IPK domeeni ja kromatiinin kypsyminen, IP6K2

 Sofistinen juttu histonien asteittaisesta kypsymisestä,  jossa on   myöhäinen deasetylaatiovaihe  histonien kypsymisessä ja siinä vaikuttaa olevan osuutta HDAC kaltaisesti toimivalla   IP6K2;n arginiinipitoisella   domeenilla. ( oma päätelmäni, mutta en löydä suoria  "valokuvia" asiasta) ihmiseltä.

https://www.ncbi.nlm.nih.gov/pubmed/31172592

J Cell Biochem. 2019 Jun 6. doi: 10.1002/jcb.29147. [Epub ahead of print]

Quercetin modifies 5'CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells.

Kedhari Sundaram M¹, Hussain A¹, Haque S², Raina R¹, Afroze N¹.

 Abstract
The central role of epigenomic alterations in carcinogenesis has been widely acknowledged, particularly the impact of DNA methylation on gene expression across all stages of carcinogenesis is considered vital for both diagnostic and therapeutic strategies. Dietary phytochemicals hold great promise as safe anticancer agents and effective epigenetic modulators. This study was designed to investigate the potential of a phytochemical, quercetin as a modulator of the epigenetic pathways for anticancer strategies. Biochemical activity of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and global genomic DNA methylation was quantitated by an enzyme-linked immunosorbent assay based assay in quercetin-treated HeLa cells. Molecular docking studies were performed to predict the interaction of quercetin with DNMTs and HDACs. Quantitative methylation array was used to assess quercetin-mediated alterations in the promoter methylation of selected tumor suppressor genes (TSGs). Quercetin induced modulation of chromatin modifiers including DNMTs, HDACs, histone acetyltransferases (HAT) and HMTs, and TSGs were assessed by quantitative reverse transcription PCR (qRT-PCR). It was found that quercetin modulates the expression of various chromatin modifiers and decreases the activity of DNMTs, HDACs, and HMTs in a dose-dependent manner. Molecular docking results suggest that quercetin could function as a competitive inhibitor by interacting with residues in the catalytic cavity of several DNMTs and HDACs. Quercetin downregulated global DNA methylation levels in a dose- and time-dependent manner. The tested TSGs showed steep dose-dependent decline in promoter methylation with the restoration of their expression. Our study provides an understanding of the quercetin's mechanism of action and will aid in its development as a candidate for epigenetic-based anticancer therapy.

A Class II Histone Deacetylase Acts on Newly Synthesized Histones in ...

https://ec.asm.org/content/7/3/471

- Översätt den här sidan

av JJ Smith - ‎2008 - ‎Citerat av 12 - ‎Relaterade artiklar

Most systems share the difficulty of separating chromatin maturation-related from ..... Thd2 is a class II HDAC with a putative IPK domain similar to Ipk2.

Kommentti: ...hiivan . (ArgRIII) ..ihmisellä IPKL domeeni, joka on arginiinipitoinen , IP6K2 entsyymin domeeni.

Front Oncol. 2019 May 22;9:432. doi: 10.3389/fonc.2019.00432. eCollection 2019. Intersection of Epigenetic and Metabolic Regulation of Histone Modifications in Acute Myeloid Leukemia.

Dhall A¹, Zee BM¹, Yan F², Blanco MA². Abstract

Acute myeloid leukemia (AML) is one of the most lethal blood cancers, accounting for close to a quarter of a million annual deaths worldwide. Even though genetically heterogeneous, all AMLs are characterized by two interrelated features-blocked differentiation and high proliferative capacity. Despite significant progress in our understanding of the molecular and genetic basis of AML, the treatment of AMLs with chemotherapeutic regimens has remained largely unchanged in the past 30 years. In this review, we will consider the role of two cellular processes, metabolism and epigenetics, in the development and progression of AML and highlight the studies that suggest an interconnection of therapeutic importance between the two. Large-scale whole-exome sequencing of AML patients has revealed the presence of mutations, translocations or duplications in several epigenetic effectors such as DNMT3, MLL, ASXL1, and TET2, often times co-occuring with mutations in metabolic enzymes such as IDH1 and IDH2. These mutations often result in impaired enzymatic activity which leads to an altered epigenetic landscape through dysregulation of chromatin modifications such as DNA methylation, histone acetylation and methylation. We will discuss the role of enzymes that are responsible for establishing these modifications, namely histone acetyl transferases (HAT), histone methyl transferases (HMT), demethylases (KDMs), and deacetylases (HDAC), and also highlight the merits and demerits of using inhibitors that target these enzymes. Furthermore, we will tie in the metabolic regulation of co-factors such as acetyl-CoA, SAM, and α-ketoglutarate that are utilized by these enzymes and examine the role of metabolic inhibitors as a treatment option for AML. In doing so, we hope to stimulate interest in this topic and help generate a rationale for the consideration of the combinatorial use of metabolic and epigenetic inhibitors for the treatment of AML.   KEYWORDS:

