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Biomolecules Jan 2021Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology.... (Review)
Review
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown. Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.
Topics: Animals; Biomarkers; Disease Progression; Encephalomyelitis; Epstein-Barr Virus Infections; Fatigue Syndrome, Chronic; Herpesvirus 4, Human; Humans; Immune System; Inflammation; Pyrophosphatases; Virus Replication
PubMed: 33572802
DOI: 10.3390/biom11020185 -
Critical Reviews in Biochemistry and... Dec 2018Derived from an ancient ATP-hydrolyzing Rossmann-like fold protein, members of the PP-loop ATP pyrophosphatase family feature an absolutely conserved P-loop-like... (Review)
Review
Derived from an ancient ATP-hydrolyzing Rossmann-like fold protein, members of the PP-loop ATP pyrophosphatase family feature an absolutely conserved P-loop-like "SxGxDS/T" motif used for binding and presenting ATP for substrate adenylylation (AMPylation). Since the first family member was reported more than 20 years ago, numerous representatives catalyzing very diverse reactions have been characterized both functionally and structurally. The availability of more than 100 high quality structures in the protein data bank provides an excellent opportunity to gain structural insights into the generally conserved catalytic mechanism and the uniqueness of the reactions catalyzed by family members. In this work, we conducted a thorough database search for the PP-loop ATP pyrophosphatase family members, resulting in the most comprehensive and up-to-date collection that includes 18 enzyme families. Structure comparison of representative family members allowed us to identify common structure features in the core catalytic domain, as well as four highly variable regions that define the unique chemistry for each enzyme family. The newly identified enzymes, particularly those from pathogens, warrant further research to enlarge the scope of this ever-expanding and highly diverse enzyme superfamily for use in potential bioengineering and biomedical applications.
Topics: Amino Acid Motifs; Animals; Humans; Pyrophosphatases
PubMed: 30280944
DOI: 10.1080/10409238.2018.1516728 -
RNA Biology Oct 2021Various kinds of cap structures, such as mG, triphosphate groups, NAD and dpCoA, protect the 5' terminus of RNA. The cap structures bond covalently to RNA and affect its...
Various kinds of cap structures, such as mG, triphosphate groups, NAD and dpCoA, protect the 5' terminus of RNA. The cap structures bond covalently to RNA and affect its stability, translation, and transport. The removal of the caps is mainly executed by Nudix hydrolase family proteins, including Dcp2, RppH and NudC. Numerous efforts have been made to elucidate the mechanism underlying the removal of mG, triphosphate group, and NAD caps. In contrast, few studies related to the cleavage of the RNA dpCoA cap have been conducted. Here, we report the hydrolytic activity of NudC towards dpCoA and dpCoA-capped RNA . We also determined the crystal structure of dimeric NudC in complex with dpCoA at 2.0 Å resolution. Structural analysis revealed that dpCoA is recognized and hydrolysed in a manner similar to NAD. In addition, NudC may also remove other dinucleotide derivative caps of RNA, which comprise the AMP moieties. NudC homologs in and exhibited similar dpCoA decapping (deCoAping) activity. These results together indicate a conserved mechanism underpinning the hydrolysis of dpCoA-capped RNA in both prokaryotes and eukaryotes.
Topics: Coenzyme A; Escherichia coli; Escherichia coli Proteins; Protein Conformation; Pyrophosphatases; RNA Caps; RNA, Bacterial; Nudix Hydrolases
PubMed: 34074215
DOI: 10.1080/15476286.2021.1936837 -
Current Opinion in Structural Biology Aug 2014Membrane-bound pyrophosphatases (M-PPases) are homodimeric enzymes that couple the generation and utilization of membrane potentials to pyrophosphate (PPi) hydrolysis... (Review)
Review
Membrane-bound pyrophosphatases (M-PPases) are homodimeric enzymes that couple the generation and utilization of membrane potentials to pyrophosphate (PPi) hydrolysis and synthesis. Since the discovery of the link between PPi use and proton transport in purple, non-sulphur bacteria in the 1960s, M-PPases have been found in all three domains of life and have been shown to have a crucial role in stress tolerance and in plant maturation. The discovery of sodium-pumping and sodium/proton-pumping M-PPases showed that the pumping specificity of these enzymes is not limited to protons, further suggesting that M-PPases are evolutionarily very ancient. The recent structures of two M-PPases, the Vigna radiata H(+)-pumping M-PPase and Thermotoga maritima Na(+)-pumping M-PPase, provide the basis for understanding the functional data. They show that M-PPases have a novel fold and pumping mechanism, different to the other primary pumps. This review discusses the current structural understanding of M-PPases and of ion selection among various M-PPases.
