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Frontiers in Plant Science 2021Proton pumps create a proton motif force and thus, energize secondary active transport at the plasma nmembrane and endomembranes of the secretory pathway. In the plant... (Review)
Review
Proton pumps create a proton motif force and thus, energize secondary active transport at the plasma nmembrane and endomembranes of the secretory pathway. In the plant cell, the dominant proton pumps are the plasma membrane ATPase, the vacuolar pyrophosphatase (V-PPase), and the vacuolar-type ATPase (V-ATPase). All these pumps act on the cytosolic pH by pumping protons into the lumen of compartments or into the apoplast. To maintain the typical pH and thus, the functionality of the cytosol, the activity of the pumps needs to be coordinated and adjusted to the actual needs. The cellular toolbox for a coordinated regulation comprises 14-3-3 proteins, phosphorylation events, ion concentrations, and redox-conditions. This review combines the knowledge on regulation of the different proton pumps and highlights possible coordination mechanisms.
PubMed: 34177988
DOI: 10.3389/fpls.2021.672873 -
Cellular and Molecular Life Sciences :... Apr 2021Extracellular NAD represents a key signaling molecule in different physiological and pathological conditions. It exerts such function both directly, through the... (Review)
Review
Extracellular NAD represents a key signaling molecule in different physiological and pathological conditions. It exerts such function both directly, through the activation of specific purinergic receptors, or indirectly, serving as substrate of ectoenzymes, such as CD73, nucleotide pyrophosphatase/phosphodiesterase 1, CD38 and its paralog CD157, and ecto ADP ribosyltransferases. By hydrolyzing NAD, these enzymes dictate extracellular NAD availability, thus regulating its direct signaling role. In addition, they can generate from NAD smaller signaling molecules, like the immunomodulator adenosine, or they can use NAD to ADP-ribosylate various extracellular proteins and membrane receptors, with significant impact on the control of immunity, inflammatory response, tumorigenesis, and other diseases. Besides, they release from NAD several pyridine metabolites that can be taken up by the cell for the intracellular regeneration of NAD itself. The extracellular environment also hosts nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase, which inside the cell catalyze key reactions in NAD salvaging pathways. The extracellular forms of these enzymes behave as cytokines, with pro-inflammatory functions. This review summarizes the current knowledge on the extracellular NAD metabolome and describes the major biochemical properties of the enzymes involved in extracellular NAD metabolism, focusing on the contribution of their catalytic activities to the biological function. By uncovering the controversies and gaps in their characterization, further research directions are suggested, also to better exploit the great potential of these enzymes as therapeutic targets in various human diseases.
Topics: ADP Ribose Transferases; Animals; Disease; Humans; Metabolome; NAD; Pentosyltransferases; Pyrophosphatases; Signal Transduction
PubMed: 33755743
DOI: 10.1007/s00018-020-03742-1 -
Frontiers in Pharmacology 2020Ectonucleotidases are extracellular enzymes with a pivotal role in inflammation that hydrolyse extracellular purine and pyrimidine nucleotides, e.g., ATP, UTP, ADP, UDP,... (Review)
Review
Ectonucleotidases are extracellular enzymes with a pivotal role in inflammation that hydrolyse extracellular purine and pyrimidine nucleotides, e.g., ATP, UTP, ADP, UDP, AMP and NAD. Ectonucleotidases, expressed by virtually all cell types, immune cells included, either as plasma membrane-associated or secreted enzymes, are classified into four main families: 1) nucleoside triphosphate diphosphohydrolases (NTPDases), 2) nicotinamide adenine dinucleotide glycohydrolase (NAD glycohydrolase/ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1), 3) ecto-5'-nucleotidase (NT5E), and 4) ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs). Concentration of ATP, UTP and NAD can be increased in the extracellular space thanks to un-regulated, e.g., cell damage or cell death, or regulated processes. Regulated processes include secretory exocytosis, connexin or pannexin hemichannels, ATP binding cassette (ABC) transporters, calcium homeostasis modulator (CALMH) channels, the ATP-gated P2X7 receptor, maxi-anion channels (MACs) and volume regulated ion channels (VRACs). Hydrolysis of extracellular purine nucleotides generates adenosine, an important immunosuppressant. Extracellular nucleotides and nucleosides initiate or dampen inflammation via P2 and P1 receptors, respectively. All these agents, depending on their level of expression or activation and on the agonist concentration, are potent modulators of inflammation and key promoters of host defences, immune cells activation, pathogen clearance, tissue repair and regeneration. Thus, their knowledge is of great importance for a full understanding of the pathophysiology of acute and chronic inflammatory diseases. A selection of these pathologies will be briefly discussed here.
