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Cell Reports Aug 2023In bacteria, archaea, protists, and plants, the hydrolysis of pyrophosphate (PPi) by inorganic pyrophosphatase (PPase) can, under stress conditions, substitute for...
In bacteria, archaea, protists, and plants, the hydrolysis of pyrophosphate (PPi) by inorganic pyrophosphatase (PPase) can, under stress conditions, substitute for ATP-driven proton flux to generate a proton gradient and induce luminal acidification. However, this strategy is considered to be lost in eukaryotes. Here, we report that LHPP, a poorly understood PPase that exhibits activity at acidic pH, is primarily expressed in astrocytes and partly localized on lysosomal membranes. Under stress conditions, LHPP is recruited to vacuolar ATPase (V-ATPase) and facilitates V-ATPase-dependent proton transport and lysosomal acidification by hydrolyzing PPi. LHPP knockout (KO) mice have no discernable phenotype but are resilient to chronic-stress-induced depression-like behaviors. Mechanistically, LHPP deficiency prevents lysosome-dependent degradation of C/EBPβ and induces the expression of a group of chemokines that promote adult neurogenesis. Together, these findings suggest that LHPP is likely to be a therapeutic target for stress-related brain disease.
PubMed: 37573508
DOI: 10.1016/j.celrep.2023.112975 -
ACS Omega Aug 2022Aberrant level of ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 is linked with numerous disorders, for instance, diabetes, cancer, osteoarthritis,...
Aberrant level of ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 is linked with numerous disorders, for instance, diabetes, cancer, osteoarthritis, chondrocalcinosis, and allergic reactions. These disorders may be cured or minimized by blocking the activity of ENPP1 and ENPP3 isozymes. In this study, arylamide sulphonates were synthesized, characterized, and evaluated for their capability to affect the activity of isozymes ENPP1 and ENPP3. Among the selective inhibitors of ENPP1, compounds and exhibited sub-micromolar IC values of 0.28 ± 0.08 and 0.37 ± 0.03 μM, respectively, followed by , with IC equal to 0.81 ± 0.05 μM, whereas out of the selective inhibitors of isozyme ENPP3, and preferably lessened the activity to half of the maximal inhibitory concentration of 0.15 ± 0.04 and 0.16 ± 0.01 μM alternatively. In addition, many structures including , , , , , , , , , , and inhibited the activity of both isozymes to a significant level. Enzyme kinetic study of compound revealed an uncompetitive mode of inhibition of ENPP1 isozyme, while competitively blocked the activity of ENPP3. Cell viability analysis revealed the compound as a cytotoxic agent against MCF7 (human breast cancer cell line) with a percentage inhibition of 63.2 ± 2.51%, whereas compounds , , , and decreased the HeLa cell viability (human cervical cancer cell line) to more than 50%. The tested compounds were non-cytotoxic against HEK293 (a human embryonic kidney cell line). Molecular docking analysis of selected inhibitors of both isozymes produced optimistic interactions with the influential amino acids, such as Leu290, Lys295, Tyr340, Asp376, His380, and Pro323 of ENPP1, whereas residues Asn226, His329, Leu239, Tyr289, Pro272, Tyr320, and Ala205 of ENPP3 crystallographic structure formed interactions with the potent inhibitors.
PubMed: 35936461
DOI: 10.1021/acsomega.2c03473 -
Trends in Biochemical Sciences Jul 2019ENPP1 is well known for its role in regulating skeletal and soft tissue mineralization. It primarily exerts its function through the generation of pyrophosphate, a key... (Review)
Review
ENPP1 is well known for its role in regulating skeletal and soft tissue mineralization. It primarily exerts its function through the generation of pyrophosphate, a key inhibitor of hydroxyapatite formation. Several previous studies have suggested that ENPP1 also contributes to a range of human diseases including diabetes, cancer, cardiovascular disease, and osteoarthritis. In this review, we summarize the pathological roles of ENPP1 in mineralization and these soft tissue disorders. We also discuss the underlying mechanisms through which ENPP1 exerts its pathological effects. A fuller understanding of the pathways through which ENPP1 acts may help to develop novel therapeutic strategies for these commonly diagnosed morbidities.
Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Neoplasms; Osteoarthritis; Phosphoric Diester Hydrolases; Pyrophosphatases
PubMed: 30799235
DOI: 10.1016/j.tibs.2019.01.010 -
Frontiers in Pharmacology 2021
PubMed: 34630115
DOI: 10.3389/fphar.2021.746925 -
Circulation Research Nov 2021[Figure: see text].
[Figure: see text].
Topics: Animals; Cells, Cultured; Fibrosis; HEK293 Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Myofibroblasts; Pyrophosphatases
PubMed: 34610755
DOI: 10.1161/CIRCRESAHA.121.319482 -
Advanced Science (Weinheim,... May 2024To evade immune surveillance, tumor cells express ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) on the surface of their membrane, which degrades...