Topics: Amino Acid Sequence; Biological Transport; Humans; Molecular Sequence Data; Protons; Pyrophosphatases; Sodium
PubMed: 24768824
DOI: 10.1016/j.sbi.2014.03.007 -
Journal of Medicinal Chemistry Nov 2023A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes...
A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a natural STING agonist; however, cGAMP is subjected to endogenous degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). To improve the ICI response rate, we developed , a novel ENPP1 inhibitor with phthalazin-1(2)-one as the core scaffold. inhibited the cGAMP hydrolysis by ENPP1 in vitro (IC = 68 nM) and enhanced the STING-mediated type I interferon response in both immune and tumor cells. demonstrated excellent metabolic stability and bioavailability ( = 65%). Orally administered promoted tumor growth inhibition in a CT26 syngeneic model and increased the anti-PD-L1 response. Furthermore, -induced immunological memory prevented the tumor relapse against tumor rechallenge, suggesting the promising therapeutic potential of .
Topics: Humans; Phosphoric Diester Hydrolases; Neoplasms; Pyrophosphatases; Immunotherapy; Tumor Microenvironment
PubMed: 37963811
DOI: 10.1021/acs.jmedchem.3c01061 -
Pediatric Radiology Nov 2022Generalized arterial calcification of infancy (GACI), also known as idiopathic infantile arterial calcification, is a very uncommon genetic disorder characterized by... (Review)
Review
BACKGROUND
Generalized arterial calcification of infancy (GACI), also known as idiopathic infantile arterial calcification, is a very uncommon genetic disorder characterized by calcifications and stenoses of large- and medium-size arteries that can lead to end-organ damage.
OBJECTIVE
To describe changes in imaging findings in 10 children with GACI at a single institution from 2010 to 2021.
MATERIALS AND METHODS
In this retrospective study we reviewed initial and follow-up body imaging in children with genetic confirmation of GACI at our hospital. All initial images were analyzed for the presence and distribution of arterial calcifications, stenoses and wall thickening/irregularity within the chest, abdomen and pelvis. We compared available follow-up studies to the initial imaging findings. We extracted clinical information including prenatal and postnatal treatment from the children's medical records.
RESULTS
We evaluated 10 children (five boys) with a diagnosis of GACI. Median age at first body imaging was 8 days (range: 1 day to 5 years). Six children were identified prenatally and four postnatally. Postnatal presentation included cardiac failure, seizures and hypertension. Images in newborns (n = 8) most commonly showed diffuse arterial calcifications (6/8; 75%), while stenoses were less common (2/8; 25%) during this period. Two children were diagnosed after the neonatal period - one in infancy and one during childhood. In total, half the children (5/10; 50%) had arterial stenoses - three cases visualized at first imaging and two identified on follow-up images during infancy. Stenoses had completely resolved in one child (1/5; 20%) at last follow-up. Eight children received prenatal or postnatal treatment or both. All children who received both prenatal and postnatal treatment (n = 4) had completely resolved calcifications at last follow-up.
CONCLUSION
Children with GACI might have characteristic vascular calcifications at birth that raise the suspicion of this disease. Arterial calcifications decrease or disappear spontaneously or after treatment, but arterial stenoses usually persist. Calcifications and arterial stenoses can be easily identified and followed with non-contrast CT and CT angiography.
Topics: Male; Child; Humans; Infant, Newborn; Pyrophosphatases; Phosphoric Diester Hydrolases; Retrospective Studies; Constriction, Pathologic; Vascular Calcification
PubMed: 35438330
DOI: 10.1007/s00247-022-05364-0 -
Purinergic Signalling Sep 2021
Review
Topics: Biomarkers, Tumor; Genetic Variation; Humans; Mutation; Neoplasms; Oncogene Proteins; Protein Isoforms; Pyrophosphatases
PubMed: 34272651
DOI: 10.1007/s11302-021-09809-3 -
Cells Jan 2022Inosine triphosphate pyrophosphatase (ITPase) is an enzyme encoded by the gene and functions to prevent the incorporation of noncanonical purine nucleotides into DNA... (Review)
Review
Inosine triphosphate pyrophosphatase (ITPase) is an enzyme encoded by the gene and functions to prevent the incorporation of noncanonical purine nucleotides into DNA and RNA. Specifically, the ITPase catalyzed the hydrolysis of (deoxy) nucleoside triphosphates ((d) NTPs) into the corresponding nucleoside monophosphate with the concomitant release of pyrophosphate. Recently, thiopurine drug metabolites such as azathioprine have been included in the lists of ITPase substrates. Interestingly, inosine or xanthosine triphosphate (ITP/XTP) and their deoxy analogs, deoxy inosine or xanthosine triphosphate (dITP/dXTP), are products of important biological reactions such as deamination that take place within the cellular compartments. However, the incorporation of ITP/XTP, dITP/dXTP, or the genetic deficiency or polymorphism of the gene have been implicated in many human diseases, including infantile epileptic encephalopathy, early onset of tuberculosis, and the responsiveness of patients to cancer therapy. This review provides an up-to-date report on the ITPase enzyme, including information regarding its discovery, analysis, and cellular localization, its implication in human diseases including cancer, and its therapeutic potential, amongst others.