PubMed: 33613285
DOI: 10.3389/fphar.2020.619458 -
Pharmaceuticals (Basel, Switzerland) Nov 2021Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly... (Review)
Review
Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly responsible for the hydrolysis of extracellular lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA can induce various responses, such as cell proliferation, migration, and cytokine production, through six G protein-coupled receptors (LPA1-6). This signaling pathway is associated with metabolic and inflammatory disorder, and inhibiting this pathway has a positive effect on the treatment of related diseases, while ATX, as an important role in the production of LPA, has been shown to be associated with the occurrence and metastasis of tumors, fibrosis and cardiovascular diseases. From mimics of ATX natural lipid substrates to the rational design of small molecule inhibitors, ATX inhibitors have made rapid progress in structural diversity and design over the past 20 years, and three drugs, GLPG1690, BBT-877, and BLD-0409, have entered clinical trials. In this paper, we will review the structure of ATX inhibitors from the perspective of the transformation of design ideas, discuss the advantages and disadvantages of each inhibitor type, and put forward prospects for the development of ATX inhibitors in the future.
PubMed: 34832985
DOI: 10.3390/ph14111203 -
Biomolecules Sep 2023Glutamine amidotransferases (GATs) catalyze the hydrolysis of glutamine and transfer the generated ammonia to diverse metabolites. The two catalytic activities,... (Review)
Review
Glutamine amidotransferases (GATs) catalyze the hydrolysis of glutamine and transfer the generated ammonia to diverse metabolites. The two catalytic activities, glutaminolysis and the subsequent amination of the acceptor substrate, happen in two distinct catalytic pockets connected by a channel that facilitates the movement of ammonia. The pathway for the synthesis of guanosine monophosphate (GMP) from xanthosine monophosphate (XMP) is enabled by the GAT GMP synthetase (GMPS). In most available crystal structures of GATs, the ammonia channel is evident in their native state or upon ligand binding, providing molecular details of the conduit. In addition, conformational changes that enable the coordination of the two catalytic chemistries are also informed by the available structures. In contrast, despite the first structure of a GMPS being published in 1996, the understanding of catalysis in the acceptor domain and inter-domain crosstalk became possible only after the structure of a glutamine-bound mutant of GMPS was determined. In this review, we present the current status of our understanding of the molecular basis of catalysis in GMPS, becoming the first comprehensive assessment of the biochemical function of this intriguing enzyme.
PubMed: 37759779
DOI: 10.3390/biom13091379 -
Biomolecules Jan 2022Most free-living organisms encode for a deoxyuridine triphosphate nucleotidohydrolase (dUTPase; EC 3.6.1.23). dUTPases represent a family of metalloenzymes that catalyze... (Review)
Review
Most free-living organisms encode for a deoxyuridine triphosphate nucleotidohydrolase (dUTPase; EC 3.6.1.23). dUTPases represent a family of metalloenzymes that catalyze the hydrolysis of dUTP to dUMP and pyrophosphate, preventing dUTP from being incorporated into DNA by DNA polymerases, maintaining a low dUTP/dTTP pool ratio and providing a necessary precursor for dTTP biosynthesis. Thus, dUTPases are involved in maintaining genomic integrity by preventing the uracilation of DNA. Many DNA-containing viruses, which infect mammals also encode for a dUTPase. This review will summarize studies demonstrating that, in addition to their classical enzymatic activity, some dUTPases possess novel functions that modulate the host innate immune response.
