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Biochimica Et Biophysica Acta.... Nov 2020In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes that take place during net biomass formation and... (Review)
Review
In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes that take place during net biomass formation and maintenance processes. During growth, both ATP/ADP and NADH/NAD molecules play a key role. Cell energy metabolism hence refers to metabolic pathways involved in ATP synthesis linked to NADH turnover. Two main pathways are thus involved in cell energy metabolism: glycolysis/fermentation and oxidative phosphorylation. Glycolysis and mitochondrial oxidative phosphorylation are intertwined through thermodynamic and kinetic constraints that are reviewed herein. Further, our current knowledge of short-term and long term regulation of cell energy metabolism will be reviewed using examples such as the Crabtree and the Warburg effect.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Cell Physiological Phenomena; Energy Metabolism; Glycolysis; Kinetics; NAD; Oxidative Phosphorylation
PubMed: 32717222
DOI: 10.1016/j.bbabio.2020.148276 -
Clinical Pharmacokinetics Dec 2022Olaparib, niraparib, rucaparib, and talazoparib are poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of ovarian, breast, pancreatic, and/or... (Review)
Review
Olaparib, niraparib, rucaparib, and talazoparib are poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of ovarian, breast, pancreatic, and/or prostate cancer. Poly (ADP-ribose) polymerase inhibitors are potent inhibitors of the PARP enzymes with comparable half-maximal inhibitory concentrations in the nanomolar range. Olaparib and rucaparib are orally dosed twice a day, extensively metabolized by cytochrome P450 enzymes, and inhibitors of several enzymes and drug transporters with a high risk for drug-drug interactions. Niraparib and talazoparib are orally dosed once a day with a lower risk for niraparib and a minimal risk for talazoparib to cause drug-drug interactions. All four PARP inhibitors show moderate-to-high interindividual variability in plasma exposure. Higher exposure is associated with an increase in toxicity, mostly hematological toxicity. For talazoparib, exposure-efficacy relationships have been described, but for olaparib, niraparib, and rucaparib this relationship remains inconclusive. Further studies are required to investigate exposure-response relationships to improve dosing of PARP inhibitors, in which therapeutic drug monitoring could play an important role. In this review, we give an overview of the pharmacokinetic properties of the four PARP inhibitors, including considerations for patients with renal dysfunction or hepatic impairment, the effect of food, and drug-drug interactions. Furthermore, we focus on the pharmacodynamics and summarize the available exposure-efficacy and exposure-toxicity relationships.
Topics: Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Ribose; Ovarian Neoplasms; Poly(ADP-ribose) Polymerases; Adenosine Diphosphate
PubMed: 36219340
DOI: 10.1007/s40262-022-01167-6 -
Journal of Hematology & Oncology Oct 2022Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly... (Review)
Review
Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through "synthetic lethality" mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.
Topics: Adenosine Diphosphate; Cell Cycle; Cell Cycle Checkpoints; DNA Damage; DNA Repair; Genomic Instability; Humans; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Ribose; Tumor Suppressor Protein p53
PubMed: 36253861
DOI: 10.1186/s13045-022-01360-x -
Biophysical Chemistry Sep 2020Recent publications have questioned the appropriateness of the chemiosmotic theory, a key tenet of modern bioenergetics originally described by Mitchell and since widely...
Recent publications have questioned the appropriateness of the chemiosmotic theory, a key tenet of modern bioenergetics originally described by Mitchell and since widely improved upon and applied. In one of them, application of Gauss' law to a model charge distribution in mitochondria was argued to refute the possibility of ATP generation through H movement in the absence of a counterion, whereas a different author advocated, for other reasons, the impossibility of chemiosmosis and proposed that a novel energy-generation scheme (referred to as "murburn") relying on superoxide-catalyzed (or superoxide-promoted) ADP phosphorylation would operate instead. In this letter, those proposals are critically examined and found to be inconsistent with established experimental data and new theoretical calculations.
