18, 201-212]. Contrarily, we provide three examples of hITPK1 stereospecificity. hITPK1 phosphorylates only the 1-hydroxyl of both Ins(3,5,6)P3 and the meso-compound, Ins(4,5,6)P3. Moreover, hITPK1 has >13,000-fold preference for Ins(3,4,5,6)P4 over its enantiomer, Ins(1,4,5,6)P4. The biological significance of hITPK1 being stereospecific, and not physiologically phosphorylating Ins(1,4,5,6)P4, is reinforced by our demonstrating that Ins(1,4,5,6)P4 is phosphorylated (K(m) = 0.18 microM) by inositolphosphate-multikinase.
authors.affiliation: Wolfson Laboratory for Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Riley
authors.forename: Sandrine
authors.initials: S
authors.lastname: Deleu
authors.forename: Xun
authors.initials: X
authors.lastname: Qian
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mitchell
authors.forename: Sung-Kee
authors.initials: SK
authors.lastname: Chung
authors.forename: Stephan
authors.initials: S
authors.lastname: Adelt
authors.forename: Günter
authors.initials: G
authors.lastname: Vogel
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Shears
mesh_terms: D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry*; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D007295:Inositol Phosphates; C081651:inositol-1,4,5,6-tetrakisphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C103909:inositol-tetrakisphosphate 1-kinase