To evade immune surveillance, tumor cells express ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) on the surface of their membrane, which degrades extracellular cyclic GMP-AMP (cGAMP), thereby inhibiting the cyclic GMP-AMP synthase (cGAS) stimulator of interferon gene (STING) DNA-sensing pathway. To fully understand this tumor stealth mechanism, it is essential to determine whether other forms of ENPP1 with hydrolytic cGAMP activity also are present in the tumor microenvironment to regulate this innate immune pathway. Herein, it is reported that various tumor-derived exosomes carry ENPP1, and can hydrolyze synthetic 2'3'-cGAMP and endogenous 2'3'-cGAMP produced by cells to inhibit cGAS-STING pathway in immune cells. Moreover, tumor exosomal ENPP1 also can hydrolyze 2'3'-cGAMP bound to LL-37 (an effective transporter of 2'3'-cGAMP) to inhibit STING signaling. Furthermore, high expression of ENPP1 in exosomes is observed isolated from human breast and lung cancer tissue, and tumor exosomal ENPP1 inhibited the immune infiltration of CD8+ T cells and CD4+ T cells. The results elucidate the essential function of tumor exosomal ENPP1 in the cGAS-STING pathway, furthering understanding of the crosstalk between the tumor cells and immune system.
Topics: Nucleotides, Cyclic; Pyrophosphatases; Signal Transduction; Phosphoric Diester Hydrolases; Membrane Proteins; Humans; Nucleotidyltransferases; Exosomes; Mice; Animals; Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38498770
DOI: 10.1002/advs.202308131 -
Cell Cycle (Georgetown, Tex.) Jun 2022Cancers continue to have high incidence and mortality rates worldwide. Therefore, cancer control remains the main public health goal. Growing research evidence suggests... (Review)
Review
Cancers continue to have high incidence and mortality rates worldwide. Therefore, cancer control remains the main public health goal. Growing research evidence suggests that phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) plays an important role in inhibiting tumor cell progression. It has been reported in the literature that LHPP is expressed at low levels in tumor tissues and cells and that patients with low LHPP expression have a poorer prognosis. Functional studies have shown that LHPP can inhibit tumor cell proliferation, metastasis, and apoptosis by affecting different target genes. In addition, researchers have used iDPP nanoparticles to deliver LHPP plasmids to treat tumors, demonstrating the great potential of LHPP plasmids for cancer therapy. In our review, we highlight the biological functions and important downstream target genes of LHPP in tumors, providing a theoretical basis for the treatment of human cancers. Although not thoroughly studied in terms of tumor mechanisms, LHPP still represents a promising and effective anticancer drug target.
Topics: Cell Proliferation; Histidine; Humans; Inorganic Pyrophosphatase; Neoplasms; Phosphoric Monoester Hydrolases
PubMed: 35239447
DOI: 10.1080/15384101.2022.2044148 -
The Journal of Molecular Diagnostics :... Oct 2022The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of... (Review)
Review
TPMT and NUDT15 Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European...
The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This article provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This article focuses on clinical TPMT and NUDT15 PGx testing, which may be applied to all thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15)-related medications. These recommendations are not to be interpreted as prescriptive, but to provide a reference guide.
Topics: Consensus; Genotype; Humans; Knowledge Bases; Methyltransferases; Pathologists; Pathology, Molecular; Pharmacists; Pharmacogenetics; Pyrophosphatases
PubMed: 35931343
DOI: 10.1016/j.jmoldx.2022.06.007 -
Medicine Aug 2023Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been identified as a potential biomarker in lung and prostate cancers; however, its expression and...
Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been identified as a potential biomarker in lung and prostate cancers; however, its expression and clinical relevance in hepatocellular carcinoma (HCC) remain incompletely understood. This study comprehensively assessed ENPP2 expression in pan-cancer using bioinformatics. We analyzed the expression of ENPP2 mRNA in primary liver cancer and adjacent tissues of patients with HCC using data from the TCGA database. Cox regression and Kaplan-Meier methods were used to identify clinicopathological factors associated with survival, and the diagnostic value of ENPP2 expression was evaluated using receiver operating characteristic curve analysis. We also validated our findings by performing real-time PCR on clinical liver cancer samples. Furthermore, we conducted gene set enrichment analysis using the Cancer Genome Atlas dataset to gain additional insights into the biological significance of ENPP2 in HCC. High ENPP2 expression in HCC patients is associated with gender and clinical stage, and is a significant prognostic factor for worse outcomes. ENPP2 expression is an independent risk factor for progression-free and disease-specific survival in both cohorts, suggesting its potential as an HCC biomarker. ENPP2's diagnostic value in HCC patients was confirmed by the area under the receiver operating characteristic curve, which was 0.806. real-time PCR analysis validated the higher expression of ENPP2 in clinical liver cancer tissues. Gene set enrichment analysis identified pathways enriched in HCC patients with high ENPP2 expression, including those related to the cell cycle, MTOR and T cell receptor signaling, and phosphatidylinositol signaling systems. We have demonstrated that ENPP2 is highly expressed in HCC and is a potential independent molecular marker for the diagnosis and prognosis of HCC.
Topics: Male; Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Biomarkers, Tumor; Prognosis
PubMed: 37543832
DOI: 10.1097/MD.0000000000034480 -
Biomedicine & Pharmacotherapy =... Dec 2023Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and...
Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.
Topics: Humans; Azathioprine; Pharmacogenetics; Immunosuppressive Agents; Genotype; Crohn Disease; Methyltransferases; Pyrophosphatases
PubMed: 37857254
DOI: 10.1016/j.biopha.2023.115706