Phosphatidylinositol phosphate kinases

Phosphatidylinositol phosphate kinases (PIPK) are kinases that phosphorylate the phosphoinositides PtdIns"P" and PtdIns"P"₂ that are derivatives of phosphatidylinositol (PtdIns). It has been found that PtdIns is only phosphorylated on three (3,4,5) of its five hydroxyl groups, possibly because D-2 and D-6 hydroxyl groups cannot be phosphorylated because of steric hindrance [Pettitt TR, Dove SK, Lubben A, Calaminus SDJ, Wakelam MJO. Analysis of intact phosphoinositides in biological samples. American Soc f Biochem and Mol Biol 2006; 47:1588-1596] . All 7 combinations of phosphorylated PtdIns have been found in animals, all except PtdIns(3,4,5)"P"₃ have been found in plants [Muller-Roeber B, Pical C. Inositol Phospholipid Metabolism in Arabidopsis. Characterized and Putative Isoforms of Inositol Phospholipid Kinase and Phosphoinositide-Specific Phospholipase C. Plant Physiol 2002 130:22–46] .

PIPKs are today divided into three groups, type I, II and III that share significant sequence homology but differ in the substrate specificities, subcellular localisations and functions. [Anderson RA, Boronenkov IV, Doughman SD, Kunz J, Loijens JC . Phosphatidylinositol phosphate kinases, a multifaceted family of signalling enzymes. J Biol Chem 1999; 274:9907-9910] Type 1 are PIPKs that phosphorylate PtdIns4"P" to PtdIns(4,5)"P"₂ and are called PtdIns4"P" 5-kinases because they phosphorylate on the D-5 hydroxyl group. Type II PIPKs phosphorylate PtdIns5"P" at the D-4 site and are called PtdIns5"P" 4-kinases. And finally PIPKs of type III are PtdIns3"P" 5-kinases that phosphorylate PtdIns to PtdIns(3,5)"P"₂, which prototype is Fab1 in yeast (see [http://jcs.biologists.org/content/vol114/issue12/images/large/JCS8533F1.jpeg] for destriptic picture). The substrate specificity of type I and II depends on the so called activation loop. The activation loop is a segment of 22 to 27 amino acid residues, located close to the C-terminal end of the catalytic domain in all PIPKs. When the activation loops of a type I and a type II PIPK were swapped, the chimera with type I backbone showed specificity for type II substrate, and vice versa for the other chimera [Kunz J, Wilson MP, Kisseleva M, Hurley JH, Majerus PW, Anderson RA. The activation loop of phosphatidylinositol phosphate kinases determines signaling specificity. Mol Cell 2000 5:1-11] .

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