Topics: Animals; DNA; Immunity, Innate; Mammals; Pyrophosphatases
PubMed: 35204728
DOI: 10.3390/biom12020227 -
Current Osteoporosis Reports Oct 2023The study aims to provide updated information on the genetic factors associated with the diagnoses 'Diffuse Idiopathic Skeletal Hyperostosis' (DISH), 'Ossification of... (Review)
Review
PURPOSE OF REVIEW
The study aims to provide updated information on the genetic factors associated with the diagnoses 'Diffuse Idiopathic Skeletal Hyperostosis' (DISH), 'Ossification of the Posterior Longitudinal Ligament' (OPLL), and in patients with spinal ligament ossification.
RECENT FINDINGS
Recent studies have advanced our knowledge of genetic factors associated with DISH, OPLL, and other spinal ossification (ossification of the anterior longitudinal ligament [OALL] and the yellow ligament [OYL]). Several case studies of individuals afflicted with monogenic disorders, such as X-linked hypophosphatemia (XLH), demonstrate the strong association of fibroblast growth factor 23-related hypophosphatemia with OPLL, suggesting that pathogenic variants in PHEX, ENPP1, and DMP1 are associated with FGF23-phosphate wasting phenotype and strong genetic factors placing patients at risk for OPLL. Moreover, emerging evidence demonstrates that heterozygous and compound heterozygous ENPP1 pathogenic variants inducing 'Autosomal Recessive Hypophosphatemic Rickets Type 2' (ARHR2) also place patients at risk for DISH and OPLL, possibly due to the loss of inhibitory plasma pyrophosphate (PP) which suppresses ectopic calcification and enthesis mineralization. Our findings emphasize the importance of genetic and plasma biomarker screening in the clinical evaluation of DISH and OPLL patients, with plasma PP constituting an important new biomarker for the identification of DISH and OPLL patients whose disease course may be responsive to ENPP1 enzyme therapy, now in clinical trials for rare calcification disorders.
Topics: Humans; Hyperostosis, Diffuse Idiopathic Skeletal; Osteogenesis; Ossification of Posterior Longitudinal Ligament; Biomarkers; Ligaments
PubMed: 37530996
DOI: 10.1007/s11914-023-00814-6 -
Theranostics 2023One of the hallmarks of osteoarthritis (OA), the most common degenerative joint disease, is increased numbers of senescent chondrocytes. Targeting senescent...
One of the hallmarks of osteoarthritis (OA), the most common degenerative joint disease, is increased numbers of senescent chondrocytes. Targeting senescent chondrocytes or signaling mechanisms leading to senescence could be a promising new therapeutic approach for OA treatment. However, understanding the key targets and links between chondrocyte senescence and OA remains unclear. Senescent chondrocytes were identified from , double-knockout mice lacking and (dKO) and applied to microarray. The presence of forkhead transcription factor M1 (FOXM1) was detected in aged, dKO, and destabilization of the medial meniscus (DMM) cartilages and articular chondrocytes, and the effect of overexpression and acetyl-CoA treatment on cartilage homeostasis was examined using immunohistochemistry, quantitative real-time PCR (qRT-PCR), cell apoptosis and proliferation assay, and safranin O staining. Delivery of Rho@PAA-MnO (MnO nanosheet) or heparin-ACBP/COS-GA- (ACBP-) nanoparticles into DMM cartilage was performed Here, we propose the specific capture of acetyl-CoA with the delivery of ( siRNA () to prevent cartilage degradation by inhibiting the axis of chondrocyte senescence. dKO stimulate chondrocyte senescence via the upregulation of and contribute to severe cartilage breakdown. We found that the accumulation of acetyl-CoA in the dKO mice may be responsible for the upregulation of during OA pathogenesis. Moreover, scavenging reactive oxygen species (ROS) induced by chondrocyte senescence via the implantation of MnO nanosheets or delivery of functionalized with acetyl-CoA binding protein (ACBP) to capture acetyl-CoA using an injectable bioactive nanoparticle (-ACBP-NP) significantly suppressed DMM-induced cartilage destruction. We found that the loss of and stimulates chondrocyte senescence via the upregulation of and accumulation of acetyl-CoA, and the application of -ACBP-NP is a potential therapeutic strategy for OA treatment.
Topics: Animals; Mice; Acetyl Coenzyme A; Cellular Senescence; Chondrocytes; Manganese Compounds; Mice, Knockout; Osteoarthritis; Oxides; Nudix Hydrolases
PubMed: 37908734
DOI: 10.7150/thno.89033