Towards pharmacological intervention in inositol pyrophosphate signalling

Shears, Stephen B.

doi:10.1042/bst20150184

Cited by 16 publications

(20 citation statements)

References 80 publications

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“…Inositol pyrophosphates regulate diverse cellular processes [19] , [20] , [21] , [22] , [23] . The most characterized inositol pyrophosphate in mammals, is 5-IP7, which is synthesized by a family of three inositol hexakisphosphate kinase enzymes, of which IP6K1 is the major isoform [19] , [24] , [25] .…”

Section: Introductionmentioning

confidence: 99%

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TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway

Ghoshal

Zhu

Asteian

et al. 2016

Molecular Metabolism

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ObjectiveObesity and type 2 diabetes (T2D) lead to various life-threatening diseases such as coronary heart disease, stroke, osteoarthritis, asthma, and neurodegeneration. Therefore, extensive research is ongoing to identify novel pathways that can be targeted in obesity/T2D. Deletion of the inositol pyrophosphate (5-IP7) biosynthetic enzyme, inositol hexakisphosphate kinase-1 (IP6K1), protects mice from high fat diet (HFD) induced obesity (DIO) and insulin resistance. Yet, whether this pathway is a valid pharmacologic target in obesity/T2D is not known. Here, we demonstrate that TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine], a pan-IP6K inhibitor, has strong anti-obesity and anti-diabetic effects in DIO mice.MethodsQ-NMR, GTT, ITT, food intake, energy expenditure, QRT-PCR, ELISA, histology, and immunoblot studies were conducted in short (2.5-week)- and long (10-week)-term TNP treated DIO C57/BL6 WT and IP6K1-KO mice, under various diet and temperature conditions.ResultsTNP, when injected at the onset of HFD-feeding, decelerates initiation of DIO and insulin resistance. Moreover, TNP facilitates weight loss and restores metabolic parameters, when given to DIO mice. However, TNP does not reduce weight gain in HFD-fed IP6K1-KO mice. TNP specifically enhances insulin sensitivity in DIO mice via Akt activation. TNP decelerates weight gain primarily by enhancing thermogenic energy expenditure in the adipose tissue. Accordingly, TNP's effect on body weight is partly abolished whereas its impact on glucose homeostasis is preserved at thermoneutral temperature.ConclusionPharmacologic inhibition of the inositol pyrophosphate pathway has strong therapeutic potential in obesity, T2D, and other metabolic diseases.

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Section: Introductionmentioning

confidence: 99%

“…Accordingly, TNP reduces 5-IP7 levels in various cells including adipocytes [19] , [32] , [45] , [54] , [56] , [57] . Furthermore, 5-IP7 is the precursor of PPIP5K mediated production of the higher inositol pyrophosphate 1,5-IP8 [22] , [55] . Accordingly, TNP reduces both 5-IP7 and 1,5-IP8 levels in NIH3T3 cells [58] .…”

Section: Introductionmentioning

confidence: 99%

TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway

Ghoshal

Zhu

Asteian

et al. 2016

Molecular Metabolism

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“…Inositol phosphate kinases (IP3K, IPMK, ITPK1, IP5K, IP6K and PPIP5K) perform numerous biological processes through their participation in a carefully-regulated, metabolic network that converts phospholipase C-derived Ins(1,4,5)P 3 into an array of more highly phosphorylated cell-signaling molecules [ 1 – 3 ]. Among these metabolites, considerable attention is currently being focused upon the inositol pyrophosphates (PP-InsPs), the distinguishing feature of which is the possession of ‘high-energy’ diphosphate groups at the 1- and/or 5-positions of the six carbons that comprise the inositol ring [ 3 , 4 ]. Multiple and diverse cellular activities have been attributed to the PP-InsPs, but an over-arching hypothesis views them as acting as an interface between energy metabolism and cell-signaling [ 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors

Baughman

Wang

et al. 2016

PLoS ONE

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Pharmacological tools—‘chemical probes’—that intervene in cell signaling cascades are important for complementing genetically-based experimental approaches. Probe development frequently begins with a high-throughput screen (HTS) of a chemical library. Herein, we describe the design, validation, and implementation of the first HTS-compatible strategy against any inositol phosphate kinase. Our target enzyme, PPIP5K, synthesizes ‘high-energy’ inositol pyrophosphates (PP-InsPs), which regulate cell function at the interface between cellular energy metabolism and signal transduction. We optimized a time-resolved, fluorescence resonance energy transfer ADP-assay to record PPIP5K-catalyzed, ATP-driven phosphorylation of 5-InsP7 to 1,5-InsP8 in 384-well format (Z’ = 0.82 ± 0.06). We screened a library of 4745 compounds, all anticipated to be membrane-permeant, which are known—or conjectured based on their structures—to target the nucleotide binding site of protein kinases. At a screening concentration of 13 μM, fifteen compounds inhibited PPIP5K >50%. The potency of nine of these hits was confirmed by dose-response analyses. Three of these molecules were selected from different structural clusters for analysis of binding to PPIP5K, using isothermal calorimetry. Acceptable thermograms were obtained for two compounds, UNC10112646 (Kd = 7.30 ± 0.03 μM) and UNC10225498 (Kd = 1.37 ± 0.03 μM). These Kd values lie within the 1–10 μM range generally recognized as suitable for further probe development. In silico docking data rationalizes the difference in affinities. HPLC analysis confirmed that UNC10225498 and UNC10112646 directly inhibit PPIP5K-catalyzed phosphorylation of 5-InsP7 to 1,5-InsP8; kinetic experiments showed inhibition to be competitive with ATP. No other biological activity has previously been ascribed to either UNC10225498 or UNC10112646; moreover, at 10 μM, neither compound inhibits IP6K2, a structurally-unrelated PP-InsP kinase. Our screening strategy may be generally applicable to inhibitor discovery campaigns for other inositol phosphate kinases.

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“…Moreover, IP6K1-KO mice are lean due to enhanced energy expenditure as energy intake is unaltered in these mice (Chakraborty A, 2010). Therefore, IP6K1 is a target in obesity/T2D (Boucher J, 2014; Chakraborty A, 2011; Mackenzie RW, 2014; Shears, 2016). However, the precise mechanism/s by which IP6K1 regulates lipid metabolism in not known.…”

Section: Introductionmentioning

confidence: 99%

Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis

Ghoshal

Tyagi

Zhu

et al. 2016

The International Journal of Biochemistry & Cell Biology

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Lipolysis leads to the breakdown of stored triglycerides (TAG) to release free fatty acids (FFA) and glycerol which is utilized by energy expenditure pathways to generate energy. Therefore, a decrease in lipolysis augments fat accumulation in adipocytes which promotes weight gain. Conversely, if lipolysis is not complemented by energy expenditure, it leads to FFA induced insulin resistance and type-2 diabetes. Thus, lipolysis is under stringent physiological regulation although, the precise mechanism of the regulation is not known. Deletion of inositol hexakisphosphate kinase-1 (IP6K1), the major inositol pyrophosphate biosynthetic enzyme, protects mice from high fat diet (HFD) induced obesity and insulin resistance. IP6K1-KO mice are lean due to enhanced energy expenditure. Therefore, IP6K1 is a target in obesity and type-2 diabetes. However, the mechanism/s by which IP6K1 regulates adipose tissue lipid metabolism is yet to be understood. Here, we demonstrate that IP6K1-KO mice display enhanced basal lipolysis. IP6K1 modulates lipolysis via its interaction with the lipolytic regulator protein perilipin1 (PLIN1). Furthermore, phosphorylation of IP6K1 at a PKC/PKA motif modulates its interaction with PLIN1 and lipolysis. Thus, IP6K1 is a novel regulator of PLIN1 mediated lipolysis.

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Towards pharmacological intervention in inositol pyrophosphate signalling

Cited by 16 publications

References 80 publications

TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway

TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway

A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors

Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis

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