AML—acute myeloid leukaemia; HDACs; epigenetics (methylation/demethylation); histone methlyation; metabolism

Orgaanisen fosforin ja epäorgaanisten fosfaattien pitoisuudesta ravinnossa. Vaikutus seerumin fosfaattiin.

Am J Clin Nutr. 2015 Aug;102(2):444-53. doi: 10.3945/ajcn.114.102715. Epub 2015 Jun 3. Association of dietary phosphate and serum phosphorus concentration by levels of kidney function.

Moore LW¹, Nolte JV², Gaber AO², Suki WN³. Abstract BACKGROUND:

The health implications of dietary phosphorus intake and the role of kidney function in managing serum phosphorus homeostasis are well studied. However, examining the source of dietary phosphorus intake and its impact on serum phosphorus has not been characterized in population studies. OBJECTIVE:
This study aimed to distinguish the association of food sources of organic phosphorus and inorganic phosphate additives with serum phosphorus concentration.
 DESIGN:
A cross-sectional analysis of 24-h food recall data from 7895 adult participants in the National Health and Nutrition Examination Survey 2003-2006 was performed. Phosphorus content of foods was categorized as organic or inorganic. Correlations of serum phosphorus to clinical and dietary intake variables were achieved by using multiple regression analysis.
RESULTS:
After controlling for estimated glomerular filtration rate (eGFR), body mass index (BMI; in kg/m²), and albumin-to-creatinine ratio, a significant increase in serum phosphorus occurred with dairy foods with inorganic phosphates [parameter estimate (PE) ± SE: 0.07 ± 0.02 mg/dL, P < 0.01] or without inorganic phosphates (PE: 0.02 ± 0.01, P < 0.001) and cereals/grains with inorganic phosphates (PE: 0.005 ± 0.002, P < 0.01). Significantly higher serum phosphorus occurred when eGRF was <30 -0.09="" -0.10="" -0.11="" 0.0001="" 0.01="" 0.03="" 0.04="" 0.05="" 0.08="" 0.18="" 0.24="" 30-44="" 45-60="" and="" associated="" bmi="" but="" egfr="" higher="" lower="" or="" p="0.014). </p" phosphorus="" serum="" was="" were="" with="">CONCLUSIONS:
This analysis shows that dairy products and cereals/grains having inorganic phosphate additives significantly increase serum phosphorus concentration, despite being consumed less frequently than foods without phosphate additives. It seems prudent for the Nutrient Facts Label to include phosphorus but also for food manufacturers to consider alternatives to phosphate additives.
TRIAL REGISTRATION:
ClinicalTrials.gov NCT02435017.

© 2015 American Society for Nutrition.

KEYWORDS:
body mass index; chronic kidney disease; diet; dietary phosphorus; kidney disease

Comment in

• Studying dietary phosphorus intake: the challenge of when a gram is not a gram. [Am J Clin Nutr. 2015]
  
  J Ren Nutr. 2017 Mar;27(2):97-105. doi: 10.1053/j.jrn.2016.08.009. Epub 2016 Oct 14.
  
