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Molecular Cell Apr 2015Hsp90 chaperones receive much attention due to their role in cancer and other pathological conditions, and a tremendous effort of many laboratories has contributed in... (Review)
Review
Hsp90 chaperones receive much attention due to their role in cancer and other pathological conditions, and a tremendous effort of many laboratories has contributed in the past decades to considerable progress in the understanding of their functions. Hsp90 chaperones exist as dimers and, with the help of cochaperones, promote the folding of numerous client proteins. Although the original view of these interactions suggested that these dimeric complexes were symmetrical, it is now clear that many features are asymmetrical. In this review we discuss several recent advances that highlight how asymmetric interactions with cochaperones as well as asymmetric posttranslational modifications provide mechanisms to regulate client interactions and the progression through Hsp90's chaperone cycle.
Topics: Acetylation; Adenosine Diphosphate; HSP90 Heat-Shock Proteins; Humans; Models, Molecular; Phosphorylation; Protein Binding; Protein Conformation; Protein Folding; Protein Isoforms; Protein Multimerization; Protein Processing, Post-Translational; Signal Transduction; Sumoylation
PubMed: 25839432
DOI: 10.1016/j.molcel.2015.02.022 -
The FEBS Journal Dec 2022ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA...
ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.
Topics: ADP Ribose Transferases; Protein Biosynthesis; Adenosine Diphosphate Ribose; Adenosine Diphosphate
PubMed: 34323016
DOI: 10.1111/febs.16142 -
International Journal of Molecular... Jun 2020A new approach to improve the effectiveness of acute myeloid leukemia (AML) treatment is to use the properties of purinergic signaling molecules secreted into the bone...
A new approach to improve the effectiveness of acute myeloid leukemia (AML) treatment is to use the properties of purinergic signaling molecules secreted into the bone marrow milieu in response to leukemic cell growth. Therefore, our study aimed to evaluate the effects of extracellular adenine nucleotides and adenosine on the growth and death parameters in the leukemic THP-1 cell line. Cells were exposed to ATP, ADP, AMP, adenosine and nonhydrolyzable analogues of ATP and ADP (ATPγS and ADPβS) in a 1-1000 μM broad concentration range. The basal mRNA expression of the P1 and P2 receptors was evaluated by real-time PCR. Changes in the processes of cell growth and death were assessed by flow cytometry analysis of proliferation, cell cycle and apoptosis. Chemotaxis toward stromal cell-derived factor-1 (SDF-1) was performed using the modified Boyden chamber assay, and chemokine receptor type 4 (CXCR4) surface expression was quantified by flow cytometry. We indicated several antileukemic actions. High micromolar concentrations (100-1000 μM) of extracellular adenine nucleotides and adenosine inhibit the growth of cells by arresting the cell cycle and/or inducing apoptosis. ATP is characterized by the highest potency and widest range of effects, and is responsible for the cell cycle arrest and the apoptosis induction. Compared to ATP, the effect of ADP is slightly weaker. Adenosine mostly has a cytotoxic effect, with the induction of apoptosis. The last studied nucleotide, AMP, demonstrated only a weak cytotoxic effect without affecting the cell cycle. In addition, cell migration towards SDF-1 was inhibited by low micromolar concentrations (10 μM). One of the reasons for this action of ATPγS and adenosine was a reduction in CXCR4 surface expression, but this only partially explains the mechanism of antimigratory action. In summary, extracellular adenine nucleotides and adenosine inhibit THP-1 cell growth, cause death of cells and modulate the functioning of the SDF-1/CXCR4 axis. Thus, they negatively affect the processes that are responsible for the progression of AML and the difficulties in AML treatment.
Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Affinity Labels; Apoptosis; Cell Cycle; Cell Movement; Cell Proliferation; Extracellular Matrix; Humans; Leukemia, Myeloid, Acute; Thionucleotides; Tumor Cells, Cultured
PubMed: 32580317
DOI: 10.3390/ijms21124425 -
Chembiochem : a European Journal of... Feb 2015Adenosine-5'-triphosphate-dependent enzyme catalysed reactions are widespread in nature. Consequently, the enzymes involved have an intrinsic potential for use in... (Review)
Review
Adenosine-5'-triphosphate-dependent enzyme catalysed reactions are widespread in nature. Consequently, the enzymes involved have an intrinsic potential for use in syntheses of high value products. Although regeneration systems for ATP starting from adenosine-5'-diphosphate are available, certain limitations exist for both in vitro and in vivo applications requiring ATP regeneration from adenosine-5'-monophosphate, or adenosine. Following a short overview of the chemical and thermodynamic background, this Minireview focuses on emerging enzymes and methodologies for ATP regeneration. A large range of as yet unexploited reactions will be accessible with new, powerful, multistep ATP regeneration systems that use cheap phosphate donors and provide high longevity, compatibility, and robustness under process conditions. Their potential might go far beyond the direct use of ATP in enzymatic reactions; enzyme discovery, and engineering, as well as immobilisation strategies, will help to realise such systems.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Biocatalysis; Enzymes; Enzymes, Immobilized; Phosphates; Protein Engineering; Thermodynamics
PubMed: 25619338
DOI: 10.1002/cbic.201402550 -
Frontiers in Immunology 2021Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care...
Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our aim was to better understand the pathophysiology of tissue repair in diabetes in order to find alternative strategies to accelerate wound healing. Nucleotides have been described as extracellular signaling molecules in different inflammatory processes, including tissue repair. Adenosine-5'-diphosphate (ADP) plays important roles in vascular and cellular response and is immediately released after tissue injury, mainly from platelets. However, despite the well described effect on platelet aggregation during inflammation and injury, little is known about the role of ADP on the multiple steps of tissue repair, particularly in skin wounds. Therefore, we used the full-thickness excisional wound model to evaluate the effect of local ADP application in wounds of diabetic mice. ADP accelerated cutaneous wound healing, improved new tissue formation, and increased both collagen deposition and transforming growth factor-β (TGF-β) production in the wound. These effects were mediated by P2Y receptor activation since they were inhibited by Clopidogrel (Clop) treatment, a P2Y receptor antagonist. Furthermore, P2Y receptor antagonist also blocked ADP-induced wound closure until day 7, suggesting its involvement early in repair process. Interestingly, ADP treatment increased the expression of P2Y and P2Y receptors in the wound. In parallel, ADP reduced reactive oxygen species (ROS) formation and tumor necrosis factor-α (TNF-α) levels, while increased IL-13 levels in the skin. Also, ADP increased the counts of neutrophils, eosinophils, mast cells, and gamma delta (γδ) T cells (Vγ4 and Vγ5 cells subtypes of γδ T cells), although reduced regulatory T (Tregs) cells in the lesion. In accordance, ADP increased fibroblast proliferation and migration, myofibroblast differentiation, and keratinocyte proliferation. In conclusion, we provide strong evidence that ADP acts as a pro-resolution mediator in diabetes-associated skin wounds and is a promising intervention target for this worldwide problem.
Topics: Adenosine Diphosphate; Administration, Cutaneous; Alloxan; Animals; Diabetes Mellitus, Experimental; Humans; Male; Mice; Purinergic P2Y Receptor Agonists; Receptors, Purinergic P2Y12; Skin; Wound Healing
PubMed: 33828561
DOI: 10.3389/fimmu.2021.651740 -
Urologie (Heidelberg, Germany) Dec 2023Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying clinical and molecular subtypes. Almost one-third of patients have... (Review)
Review
[Combination therapy with poly(adenosine diphosphate-ribose) polymerase (PARPi) and androgen receptor signaling pathway (ARPi) inhibitors for metastatic castration-resistant prostate cancer].
Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying clinical and molecular subtypes. Almost one-third of patients have abnormalities in homologous recombinant repair genes. Again, about one third of these mutations affect the BReast CAncer 1 or 2 (BRCA 1 or BRCA 2) genes, which generally render tumours receptive to treatment with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi). In 2020 the PARPi olaparib was approved for the treatment of mCRPC after progression with a new hormonal drug (androgen receptor signaling pathway inhibitors, ARPi). In 2022 and 2023 approval of two combination therapies followed, each combining a PARPi and an ARPi (olaparib plus abiraterone and niraparib plus abiraterone). The combination of talazoparib plus enzalutamide will be approved soon. This article introduces the pivotal clinical trials that led to the approval of the respective substances, reports the side effects that may occur during therapy with PARPi plus ARPi, and offers recommendations for management of these side effects.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Ribose; Poly(ADP-ribose) Polymerases; Signal Transduction; Adenosine Diphosphate
PubMed: 37978072
DOI: 10.1007/s00120-023-02230-1 -
Methods in Molecular Biology (Clifton,... 2022Mitochondrial energy production is crucial for normal daily activities and maintenance of life. Herein, the logic and execution of two main classes of measurements are...
Mitochondrial energy production is crucial for normal daily activities and maintenance of life. Herein, the logic and execution of two main classes of measurements are outlined to delineate mitochondrial function: ATP production and oxygen consumption. Aerobic ATP production is quantified by phosphorus magnetic resonance spectroscopy (PMRS) in vivo in both human subjects and animal models using the same protocols and maintaining the same primary assumptions. Mitochondrial oxygen consumption is quantified by oxygen polarography and applied in isolated mitochondria, cultured cells, and permeabilized fibers derived from human or animal tissue biopsies. Traditionally, mitochondrial functional measures focus on maximal oxidative capacity-a flux rate that is rarely, if ever, observed outside of experimental conditions. Perhaps more physiologically relevant, both measurement classes herein focus on one principal design paradigm; submaximal mitochondrial fluxes generated by graded levels of ADP to map the function for ADP sensitivity. We propose this function defines the bioenergetic role that mitochondria fill within the myoplasm to sense and match ATP demands. Any deficit in this vital role for ATP homeostasis leads to symptoms often seen in cardiovascular and cardiopulmonary diseases, diabetes, and metabolic syndrome.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Energy Metabolism; Humans; Mitochondria; Oxidative Phosphorylation; Oxygen Consumption; Polarography
PubMed: 35771441
DOI: 10.1007/978-1-0716-2309-1_10 -
Cancer Jun 2023
Topics: Humans; Poly(ADP-ribose) Polymerases; Adenosine Diphosphate Ribose
PubMed: 37060235
DOI: 10.1002/cncr.34705 -
GeroScience Dec 2023Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and...
The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT).
Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH (flavin adenine dinucleotide), O (oxygen), ELAM (elamipretide), -SH (free thiol), -SSG (glutathionylated protein).
Topics: Mitochondria; Adenosine Triphosphate; Adenosine Diphosphate; Peptides
PubMed: 37462785
DOI: 10.1007/s11357-023-00861-y -
Annales de Biologie Clinique Feb 2021During primary hemostasis the platelets aggregate to form the platelet thrombus. ADP and thrombin generated by coagulation are the main agonists in platelet aggregation....
During primary hemostasis the platelets aggregate to form the platelet thrombus. ADP and thrombin generated by coagulation are the main agonists in platelet aggregation. In a previous study we were able to show that patients with lung cancer had hypercoagulability, hyperfibrinogemia (≥ 6.22 g/L) was predictive of thromboembolic disease at the start of diagnosis before any therapy. In this study, we studied platelet aggregation in these patients in order to demonstrate whether they have hyperaggregability associated with the hypercoagulability demonstrated previously, and this by evaluating abnormalities in primary hemostasis (platelet count and platelet aggregation). One hundred and one patients diagnosed before any therapy and 72 blood donors were included. Agonists used for platelet aggregation are collagen and adenosine diphosphate at low concentrations. Hyperaggregability is observed when blood platelets are stimulated by ADP at different concentrations (p ≤ 0.01). This hyperaggregability is influenced by the histological type and not the development of the cancer, the age of the subjects and the platelet count, it is independent of hyperfibrinogemia and the occurrence of thromboembolic disease. However, an increase in the platelet level is found in patients with hyperfibrinogemia. Patients with lung cancer present platelet activation observed by aggregometry in response to ADP; which is not influenced by hyperfibrinogemia during cancer.
Topics: Adenosine Diphosphate; Blood Platelets; Humans; Lung Neoplasms; Platelet Aggregation; Thrombin
PubMed: 33648917
DOI: 10.1684/abc.2021.1623