Topics: Adenosine Diphosphate; Energy Metabolism; Hydrogen-Ion Concentration; Mitochondria; Osmosis; Phosphorylation; Protons
PubMed: 32717593
DOI: 10.1016/j.bpc.2020.106424 -
Cells Feb 2022Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling... (Review)
Review
Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA found in mitochondria themselves, and are termed mitochondrial DNA (mtDNA). Mutations striking either genome can lead to mitochondrial impairment, determining infantile, childhood or adult neurodegeneration. Mitochondrial disorders are complex neurological syndromes, and are often part of a multisystem disorder. In this paper, we divide the diseases into those caused by mtDNA defects and those that are due to mutations involving nuclear genes; from a clinical point of view, we discuss pediatric disorders in comparison to juvenile or adult-onset conditions. The complementary genetic contributions controlling organellar function and the complexity of the biochemical pathways present in the mitochondria justify the extreme genetic and phenotypic heterogeneity of this new area of inborn errors of metabolism known as 'mitochondrial medicine'.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adult; Child; DNA, Mitochondrial; Humans; Mitochondria; Protons
PubMed: 35203288
DOI: 10.3390/cells11040637 -
Cancer Letters Dec 2022In cancer cells, poly (ADP-ribose) polymerase (PARP)-1 and PARP2 initiate and regulate DNA repair pathways to protect against DNA damage and cell death caused by...
In cancer cells, poly (ADP-ribose) polymerase (PARP)-1 and PARP2 initiate and regulate DNA repair pathways to protect against DNA damage and cell death caused by radiotherapy or chemotherapy. Radiotherapy and PARP inhibitors (PARPis) have been combined in clinical trials, but their action mechanisms remain unclear. Here, we show that activated by ionizing radiation (IR) generated dsDNA, cyclic GMP-AMP synthase (cGAS) signaling promoted regulated cell death, specifically ferroptosis, via the activating transcription factor 3 (ATF3)-solute carrier family 7 member 11 axis and the antitumor immune response via the interferon-β-CD8 T cell pathway. Niraparib, a widely used PARPi, augmented cGAS-mediated ferroptosis and immune activation. In colorectal cancer models, cGAS knockdown (KD) compromised IR-induced ferroptosis via downregulation of ATF3 (key ferroptosis regulator) expression. cGAS depletion reversed IR-induced infiltration of CD8 T or CD8GZMB T cells in the cGAS KD group. Survival analysis of paired tumor samples before and after standard radiotherapy revealed that high expression levels of cGAS, ATF3, and PTGS2 and high density of CD8 T cells resulted in a significantly high disease-free survival rate in patients with rectal cancer. Therefore, PARPi treatment increases the cytoplasmic accumulation of dsDNA caused by IR, triggering the cGAS signaling-mediated tumor control in cancer cell lines and mouse xenograft models.
Topics: Activating Transcription Factor 3; Adenosine Diphosphate; Animals; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Cyclooxygenase 2; Ferroptosis; Humans; Immunity; Interferon-beta; Membrane Proteins; Mice; Nucleotidyltransferases; Poly(ADP-ribose) Polymerase Inhibitors; Ribose; Signal Transduction
PubMed: 36116741
DOI: 10.1016/j.canlet.2022.215919 -
Diabetes & Metabolic Syndrome Aug 2022The pathophysiology of different types of diabetes is incompletely understood. Fatty acid binding protein 4 (FABP4), an intracellular lipid chaperone, is secreted from... (Review)
Review
BACKGROUND AND AIMS
The pathophysiology of different types of diabetes is incompletely understood. Fatty acid binding protein 4 (FABP4), an intracellular lipid chaperone, is secreted from adipocytes (during lipolysis) and macrophage. FABP4 is known to be associated with insulin resistance. However its precise role in the pathogenesis of T2DM is unclear. Fabkin, the hormonal complex of FABP4 with ADK (Adenosine Kinase) and NDPK (Nucleoside Diphosphate Kinase) is suggested to fill this gap in understanding pathogenesis. Herein, we summarize the role Fabkin in glucose homeostasis.
