Reference: Lin H, et al. (2009) Structural Analysis and Detection of Biological Inositol Pyrophosphates Reveal That the Family of VIP/Diphosphoinositol Pentakisphosphate Kinases Are 1/3-Kinases. J Biol Chem 284(3):1863-72

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Abstract


We have characterized the positional specificity of the mammalian and yeast VIP/PPIP5K family of inositol phosphate kinases. We deployed a micro-scale metal-dye detection protocol coupled to a high-performance liquid chromatography system that was calibrated with synthetic and biologically-synthesized standards of inositol pyrophosphates. In addition, we have directly analyzed the structures of biological inositol pyrophosphates using two-dimensional 1H-1H and 1H-31P nuclear magnetic resonance spectroscopy. Using these tools, we have determined that the mammalian and yeast VIP/PPIP5K family phosphorylate the 1/3-position of the inositol ring in vitro and in vivo. For example, the VIP/PPIP5K enzymes convert inositol hexakisphosphate to 1/3-diphosphoinositol pentakisphosphate. The latter compound has not previously been identified in any organism. We have also unequivocally determined that 1/3,5-(PP)2-IP4 is the isomeric structure of the bis-diphosphoinositol tetrakisphosphate that is synthesized by yeasts and mammals, through a collaboration between the IP6K and VIP/PPIP5K enzymes. These data uncover phylogenetic variability within the crown taxa in the structures of inositol pyrophosphates. For example, in the Dictyostelids the major bis-diphosphoinositol tetrakisphosphate is 5,6-(PP)2-IP4 (Laussmann et al., Biochem. J. 1996 315 715-720). Our study brings us closer to the goal of understanding the structure/function relationships that control specificity in the synthesis and biological actions of inositol pyrophosphates.

Reference Type
Journal Article
Authors
Lin H, Fridy PC, Ribeiro AA, Choi JH, Barma DK, Vogel G, Falck JR, Shears SB, York JD, Mayr GW
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