  Replacing Phosphorus-Containing Food Additives With Foods Without Additives Reduces Phosphatemia in End-Stage Renal Disease Patients: A Randomized Clinical Trial.
  de Fornasari ML¹, Dos Santos Sens YA².AbstractOBJECTIVE:
  The purpose of the study was to verify the effects of replacing phosphorus-containing food additives with foods without additives on phosphatemia in end-stage renal disease (ESRD) patients. DESIGN:
  Randomized clinical trial.SETTING:
  Adult patients on hemodialysis for ≥6 months at a single center. SUBJECTS:
  A total of 134 patients with phosphorus levels of >5.5 mg/dL were included and were randomized into an intervention group (n = 67) and a control group (n = 67). INTERVENTION:
  The IG received individual orientation to replace processed foods that have phosphorus additives with foods of similar nutritional value without these additives. The CG received only the nutritional orientation given before the study. Clinical laboratory data, nutritional status, energy and protein intake, and normalized protein nitrogen appearance (nPNA) were evaluated at the beginning of the study and after 90 days. RESULTS:
  There was no initial difference between the groups in terms of serum phosphorus levels, nutritional status, and energy intake. After 3 months, there was a decline in phosphorus levels in the IG (from 7.2 ± 1.4 to 5.0 ± 1.3 mg/dL, P < .001), but there was no significant difference in the CG (from 7.1 ± 1.2 to 6.7 ± 1.2 mg/dL, P = .65). In the IG, 69.7% of the patients reached the serum phosphorus target of ≤5.5 mg/dL; however, only 18.5% of the CG subjects reached this level (P < .001). CONCLUSION: At the end, there was no difference between the two groups in terms of nutritional status, energy intake, protein intake, and nPNA. The replacing phosphorus-containing food additives with foods without additives reduced serum phosphorus without interfering in the nutritional status of ESRD patients.
  

  Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.PMID: 27751628 DOI: 10.1053/j.jrn.2016.08.009
  
  
  
  Jos minulta kysyttäisiin, miten käytännössä voi tasapainotaa tätä orgaanista ja epäorgaanista  fosfaatinsaantiaan, sanoisin  neuvon jota itse noudatan kautta vuoden:  Vältän hiivalla leipomista. Harvoin ostan hiivalla leivottua leipää. Mielelläni käytän  hiilihydraattina  keitettyä riisiä, riisi- ja maissikeksiä , myslejä, tattaripuuroa,  kuivia hedelmiä , tuorehedelmiä, perunaa. Voin olla  itse koko vuoden käyttämättä hiivaa, mutta teen kyllä simaa vapuksi hiivalla.
  ... Hiiva nimittäin rikkoo fytiinin IP6  alemmiksi fosfaattimuodoiksi ja lopulta inositoliksi ja epäorgaaniseksi fosfaatiksi, jolloin  IP6:n antioksidanttista ja munuaisedullsita vaikutusta ei enää dieetistä  ole.
  Toinen tapa nostaa fytiinin saantia on nuo pähkinät , jyvät,  ym joita ei ole hiivalla hajoitettu.
  Fytiiniä on  monissa  kasviperäisissä ruoissa,  kaakaossakin.  ( Tässä blogissa on taulukkoja Spiller A Gene) .
  Samalla kun vältän hiivaa ja siitä tulevaa orgaanista  fosforia, koetan välttää myös bikarbonaattia, vaikka  sitä on vaikea välttää keliakiadieetissä, koska kaikki valmisjauhot  sisältävät natriumbikarbonaattia.  Jos tekee kakkuja tai torttuja, niihin  kyllä tulee bikarbonaattia, mutta  ei niitä tarvitse usein tehdä., juhliin vain.
  Valkoisen sokerin käytön koetan minimoida, sillä valkoinen sokeri kilpailee kovasti inositolin kanssa soluun pääsystä ja sokeri voittaa inositolin, varsinkin liikasokeri, joka lisäksi vähentää magnesiumpitoisuutta solusta.
  Kuitenkin näen aivan  mahdottomaksi  antaa tällaisia neuvoja, koska  esim  vehnäpulla ja kohotettu  leipä  on  perustava elintarvike   Pohjolassa.
  Minulla on tietysti  vahva motivaatio, joka auttaa pitämään  tällaista dieettiperiaatetta läpi vuoden:    verenpaine, joka  helposti nousee ja  munuaistoiminta, joka vaikuttaa  vuosien varrella hieman   alamäkiseltä.  Joudun myös  pitämään  vähäsuolaista  dieettiä ruokasuolan suhteen ja  hyvin vahvasti  mineraalipitoista  kasvisperäisen  kaliumin ja magnesiumin suhteen, joita saan hedelmistä, jotta kalium pysyy normaalin puolella eikä  menety liikaa.. Minun ei mistään tableteista kuitenkaan kannata kaliuma
• ia ottaa, koska niitä on  runsaasti tietyissä ravinteissa (mm.  kuivahedelmät, viikuna, taateli, luumu , pähkinät, mantelit) .
  
