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International Journal of Molecular... Apr 2021Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in... (Review)
Review
Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the "PXE gene" and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.
Topics: 5'-Nucleotidase; ATP-Binding Cassette Transporters; Animals; Calcification, Physiologic; Calcinosis; Diphosphates; GPI-Linked Proteins; Humans; Joint Diseases; Mice; Multidrug Resistance-Associated Proteins; Phosphoric Diester Hydrolases; Pseudoxanthoma Elasticum; Pyrophosphatases; Rats; Vascular Calcification; Vascular Diseases
PubMed: 33925341
DOI: 10.3390/ijms22094555 -
The Journal of Clinical Investigation Jan 2022Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a...
Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a murine model of ischemic cardiac injury, we demonstrate that cardiomyocytes play a pivotal role in heart repair by regulating nucleotide metabolism and fates of nonmyocytes. Cardiac injury induced the expression of the ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at the orotidine monophosphate (OMP) synthesis step and induced genotoxic stress and p53-mediated cell death of cycling nonmyocytes. As nonmyocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of the ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors using small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in nonmyocyte cells and augmented cardiac repair and postinfarct heart function. These observations demonstrate that the cardiac muscle cell regulates pyrimidine metabolism in nonmuscle cells by releasing adenine and specific nucleosides after heart injury and provide insight into how intercellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.
Topics: Adenosine Monophosphate; Adenosine Triphosphate; Animals; Heart Injuries; Mice; Myocardium; Myocytes, Cardiac; Phosphoric Diester Hydrolases; Pyrimidines; Pyrophosphatases; Regeneration; Signal Transduction
PubMed: 34813507
DOI: 10.1172/JCI149711 -
Nature Metabolism Mar 2020Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and...
Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and degradation of (p)ppGpp by RelA and SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Here, we show that human MESH1 is an efficient cytosolic NADPH phosphatase that facilitates ferroptosis. Visualization of the MESH1-NADPH crystal structure revealed a bona fide affinity for the NADPH substrate. Ferroptosis-inducing erastin or cystine deprivation elevates MESH1, whose overexpression depletes NADPH and sensitizes cells to ferroptosis, whereas MESH1 depletion promotes ferroptosis survival by sustaining the levels of NADPH and GSH and by reducing lipid peroxidation. The ferroptotic protection by MESH1 depletion is ablated by suppression of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. Collectively, these data shed light on the importance of cytosolic NADPH levels and their regulation under ferroptosis-inducing conditions in mammalian cells.
Topics: Cytosol; Ferroptosis; Humans; NADP; Pyrophosphatases
PubMed: 32462112
DOI: 10.1038/s42255-020-0181-1 -
Frontiers in Immunology 2023Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is a type II transmembrane glycoprotein expressed in many tissues. High expression levels of ENPP1 have been...
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is a type II transmembrane glycoprotein expressed in many tissues. High expression levels of ENPP1 have been observed in many cancer types such as lung cancer, ovarian cancer, and breast cancer. Such overexpression has been associated with poor prognosis in these diseases. Hence, ENPP1 is a potential target for immunotherapy across multiple cancers. Here, we isolated and characterized two high-affinity and specific anti-ENPP1 Fab antibody candidates, 17 and 3G12, from large phage-displayed human Fab libraries. After conversion to IgG1, the binding of both antibodies increased significantly due to avidity effects. Based on these antibodies, we generated antibody-drug conjugates (ADCs), IgG-based bispecific T-cell engagers (IbTEs), and CAR T-cells which all exhibited potent killing of ENPP1-expressing cells. Thus, these various antibody-derived modalities are promising therapeutic candidates for cancers expressing human ENPP1.
Topics: Humans; Female; Phosphoric Diester Hydrolases; Immunoconjugates; Breast Neoplasms; Immunoglobulin G; Pyrophosphatases
PubMed: 36761762
DOI: 10.3389/fimmu.2023.1070492 -
Annual Review of Pathology Jan 2024The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 () codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate... (Review)
Review
The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 () codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PP) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.
Topics: Adult; Humans; Middle Aged; Phosphoric Diester Hydrolases; Vascular Calcification; Pyrophosphatases
PubMed: 37871131
DOI: 10.1146/annurev-pathmechdis-051222-121126 -
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 -
Biochimica Et Biophysica Acta.... Jan 2019Mammalian haloacid dehalogenase (HAD)-type phosphatases have evolved to dephosphorylate a wide range of small metabolites, but can also target macromolecules such as... (Review)
Review
Mammalian haloacid dehalogenase (HAD)-type phosphatases have evolved to dephosphorylate a wide range of small metabolites, but can also target macromolecules such as serine/threonine, tyrosine-, and histidine-phosphorylated proteins. To accomplish these tasks, HAD phosphatases are equipped with cap domains that control access to the active site and provide substrate specificity determinants. A number of capped HAD phosphatases impact protein phosphorylation, although structural data are consistent with small metabolite substrates rather than protein substrates. This review discusses the structures, functions and disease implications of the three closely related, capped HAD phosphatases pyridoxal phosphatase (PDXP or chronophin), phosphoglycolate phosphatase (PGP, also termed AUM or glycerol phosphatase) and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP or HDHD2B). Evidence in support of small metabolite and protein phosphatase activity is discussed in the context of the diversity of their biological functions.
Topics: Actin Cytoskeleton; Animals; Humans; Hydrolases; Inorganic Pyrophosphatase; Neoplasms; Phosphoprotein Phosphatases; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Tyrosine Phosphatases
PubMed: 30030002
DOI: 10.1016/j.bbamcr.2018.07.007 -
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