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Review
. 2009;49(1):87-96.
doi: 10.1016/j.advenzreg.2008.12.008. Epub 2009 Jan 3.

Molecular basis for the integration of inositol phosphate signaling pathways via human ITPK1

Stephen B Shears  1
Affiliations
Review

Molecular basis for the integration of inositol phosphate signaling pathways via human ITPK1

Stephen B Shears. Adv Enzyme Regul. 2009.
No abstract available

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Figures

Fig. 1
Fig. 1
The structures of Ins(3,4,5,6)P4 and Ins(1,3,4,5,6)P5. The myo-inositol building block is a ring structure made from six carbon groups, each of which has a free hydroxyl. The hydroxyl attached to the 2-carbon is axial (perpendicular) to the plane of the ring, and the remaining hydroxyls are equatorial (i.e. approximately in the same plane as the ring). The carbons are numbered in an anticlockwise direction when the ring is viewed from above. Substitution of four of the hydroxyls with phosphates at positions 3, 4, 5 and 6 produces inositol 3,4,5,6-tetrakisphosphate. The standard abbreviation for this polyphosphate – Ins(3,4,5,6)P4 – therefore reflects the recognition by inositol phosphate nomenclature of the number of phosphate groups (denoted by the subscript), as well as their positions around the inositol ring.
Fig. 2
Fig. 2
The metabolic link between Ins(1,4,5)P3 and Ins(1,3,4,5,6)P5 in animal cells. The figure shows the quantitatively most important reactions in animal cells that link Ins(1,4,5)P3 to Ins(1,3,4,5,6)P5. Numbers in the figure refer to various enzymes as follows: 1. Ins(1,4,5)P3 3-kinase (EC 2.7.1.127); 2. Ins(1,4,5)P3/Ins(1,3,4,5)P4 5-phosphatase (EC 3.1.3.56); 3. ITPK1 (EC 2.7.1.134); 4. Inositol phosphate multikinase (EC 2.7.1.151); note that kinetic data have led to it being questioned whether IPMK can contribute significantly to Ins(1,3,4,5)P4 synthesis de novo in animal cells (Chang et al., 2002).
Fig. 3
Fig. 3
The phosphotransferase activity of ITPK1. The graphic illustrates the proposed enzymatic reactions by which the 1-phosphate on Ins(1,3,4,5,6)P5 (coloured red) is transferred to Ins(1,3,4)P3. The evidence for this reaction pathway came from HPLC analysis of the reaction products following the metabolism of [1-32P]-Ins(1,3,4,5,6)P5 by ITPK1 (Chamberlain et al., 2007). It has not yet been established whether or not a phosphoryl-enzyme (E–P) intermediate is involved, but this is a likely possibility.
Fig. 4
Fig. 4
A model for the structural determinants of ligand specificity for mamalian ITPK1. The figure depicts our proposal (Ho et al., 2002; Riley et al., 2006) that there are three modes of binding of inositol phosphates to mamalian ITPK1. It can be illuminating to consider these different binding modes (i.e., “1”, “2” and “3”) as permitting 1-kinase, 6-kinase and 5-kinase activities, respectively. These phosphorylation sites are marked with a yellow circle. Three groups in Ins(3,4,5,6)P4, Ins(1,3,4)P3 and Ins(1,2,4)P3 (coloured red) are conserved in all three of these proposed binding modes. We have previously noted that these groups by themselves are insufficient to designate substrate specificity, so we have proposed a combinatorial recognition model in which some of the additional groups (coloured green) contribute to ligand recognition, but in a mode-specific manner.
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