  
   

IP6K2 ja PPIP5K. Vaikutus solusykliin, p53:een ja bioenergeettisen tasapainoon

1. PPIP5K

KO of 5-InsP₇ kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype.

Gu C, Nguyen HN, Ganini D, Chen Z, Jessen HJ, Gu Z, Wang H, Shears SB.

Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11968-11973. doi: 10.1073/pnas.1702370114. Epub 2017 Oct 25. Abstract

The inositol pyrophosphates 5-InsP₇ (diphosphoinositol pentakisphosphate) and 1,5-InsP₈ (bis-diphosphoinositol tetrakisphosphate) are highly energetic cellular signals interconverted by the diphosphoinositol pentakisphosphate kinases (PPIP5Ks). 
Here, we used CRISPR to KO PPIP5Ks in the HCT116 colon cancer cell line. This procedure eliminates 1,5-InsP₈ and raises 5-InsP₇ levels threefold. Expression of p53 and p21 was up-regulated; proliferation and G1/S cell-cycle transition slowed. Thus, PPIP5Ks are potential targets for tumor therapy. Deletion of the PPIP5Ks elevated [ATP] by 35%; both [ATP] and [5-InsP₇] were restored to WT levels by overexpression of PPIP5K1, and a kinase-compromised PPIP5K1 mutant had no effect. This covariance of [ATP] with [5-InsP₇] provides direct support for an energy-sensing attribute (i.e., 1 mM K_m for ATP) of the 5-InsP₇-generating inositol hexakisphosphate kinases (IP6Ks). We consolidate this conclusion by showing that 5-InsP₇ levels are elevated on direct delivery of ATP into HCT116 cells using liposomes. Elevated [ATP] in PPIP5K^-/- HCT116 cells is underpinned by increased mitochondrial oxidative phosphorylation and enhanced glycolysis. To distinguish between 1,5-InsP₈ and 5-InsP₇ as drivers of the hypermetabolic and p53-elevated phenotypes, we used IP6K2 RNAi and the pan-IP6K inhibitor, N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl) purine (TNP), to return 5-InsP₇ levels in PPIP5K^-/- cells to those of WT cells without rescuing 1,5-InsP₈ levels. Attenuation of IP6K restored p53 expression but did not affect the hypermetabolic phenotype. Thus, we conclude that 5-InsP₇ regulates p53 expression, whereas 1,5-InsP₈ regulates ATP levels. These findings attribute hitherto unsuspected functionality for 1,5-InsP₈ to bioenergetic homeostasis.

Published under the PNAS license.

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Select item 224469642.

Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles.

Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C, Vannberg FO, Knight JC.

Nat Genet. 2012 Mar 25;44(5):502-10. doi: 10.1038/ng.2205.

-- Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 (znf) in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10(-15)), PRIC285 (P = 3.0 × 10(-10)) and an upstream region of CDKN1A (P = 2 × 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis.Free PMC Article

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Select item 210789643.

p53-mediated apoptosis requires inositol hexakisphosphate kinase-2.

Koldobskiy MA, Chakraborty A, Werner JK Jr, Snowman AM, Juluri KR, Vandiver MS, Kim S, Heletz S, Snyder SH.

Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20947-51. doi: 10.1073/pnas.1015671107. Epub 2010 Nov 15.

Inositol pyrophosphates (PP-InsPx)  have been implicated in numerous biological processes.

 Inositol hexakisphosphate kinase-2 (IP6K2), which generates the inositol pyrophosphate , PP-IP5, diphosphoinositol pentakisphosphate (IP7), influences apoptotic cell death. The tumor suppressor p53 responds to genotoxic stress by engaging a transcriptional program leading to cell-cycle arrest or apoptosis. 

We demonstrate that IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21.Free PMC Article

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Select item 113374974.

Inositol hexakisphosphate (IP6)kinase 2 mediates growth suppressive and apoptotic effects of interferon-beta in ovarian carcinoma cells.

Morrison BH, Bauer JA, Kalvakolanu DV, Lindner DJ.

