更新于：2024-11-01

IP6K2

更新于：2024-11-01

基本信息

别名

IHPK2、inositol hexakisphosphate kinase 2、InsP6 kinase 2

+ [4]

简介

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

关联

项与 IP6K2 相关的药物

SCO-006

靶点

IP6K1 x IP6K2 x IP6K3

作用机制

IP6K1抑制剂 [+2]

在研机构

SCOHIA PHARMA, Inc.初创企业

原研机构

Takeda Pharmaceutical Co., Ltd.

在研适应症

卵巢透明细胞癌

非在研适应症

高磷血症

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

UNC7467

靶点

IP6K1 x IP6K2

作用机制

IP6K1抑制剂 [+1]

在研机构

The University of North Carolina at Chapel Hill

原研机构

The University of North Carolina at Chapel Hill

在研适应症

肥胖

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 IP6K2 相关的临床结果

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100 项与 IP6K2 相关的转化医学

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0 项与 IP6K2 相关的专利（医药）

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项与 IP6K2 相关的文献（医药）

2024-07-01·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

作者: 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.

2024-04-01·Journal of Biological Chemistry

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

Review

作者: 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.

2024-04-01·Journal of the American Society of Nephrology

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

Article

作者: 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.