Inositol polyphosphate multikinase

Definition:

Inositol phosphate kinase with a broad substrate specificity. Phosphorylates inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) first to inositol 1,3,4,5-tetrakisphosphate and then to inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5). Phosphorylates inositol 1,3,4,6-tetrakisphosphate (Ins(1,3,4,6)P4). Phosphorylates glycero-3-phospho-1D-myo-inositol 4,5-bisphosphate to glycero-3-phospho-1D-myo-inositol 3,4,5-trisphosphate. Plays an important role in MLKL-mediated necroptosis via its role in the biosynthesis of inositol pentakisphosphate (InsP5) and inositol hexakisphosphate (InsP6). Binding of these highly phosphorylated inositol phosphates to MLKL mediates the release of an N-terminal auto-inhibitory region, leading to activation of the kinase. Essential for activated phospho-MLKL to oligomerize and localize to the cell membrane during necroptosis. Required for normal embryonic development, probably via its role in the biosynthesis of inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) and inositol hexakisphosphate (InsP6) (By similarity).

References:

[1]. Cole M Dovey, et al. MLKL Requires the Inositol Phosphate Code to Execute Necroptosis. Mol Cell. 2018 Jun 7;70(5):936-948.e7. [Content Brief]

[2]. Chunfang Gu, et al. Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis. J Med Chem. 2019 Feb 14;62(3):1443-1454. [Content Brief]

[3]. Corey D Seacrist, et al. Crystallographic and kinetic analyses of human IPMK reveal disordered domains modulate ATP binding and kinase activity. Sci Rep. 2018 Nov 12;8(1):16672. [Content Brief]

[4]. Shao-Chun Chang, et al. The human homolog of the rat inositol phosphate multikinase is an inositol 1,3,4,6-tetrakisphosphate 5-kinase. J Biol Chem. 2002 Nov 15;277(46):43836-43. [Content Brief]

[5]. Marcus M Nalaskowski, et al. The human homologue of yeast ArgRIII protein is an inositol phosphate multikinase with predominantly nuclear localization. Biochem J. 2002 Sep 1;366(Pt 2):549-56. [Content Brief]

[6]. Huanchen Wang, et al. Structural features of human inositol phosphate multikinase rationalize its inositol phosphate kinase and phosphoinositide 3-kinase activities. J Biol Chem. 2017 Nov 3;292(44):18192-18202. [Content Brief]

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