METHODS
Published relevant manuscripts that discussed the effect of FABP4 and Fabkin on glucose homeostasis were reviewed.
RESULTS
The formation of Fabkin complex is driven by the strong affinities of FABP4 to ADK and to inherent high-affinity interaction of ADK with NDPK. It does not have any definite receptors. The complex acts through the following pathways: i) by modulation of Glucose-Stimulated Insulin Signalling (GSIS) through extracellular ADP/ATP interaction via G-protein-coupled purinergic P2Y receptors in pancreatic β-cells which are potently agonized by ADP and antagonized by ATP. Fabkin drives ADK to produce ATP, coupled with reduced generation of ADP. This results in low extracellular ADP/ATP ratio which leads to impairment of insulin secretion, ii) by regulating intracellular calcium dynamics iii) by producing Endoplasmic Reticulum (ER) stress.
CONCLUSIONS
Fabkin may integrate energy balance with functions of metabolic organs and thus play a major role in glucose homeostasis.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Glucose; Homeostasis; Humans; Insulin; Insulin Secretion
PubMed: 35850074
DOI: 10.1016/j.dsx.2022.102565 -
Cell Sep 2020SARS-CoV-2 is the causative agent of the 2019-2020 pandemic. The SARS-CoV-2 genome is replicated and transcribed by the RNA-dependent RNA polymerase holoenzyme (subunits...
SARS-CoV-2 is the causative agent of the 2019-2020 pandemic. The SARS-CoV-2 genome is replicated and transcribed by the RNA-dependent RNA polymerase holoenzyme (subunits nsp7/nsp8/nsp12) along with a cast of accessory factors. One of these factors is the nsp13 helicase. Both the holo-RdRp and nsp13 are essential for viral replication and are targets for treating the disease COVID-19. Here we present cryoelectron microscopic structures of the SARS-CoV-2 holo-RdRp with an RNA template product in complex with two molecules of the nsp13 helicase. The Nidovirales order-specific N-terminal domains of each nsp13 interact with the N-terminal extension of each copy of nsp8. One nsp13 also contacts the nsp12 thumb. The structure places the nucleic acid-binding ATPase domains of the helicase directly in front of the replicating-transcribing holo-RdRp, constraining models for nsp13 function. We also observe ADP-Mg bound in the nsp12 N-terminal nidovirus RdRp-associated nucleotidyltransferase domain, detailing a new pocket for anti-viral therapy development.
Topics: Adenosine Diphosphate; Betacoronavirus; Binding Sites; Coronavirus RNA-Dependent RNA Polymerase; Cryoelectron Microscopy; Holoenzymes; Magnesium; Methyltransferases; Protein Binding; RNA Helicases; RNA, Viral; RNA-Dependent RNA Polymerase; SARS-CoV-2; Viral Nonstructural Proteins; Virus Replication
PubMed: 32783916
DOI: 10.1016/j.cell.2020.07.033 -
Trends in Biochemical Sciences Jun 2021The renaissance of interest in metabolism has focused mostly on techniques to measure massive numbers of metabolites. Yet, established metabolic theory has been...
The renaissance of interest in metabolism has focused mostly on techniques to measure massive numbers of metabolites. Yet, established metabolic theory has been abandoned. Here, I highlight one misconception: how ATP (and ADP and AMP) are currently understood. A critical point was established early on: cellular [ATP] is constant.
Topics: Adenosine Diphosphate; Adenosine Triphosphate
PubMed: 33741213
DOI: 10.1016/j.tibs.2021.03.001 -
Nature Reviews. Microbiology Feb 2021
Topics: Adenosine Diphosphate; Calcium; Calcium Signaling; Rotavirus
PubMed: 33299173
DOI: 10.1038/s41579-020-00496-2