J Biol Chem. 2001 Jul 6;276(27):24965-70. Epub 2001 May 3. Abstract

Interferons (IFNs) regulate the expression of genes that mediate their antiviral, antitumor, and immunomodulatory actions. We have previously shown that IFN-beta suppresses growth of human ovarian carcinoma xenografts in vivo and induces apoptosis of ovarian carcinoma cells in vitro. To investigate mechanisms of IFN-beta-induced apoptosis we employed an antisense technical knockout approach to identify gene products that mediate cell death and have isolated several regulators of interferon-induced death (RIDs). In this investigation, we have characterized one of the RIDs, RID-2. Sequence analysis revealed that RID-2 was identical to human inositol hexakisphosphate kinase 2 (IP6K2). IP6K2 is post-transcriptionally induced by IFN-beta in ovarian carcinoma cells. A mutant IP6K2 with substitutions in the putative inositol phosphate binding domain abrogates IFN-beta-induced apoptosis. These studies identify a novel function for IP6K2 in cell growth regulation and apoptosis.

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 https://www.ncbi.nlm.nih.gov/pubmed/29512757

IPK ja kromatiinin kypsyminen

A Class II Histone Deacetylase Acts on Newly Synthesized Histones in ...

https://ec.asm.org/content/7/3/471

- Översätt den här sidan

av JJ Smith - ‎2008 - ‎Citerat av 12 - ‎Relaterade artiklar

Most systems share the difficulty of separating chromatin maturation-related from ..... Thd2 is a class II HDAC with a putative IPK domain similar to Ipk2. (A) ..

.

IP6K1 ja IP6K2 poistogeenisyystutkimustuloksia. Ins-PP aineenvaihdunta

The inositol hexakisphosphate kinases IP6K1 and -2 regulate human cellular phosphate homeostasis, including XPR1-mediated phosphate export.

Wilson MS, Jessen HJ, Saiardi A.

J Biol Chem. 2019 Jun 11. pii: jbc.RA119.007848. doi: 10.1074/jbc.RA119.007848. [Epub ahead of print] PMID: 31186349

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Phosphate's central role in most biochemical reactions in a living organism requires carefully maintained phosphate homeostasis. Although phosphate homeostasis in mammals has long been studied at the organismal level, the intracellular mechanisms controlling phosphate metabolism are not well understood. Inositol pyrophosphates (PP-IPx)  have emerged as important regulatory elements controlling yeast phosphate homeostasis. To verify whether inositol pyrophosphates also regulate mammalian cellular phosphate homeostasis, here we knocked out inositol hexakisphosphate kinase (IP6K) 1 and IP6K2 to generate human HCT116 cells devoid of any inositol pyrophosphates. Using  PAGE and HPLC analysis, we observed that the IP6K1/2-knockout cells have non-detectable levels of the IP₆-derived IP₇ and IP₈ and also exhibit reduced synthesis of the IP₅-derived PP-IP₄ Nucleotide analysis showed that the knockout cells contain increased amounts of ATP, while the Malachite green assay found elevated levels of free intracellular phosphate. Furthermore, [³²Pi] pulse labeling experiments uncovered alterations in phosphate flux, with both import and export of phosphate being decreased in the knockout cells. Functional analysis of the phosphate exporter xenotropic and polytropic retrovirus receptor 1 (XPR1) revealed that it is regulated by inositol pyrophosphates, which can bind to its SPX domain. We conclude that IP6K1 and -2 together control inositol pyrophosphate metabolism and thereby physiologically regulate phosphate export and other aspects of mammalian cellular phosphate homeostasis.

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Select item 300063602.

Inositol Hexakisphosphate Kinase-2 in Cerebellar Granule Cells Regulates Purkinje Cells and Motor Coordination via Protein 4.1N.

Nagpal L, Fu C, Snyder SH.

J Neurosci. 2018 Aug 22;38(34):7409-7419. doi: 10.1523/JNEUROSCI.1165-18.2018. Epub 2018 Jul 13.  Abstract

Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. Among pyrophosphates generated by IP6Ks, diphosphoinositol pentakisphosphate (IP7/PP-InsP5), and bis-diphosphoinositol tetrakisphosphate (PP-InsP4)  have been extensively characterized.
IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. 
 We report that IP6K2 binds protein 4.1.N with high affinity and specificity. Nuclear translocation of 4.1N, which is required for its principal functions, is dependent on IP6K2. Both of these proteins are highly expressed in granule cells of the cerebellum where their interaction regulates Purkinje cell morphology and cerebellar synapses. The deletion of IP6K2 in male/female mice elicits substantial defects in synaptic influences of granule cells upon Purkinje cells as well as notable impairment of locomotor function. Moreover, the disruption of IP6K2-4.1N interactions impairs cell viability. Thus, IP6K2 and its interaction with 4.1N appear to be major determinants of cerebellar disposition and psychomotor behavior.SIGNIFICANCE STATEMENT Inositol phosphates are produced by a family of inositol hexakisphosphate kinases (IP6Ks)-IP6K1, IP6K2, and IP6K3. Of these, the physiological roles of IP6K2 in the brain have been least characterized. In the present study, we report that IP6K2 binds selectively to the neuronal protein 4.1N. Both of these proteins are highly expressed in granule cells of the cerebellum. Using IP6K2 knock-out (KO) mice, we establish that IP6K2-4.1N interactions in granule cells regulate Purkinje cell morphology, the viability of cerebellar neurons, and psychomotor behavior.
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Select item 298428353.

Use of Protein Kinase-Focused Compound Libraries for the Discovery of New Inositol Phosphate Kinase Inhibitors.

Puhl-Rubio AC, Stashko MA, Wang H, Hardy PB, Tyagi V, Li B, Wang X, Kireev D, Jessen HJ, Frye SV, Shears SB, Pearce KH.

SLAS Discov. 2018 Oct;23(9):982-988. doi: 10.1177/2472555218775323. Epub 2018 May 29. PMID: 29842835

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ENPP1 (6q23.2) pyrofosfataasi/fosfodiesteraasi 1

Tämä entsyymi tuottaa  epäorgaanisia  fosfaattimuotoja PPi ja Pi   lehossa.

https://www.ncbi.nlm.nih.gov/gene/5167

Official Symbol ENPP1

Official Full Name: ectonucleotide pyrophosphatase/phosphodiesterase 1provided by HGNC

Gene type protein coding

Also known as M6S1; NPP1; NPPS; PC-1; PCA1; ARHR2; COLED; PDNP1

Summary:  This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with 'idiopathic' infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. [provided by RefSeq, Jul 2008]

Expression

Biased expression in placenta (RPKM 22.6), thyroid (RPKM 14.0) and 13 other tissues See more

Orthologs

Preferred Names

ectonucleotide pyrophosphatase/phosphodiesterase family member 1

Names

E-NPP 1

Ly-41 antigen

alkaline phosphodiesterase 1

membrane component, chromosome 6, surface marker 1

phosphodiesterase I/nucleotide pyrophosphatase 1

plasma-cell membrane glycoprotein 1

plasma-cell membrane glycoprotein PC-1

Zn.binding site: D-T-D-H-D-H-H

Conserved Domains (4) summary

smart00201
Location:145 → 188

SO; Somatomedin B -like domains

smart00477
Location:676 → 907

NUC; DNA/RNA non-specific endonuclease

pfam01663
Location:212 → 538

Phosphodiest; Type I phosphodiesterase / nucleotide pyrophosphatase

cd16018
Location:210 → 578

Enpp; Ectonucleotide pyrophosphatase/phosphodiesterase, also called autotaxin

Related articles in PubMed

1. Neutrophils as sources of dinucleotide polyphosphates and metabolism by epithelial ENPP1 to influence barrier function via adenosine signaling. Curtis VF, et al. Mol Biol Cell, 2018 Nov 1. PMID 30188771, Free PMC Article
2. [The analysis of association between ENPP1 K121Q polymorphism and risk factors of type 2 diabetes mellitus in ukrainian population]. Marchenko IV, et al. Wiad Lek, 2018. PMID 30099416
3. ENPP1 K121Q (rs1044498 C > A) genetic polymorphism confers a high risk of susceptibility to coronary heart disease: A PRISMA-compliant article. Di JY, et al. Medicine (Baltimore), 2018 Jul. PMID 29979387, Free PMC Article
4. Association and in silico studies of ENPP1 gene variants with type 2 diabetes mellitus in a Northern Iranian population. Sharafshah A, et al. Gene, 2018 Oct 30. PMID 29958952
5. [The association between enpp1 rs997509 polymorphism and type 2 diabetes mellitus development in ukrainian population]. Marchenko IV, et al. Wiad Lek, 2018. PMID 29783211

