Last update 01 Nov 2024

IP6K2

Last update 01 Nov 2024

Basic Info

Synonyms

IHPK2, inositol hexakisphosphate kinase 2, InsP6 kinase 2

+ [4]

Introduction

Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5).

Drugs associated with IP6K2

SCO-006

Target

IP6K1 x IP6K2 x IP6K3

Mechanism

IP6K1 inhibitors [+2]

Active Org.

SCOHIA PHARMA, Inc.Startup

Originator Org.

Takeda Pharmaceutical Co., Ltd.

Active Indication

Ovarian clear cell carcinoma

Inactive Indication

Hyperphosphatemia

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

UNC7467

Target

IP6K1 x IP6K2

Mechanism

IP6K1 inhibitors [+1]

Active Org.

The University of North Carolina at Chapel Hill

Originator Org.

The University of North Carolina at Chapel Hill

Active Indication

Obesity

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with IP6K2

100 Translational Medicine associated with IP6K2

0 Patents (Medical) associated with IP6K2

Literatures (Medical) associated with IP6K2

01 Jul 2024·Clinical Pharmacology & Therapeutics

Phenotype–Genotype Correlation Applying a Cocktail Approach and an Exome Chip Analysis Reveals Further Variants Contributing to Variation of Drug Metabolism

Article

Author: Siegmund, Werner ; Bruckmueller, Henrike ; Böhm, Ruwen ; Höcker, Jan ; Cascorbi, Ingolf ; Kaehler, Meike ; Franke, Andre ; Hübenthal, Matthias ; Ehmke, Lena ; Oswald, Stefan

Although great progress has been made in the fine‐tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of pharmacogenetically relevant enzymes. The aim of this study was to analyze the additional contribution of sex and variants identified by exome chip analysis to the metabolic ratio of five probe drugs. A cocktail study applying dextromethorphan, losartan, omeprazole, midazolam, and caffeine was conducted on 200 healthy volunteers. CYP2D6, 2C9, 2C19, 3A4/5, and 1A2 genotypes were analyzed and correlated with metabolic ratios. In addition, an exome chip analysis was performed. These SNPs correlating with metabolic ratios were confirmed by individual genotyping. The contribution of various factors to metabolic ratios was assessed by multiple regression analysis. Genotypically predicted phenotypes defined by CPIC discriminated very well the log metabolic ratios with the exception of caffeine. There were minor sex differences in the activity of CYP2C9, 2C19, 1A2, and CYP3A4/5. For dextromethorphan (CYP2D6), IP6K2 (rs61740999) and TCF20 (rs5758651) affected metabolic ratios, but only IP6K2 remained significant after multiple regression analysis. For losartan (CYP2C9), FBXW12 (rs17080138), ZNF703 (rs79707182), and SLC17A4 (rs11754288) together with CYP diplotypes, and sex explained 50% of interindividual variability. For omeprazole (CYP2C19), no significant influence of CYP2C:TG haplotypes was observed, but CYP2C19 rs12777823 improved the predictability. The comprehensive genetic analysis and inclusion of sex in a multiple regression model significantly improved the explanation of variability of metabolic ratios, resulting in further improvement of algorithms for the prediction of individual phenotypes of drug‐metabolizing enzymes.

01 Apr 2024·Journal of Biological Chemistry

Insights into the roles of inositol hexakisphosphate kinase 1 (IP6K1) in mammalian cellular processes

Review

Author: Chakkour, Mohamed ; Greenberg, Miriam L

Inositol phosphates and their metabolites play a significant role in several biochemical pathways, gene expression regulation, and phosphate homeostasis. Among the different inositol phosphates, inositol hexakisphosphate (IP6) is a substrate of inositol hexakisphosphate kinases (IP6Ks), which phosphorylate one or more of the IP6 phosphate groups. Pyrophosphorylation of IP6 leads to the formation of inositol pyrophosphates, high-energy signaling molecules that mediate physiological processes through their ability to modify target protein activities, either by directly binding to their target protein or by pyrophosphorylating protein serine residues. 5-diphosphoinositol pentakisphosphate, the most abundant inositol pyrophosphate in mammals, has been extensively studied and found to be significantly involved in a wide range of physiological processes. Three IP6K (IP6K1, IP6K2, and IP6K3) isoforms regulate IP7 synthesis in mammals. Here, we summarize our current understanding of IP6K1's roles in cytoskeletal remodeling, trafficking, cellular migration, metabolism, gene expression, DNA repair, and immunity. We also briefly discuss current gaps in knowledge, highlighting the need for further investigation.

01 Apr 2024·Journal of the American Society of Nephrology

The Ip6k1 and Ip6k2 Kinases Are Critical for Normal Renal Tubular Function

Article

Author: Haykir, Betül ; Saiardi, Adolfo ; Qiu, Danye ; Prucker, Isabel ; Jessen, Henning J. ; Moser, Seraina Olivia ; Fiedler, Dorothea ; Hernando, Nati ; Schnitzbauer, Udo ; Wagner, Carsten A. ; Radvanyi, Zsuzsa ; Pastor-Arroyo, Eva Maria

Significance StatementKidneys are gatekeepers of systemic inorganic phosphate balance because they control urinary phosphate excretion. In yeast and plants, inositol hexakisphosphate kinases (IP6Ks) are central to regulate phosphate metabolism, whereas their role in mammalian phosphate homeostasis is mostly unknown. We demonstrate in a renal cell line and in mice that Ip6k1 and Ip6k2 are critical for normal expression and function of the major renal Na+/Pi transporters NaPi-IIa and NaPi-IIc. Moreover, Ip6k1/2 −/− mice also show symptoms of more generalized kidney dysfunction. Thus, our results suggest that IP6Ks are essential for phosphate metabolism and proper kidney function in mammals.BackgroundInorganic phosphate is an essential mineral, and its plasma levels are tightly regulated. In mammals, kidneys are critical for maintaining phosphate homeostasis through mechanisms that ultimately regulate the expression of the Na+/Pi cotransporters NaPi-IIa and NaPi-IIc in proximal tubules. Inositol pyrophosphate 5-IP7, generated by IP6Ks, is a main regulator of phosphate metabolism in yeast and plants. IP6Ks are conserved in mammals, but their role in phosphate metabolism in vivo remains unexplored.MethodsWe used in vitro (opossum kidney cells) and in vivo (renal tubular-specific Ip6k1/2 −/− mice) models to analyze the role of IP6K1/2 in phosphate homeostasis in mammals.ResultsIn both systems, Ip6k1 and Ip6k2 are responsible for synthesis of 5-IP7. Depletion of Ip6k1/2 in vitro reduced phosphate transport and mRNA expression of Na+/Pi cotransporters, and it blunts phosphate transport adaptation to changes in ambient phosphate. Renal ablation of both kinases in mice also downregulates the expression of NaPi-IIa and NaPi-IIc and lowered the uptake of phosphate into proximal renal brush border membranes. In addition, the absence of Ip6k1 and Ip6k2 reduced the plasma concentration of fibroblast growth factor 23 and increased bone resorption, despite of which homozygous males develop hypophosphatemia. Ip6k1/2 −/− mice also show increased diuresis, albuminuria, and hypercalciuria, although the morphology of glomeruli and proximal brush border membrane seemed unaffected.ConclusionsDepletion of renal Ip6k1/2 in mice not only altered phosphate homeostasis but also dysregulated other kidney functions.

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IP6K2

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