Abstract
Inositol phosphates (InsPs) are signaling molecules with multiple roles in cells. In particular (InsP(6)) is involved in mRNA export and editing or chromatin remodeling among other events. InsP(6) accumulates as mixed salts (phytate) in storage tissues of plants and plays a key role in their physiology. Human diets that are exclusively grain-based provide an excess of InsP(6) that, through chelation of metal ions, may have a detrimental effect on human health. Ins(1,3,4,5,6)P(5) 2-kinase (InsP(5) 2-kinase or Ipk1) catalyses the synthesis of InsP(6) from InsP(5) and ATP, and is the only enzyme that transfers a phosphate group to the axial 2-OH of the myo-inositide. We present the first structure for an InsP(5) 2-kinase in complex with both substrates and products. This enzyme presents a singular structural region for inositide binding that encompasses almost half of the protein. The key residues in substrate binding are identified, with Asp368 being responsible for recognition of the axial 2-OH. This study sheds light on the unique molecular mechanism for the synthesis of the precursor of inositol pyrophosphates.
Highlights
Inositol phosphates (InsPs) are signaling molecules with multiple roles in cells
The family of enzymes that catalyzes the phosphorylation of IP5 to form IP6 are known as Ipk1, after the ortholog first identified in yeast [3] or InsP5 2-kinases (IP5 2-Ks), after the enzyme activity characterized from various sources [19,20,21,22,23,24]
IP5 2-Ks are unique among inositol phosphate kinases (InsP Ks) in that they phosphorylate the axial 2-position of the myo-inositide ring, whereas the other enzymes act on equatorial positions of the ring
Summary
Inositol phosphates (InsPs) are signaling molecules with multiple roles in cells. In particular Insð1,2,3,4,5,6ÞP6 (InsP6) is involved in mRNA export and editing or chromatin remodeling among other events. The family of enzymes that catalyzes the phosphorylation of IP5 to form IP6 are known as Ipk, after the ortholog first identified in yeast [3] or InsP5 2-kinases (IP5 2-Ks), after the enzyme activity characterized from various sources [19,20,21,22,23,24]. It is only recently, that important physiological roles other than a biosynthetic enzyme have been ascribed to IP5 2-K. IP5 2-K structure reveals key features of IPKs that elucidate the functionality of this essential family of enzymes
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