See all (228) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

1. These studies demonstrate the cooperative metabolism between diadenosine triphosphate and ENPP1 function to provide a significant source of adenosine, subserving its role in inflammatory resolution.
2. Pilot study examined 3 candidate genes, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), ATP Binding Cassette Subfamily C Member 6 (ABCC6), and 5'-Nucleotidase Ecto (NT5E) involved in pyrophosphate (PPi) and inorganic phosphate (Pi) metabolism, which may predispose to coronary arterial or valvular calcification; report 4 new genetic variants potentially related to coronary calcification.
3. The promiscuous ectonucleotidase NPP1: molecular insights into substrate binding and hydrolysis.
4. This study for the first time analyzed the effect of decreased PPi on dental development in individuals with generalized arterial calcification of infancy (GACI) due to loss-of-function mutations in the ENPP1 gene.These findings reveal a novel dental phenotype in GACI and identify ENPP1 genetic mutations associated with hypercementosis.
5. Study concludes that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p.Cys120Arg allele represents a recessive and more severe form of Cole disease.
6. Findings provide insights into how ENPP1 hydrolyzes both ATP and cGAMP to participate in the two distinct biological processes.
7. ENPP1 gene variants may have a potential impact on the occurrence of T2 diabetes mellitus in Northern Iranians.
8. ENPP1 K121Q polymorphism is associated with type 2 diabetes mellitus in Ukrainian population. In carriers of the minor Q-allele the risk of T2DM is 1.4x higher than in homozygotes in the main K-allele. The risk increases in patients with BMI >/= 25 kg/m2
9. this study shows that ENPP1 is biomarker candidate for endometriosis
10. ENPP1 rs997509 polymorphism is associated with type 2 diabetes mellitus development in Ukrainian population.

Submit: New GeneRIF Correction See all GeneRIFs (166)

 

 

UPR;iin eli laskostumattomien proteiinien aiheuttamaan vasteeseen vaikuttava geeni: PXE eli URG7

uutiset Tiede, sitaatti:

" Harvinainen parantumaton sairaus tukki Markku Laitisen valtimot ja vei näön – lääkärin nerokkaan oivalluksen ansiosta tautiin kehitetään nyt lääkettä

Markku Laitisen sairastama PXE-sairaus on diagnosoitu Suomessa vain 28 ihmisellä. Tähän ihoon, silmiin ja verisuoniin vaikuttavaan salakavalasti etenevään sairauteen ei ole olemassa hoitoa. Kunnes Tampereella Taysissa työskentelevä lääkäri Pasi Nevalainen keksi, että sairautta voidaan hoitaa elintarvikkeissa lisäaineena käytettävällä pyrofosfaatilla."

 http://www.socialstyrelsen.se/rarediseases/pseudoxanthomaelasticum#anchor_3

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022264/

 

 

Tässä on tärkeä kartta PXE asiasta. 

Muistiin 19.3. 2019 

Sitaatti linkistä 2. 

"Background

Pseudoxanthoma elasticum (PXE) is characterized by skin (papular lesions), ocular (subretinal neovascularisation) and cardiovascular manifestations (peripheral artery disease), due to mineralization and fragmentation of elastic fibres in the extracellular matrix (ECM). Caused by mutations in the ABCC6 gene, the mechanisms underlying this disease remain unknown. The knowledge on the molecular background of soft tissue mineralization largely comes from insights in vascular calcification, with involvement of the osteoinductive Transforming Growth Factor beta (TGFβ) family (TGFβ1-3 and Bone Morphogenetic Proteins [BMP]), together with ectonucleotides (ENPP1), Wnt signalling and a variety of local and systemic calcification inhibitors. In this study, we have investigated the relevance of the signalling pathways described in vascular soft tissue mineralization in the PXE knock-out mouse model and in PXE patients.
Methods

The role of the pro-osteogenic pathways  

BMP2-SMADs-RUNX2, 

TGFβ-SMAD2/3 and 

Wnt-MSX2,

 apoptosis and ER stress was evaluated using immunohistochemistry, mRNA expression profiling and immune-co-staining in dermal tissues and fibroblast cultures of PXE patients and the eyes and whiskers of the PXE knock-out mouse. Apoptosis was further evaluated by TUNEL staining and siRNA mediated gene knockdown. ALPL activity in PXE fibroblasts was studied using ALPL stains.

 Results

We demonstrate the upregulation of the BMP2-SMADs-RUNX2 and TGFβ-2-SMAD2/3 pathway, co-localizing with the mineralization sites, and the involvement of MSX2-canonical Wnt signalling. Further, we show that apoptosis is also involved in PXE with activation of Caspases and BCL-2. 