Topics: Humans; Inosine; Inosine Triphosphate; Mutation; Neoplasms; Nucleosides; Nucleotides; Pyrophosphatases; Inosine Triphosphatase
PubMed: 35159194
DOI: 10.3390/cells11030384 -
Nucleic Acids Research Sep 2022Failure to prevent accumulation of the non-canonical nucleotide inosine triphosphate (ITP) by inosine triphosphate pyrophosphatase (ITPase) during nucleotide synthesis...
Failure to prevent accumulation of the non-canonical nucleotide inosine triphosphate (ITP) by inosine triphosphate pyrophosphatase (ITPase) during nucleotide synthesis results in misincorporation of inosine into RNA and can cause severe and fatal developmental anomalies in humans. While the biochemical activity of ITPase is well understood, the pathogenic basis of ITPase deficiency and the molecular and cellular consequences of ITP misincorporation into RNA remain cryptic. Here, we demonstrate that excess ITP in the nucleotide pool during in vitro transcription results in T7 polymerase-mediated inosine misincorporation in luciferase RNA. In vitro translation of inosine-containing luciferase RNA reduces resulting luciferase activity, which is only partly explained by reduced abundance of the luciferase protein produced. Using Oxford Nanopore Direct RNA sequencing, we reveal inosine misincorporation to be stochastic but biased largely towards misincorporation in place of guanosine, with evidence for misincorporation also in place of cytidine, adenosine and uridine. Inosine misincorporation into RNA is also detected in Itpa-null mouse embryonic heart tissue as an increase in relative variants compared with the wild type using Illumina RNA sequencing. By generating CRISPR/Cas9 rat H9c2 Itpa-null cardiomyoblast cells, we validate a translation defect in cells that accumulate inosine within endogenous RNA. Furthermore, we observe hindered cellular translation of transfected luciferase RNA containing misincorporated inosine in both wild-type and Itpa-null cells. We therefore conclude that inosine misincorporation into RNA perturbs translation, thus providing mechanistic insight linking ITPase deficiency, inosine accumulation and pathogenesis.
Topics: Humans; Animals; Mice; Rats; Inosine Triphosphate; RNA; Pyrophosphatases; Inosine; Nucleotides
PubMed: 35979951
DOI: 10.1093/nar/gkac709 -
Cancer Discovery May 2022Locoregional failure (LRF) in patients with breast cancer post-surgery and post-irradiation is linked to a dismal prognosis. In a refined new model, we identified...
ABSTRACT
Locoregional failure (LRF) in patients with breast cancer post-surgery and post-irradiation is linked to a dismal prognosis. In a refined new model, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1/CD203a (ENPP1) to be closely associated with LRF. ENPP1hi circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of polymorphonuclear myeloid-derived suppressor cells and neutrophil extracellular trap (NET) formation. Genetic and pharmacologic ENPP1 inhibition or NET blockade extends relapse-free survival. Furthermore, in combination with fractionated irradiation, ENPP1 abrogation obliterates LRF. Mechanistically, ENPP1-generated adenosinergic metabolites enhance haptoglobin (HP) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.
SIGNIFICANCE
CTC exploit the ENPP1/HP axis to promote local recurrence post-surgery and post-irradiation by subduing myeloid suppressor cells in breast tumors. Blocking this axis impairs tumor engraftment, impedes immunosuppression, and obliterates NET formation, unveiling new opportunities for therapeutic intervention to eradicate local relapse and ameliorate patient survival. This article is highlighted in the In This Issue feature, p. 1171.
Topics: Breast Neoplasms; Female; Haptoglobins; Humans; Myeloid-Derived Suppressor Cells; Neoplasm Recurrence, Local; Phosphoric Diester Hydrolases; Pyrophosphatases
PubMed: 35191482
DOI: 10.1158/2159-8290.CD-21-0932