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Review
. 2020 Oct 2;25(19):4515.
doi: 10.3390/molecules25194515.

Metabolism and Functions of Inositol Pyrophosphates: Insights Gained from the Application of Synthetic Analogues

Stephen B Shears  1 , Huanchen Wang  1
Affiliations
Review

Metabolism and Functions of Inositol Pyrophosphates: Insights Gained from the Application of Synthetic Analogues

Stephen B Shears et al. Molecules. .

Abstract

Inositol pyrophosphates (PP-InsPs) comprise an important group of intracellular, diffusible cellular signals that a wide range of biological processes throughout the yeast, plant, and animal kingdoms. It has been difficult to gain a molecular-level mechanistic understanding of the actions of these molecules, due to their highly phosphorylated nature, their low levels, and their rapid metabolic turnover. More recently, these obstacles to success are being surmounted by the chemical synthesis of a number of insightful PP-InsP analogs. This review will describe these analogs and will indicate the important chemical and biological information gained by using them.

Keywords: cell biology; energy; homeostasis; metabolism; phosphate.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The inositol pyrophosphate (PP-InsP) metabolic pathway. This graphic incorporates a proposal [1,2] that the pathway for 1,5-InsP8 turnover principally comprises a cyclical interconversion of InsP6, 5-InsP7, 1,5-InsP8, and 1-InsP7. ITPK1 = inositol 3,4,5,6-tetrakisphosphate 1-kinase; IP6K = inositol hexakisphosphate 5-kinase; PPIP5K = diphosphoinositol pentakisphosphate 1-kinase (in addition to hosting a self-contained kinase domain, this class of enzyme also contains a phosphatase domain that possesses 1,5-InsP8 1-phosphatase activity [2,3,4]); DIPP = diphosphoinositol polyphosphate phosphatase.
Figure 2
Figure 2
Metabolically stable bioisosteres of 5-InsP7. This figure shows synthetic analogs of 5-InsP7 in which the phosphoanhydride group is replaced with either (A) methylene-bisphosphonate (PCP), (B) phosphonoacetate (PA), (C) phosphonodifluoroacetamide.
Figure 3
Figure 3
PPIP5KKD has two substrate binding sites. X-ray crystallographic analysis of PPIP5KKD/5-PA-InsP7 crystal complexes uncovered two mutually exclusive ligand binding sites: (A) catalytic pocket; (B) substrate capture site. The protein is depicted in surface plot format, in which the intensity of the coloration (blue = positive, red = negative) corresponds to the degree of electrostatic polarization. The ligand is shown in stick form: carbon is green, phosphorous is orange, and oxygen is red.
Figure 4
Figure 4
The structure of a (A) caged 5-InsP7 and (B) its ‘prometabolite’.
See this image and copyright information in PMC

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