 In contrast to vascular calcification, neither the other BMPs and TGFβs nor endoplasmic reticulum stress pathways seem to be perturbed in PXE.

Conclusions 

Our study shows that we cannot simply extrapolate knowledge on cell signalling in vascular soft tissue calcification to a multisystem ectopic mineralisation disease as PXE. 

Contrary, we demonstrate a specific set of perturbed signalling pathways in PXE patients and the knock-out mouse model. Based on our findings and previously reported data, we propose a preliminary cell model of ECM calcification in PXE. Keywords: Pseudoxanthoma elasticum, Ectopic mineralization, Elastic fibres, Osteogenic signalling pathway, BMP2-SMADs-RUNX2, TGFβ signalling, Canonical Wnt pathway, Apoptosis, Endoplasmic reticulum stress.

ABC- geeneistäL

ABCC6 (MRP alaperhettä)
 https://www.ncbi.nlm.nih.gov/gene/4363
Also known as ARA; PXE; MLP1; MRP6; PXE1; URG7; ABC34; GACI2; MOATE; MOAT-E; EST349056
Summary The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008] Expression Biased expression in liver (RPKM 16.7), kidney (RPKM 9.5) and 9 other tissues See more Orthologsmouse all

URG: BACKGROUND INFORMATION: Up-regulated Gene clone 7 (URG7) is an ER resident protein, whose expression is up-regulated in the presence of hepatitis B virus X antigen (HBxAg) during HBV infection. In virus-infected hepatocytes, URG7 shows an anti-apoptotic activity due to the PI3K/AKT signalling activation, does not seem to have tumorigenic properties, but it appears to promote the development and progression of fibrosis. However, the molecular mechanisms underlying URG7 activity remain largely unknown. To shed light on URG7 activity, we first analysed its interactome in HepG2 transfected cells: this analysis suggests that URG7 could have a role in affecting protein synthesis, folding and promoting proteins degradation. Moreover, keeping into account its subcellular localisation in the ER and that several viral infections give rise to ER stress, a panel of experiments was performed to evaluate a putative role of URG7 in ER stress. Our main results demonstrate that in ER-stressed cells URG7 is able to modulate the expression of Unfolded Protein Response (UPR) markers towards survival outcomes, up-regulating GRP78 protein and down-regulating the pro-apoptotic protein CHOP. Furthermore, URG7 reduces the ER stress by decreasing the amount of unfolded proteins, by increasing both the total protein ubiquitination and the AKT activation and reducing Caspase 3 activation. CONCLUSIONS: All together these data suggest that URG7 plays a pivotal role as a reliever of ER stress-induced apoptosis. SIGNIFICANCE: This is the first characterisation of URG7 activity under ER stress conditions. The results presented here will help to hypothesise new strategies to counteract the antiapoptotic activity of URG7 in the context of the viral infection.

GeneCards tieto tästä URG7 geenistä: 

https://www.genecards.org/cgi-bin/carddisp.pl?gene=ABCC6&keywords=URG7

GeneCards Summary for ABCC6 Gene

ABCC6 (ATP Binding Cassette Subfamily C Member 6) is a Protein Coding gene. Diseases associated with ABCC6 include Pseudoxanthoma Elasticum and Arterial Calcification, Generalized, Of Infancy, 2. Among its related pathways are Regulation of activated PAK-2p34 by proteasome mediated degradation and Photodynamic therapy-induced NFE2L2 (NRF2) survival signaling. Gene Ontology (GO) annotations related to this gene include transporter activity and ATPase-coupled transmembrane transporter activity. An important paralog of this gene is ABCC1.

 

Linkki lisää:  NRF2 kohdegeenit ovat iso joukko ja liittyvät mm UPR järjestelmän.

NRF2 proteiinin omassa funktiossa ja säätelyjärjestelmässä on tärkeä KELCH-proteiini  KLHL19 eli Keap1( eräs kelch-propellirakenteinen proteiini) https://www.genecards.org/cgi-bin/carddisp.pl?gene=NFE2L2&keywords=NRF2

EnzymeRegulation:

• Activated by cell derived metabolites including itaconate and fumarate. NF2L2_HUMAN,Q16236
• (Microbial infection) Transcription factor activity on antioxidant target genes is significantly inhibited by SARS coronavirus-2/SARS-COV-2. NF2L2_HUMAN,Q16236