-
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 -
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 -
Hypertension (Dallas, Tex. : 1979) Nov 2018
Topics: Adenosine Diphosphate Ribose; Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Mice
PubMed: 30354832
DOI: 10.1161/HYPERTENSIONAHA.118.11830 -
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 -
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 -
Genes & Development Mar 2020ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life.... (Review)
Review
ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life. Its complexity derives from the varied range of different chemical linkages, including to several amino acid side chains as well as nucleic acids termini and bases, it can adopt. In this review, we provide an overview of the different families of (ADP-ribosyl)hydrolases. We discuss their molecular functions, physiological roles, and influence on human health and disease. Together, the accumulated data support the increasingly compelling view that (ADP-ribosyl)hydrolases are a vital element within ADP-ribosyl signaling pathways and they hold the potential for novel therapeutic approaches as well as a deeper understanding of ADP-ribosylation as a whole.
Topics: ADP-Ribosylation; Adenosine Diphosphate; Humans; Hydrolases; Protein Domains; Structure-Activity Relationship
PubMed: 32029451
DOI: 10.1101/gad.334631.119 -
ELife Aug 2017The modification of serines by molecules of ADP-ribose plays an important role in signaling that the DNA in a cell has been damaged and needs to be repaired.
The modification of serines by molecules of ADP-ribose plays an important role in signaling that the DNA in a cell has been damaged and needs to be repaired.
Topics: ADP-Ribosylation; Adenosine Diphosphate Ribose; Hydrolases; Serine; Signal Transduction
PubMed: 28796599
DOI: 10.7554/eLife.29942 -
Biochemistry. Biokhimiia Oct 2018H+-FF-ATP synthase (F-ATPase, F-type ATPase, FF complex) catalyzes ATP synthesis from ADP and inorganic phosphate in eubacteria, mitochondria, chloroplasts, and some... (Review)
Review
H+-FF-ATP synthase (F-ATPase, F-type ATPase, FF complex) catalyzes ATP synthesis from ADP and inorganic phosphate in eubacteria, mitochondria, chloroplasts, and some archaea. ATP synthesis is powered by the transmembrane proton transport driven by the proton motive force (PMF) generated by the respiratory or photosynthetic electron transport chains. When the PMF is decreased or absent, ATP synthase catalyzes the reverse reaction, working as an ATP-dependent proton pump. The ATPase activity of the enzyme is regulated by several mechanisms, of which the most conserved is the non-competitive inhibition by the MgADP complex (ADP-inhibition). When ADP binds to the catalytic site without phosphate, the enzyme may undergo conformational changes that lock bound ADP, resulting in enzyme inactivation. PMF can induce release of inhibitory ADP and reactivate ATP synthase; the threshold PMF value required for enzyme reactivation might exceed the PMF for ATP synthesis. Moreover, membrane energization increases the catalytic site affinity to phosphate, thereby reducing the probability of ADP binding without phosphate and preventing enzyme transition to the ADP-inhibited state. Besides phosphate, oxyanions (e.g., sulfite and bicarbonate), alcohols, lauryldimethylamine oxide, and a number of other detergents can weaken ADP-inhibition and increase ATPase activity of the enzyme. In this paper, we review the data on ADP-inhibition of ATP synthases from different organisms and discuss the in vivo role of this phenomenon and its relationship with other regulatory mechanisms, such as ATPase activity inhibition by subunit ε and nucleotide binding in the noncatalytic sites of the enzyme. It should be noted that in Escherichia coli enzyme, ADP-inhibition is relatively weak and rather enhanced than prevented by phosphate.
Topics: Adenosine Diphosphate; Animals; Chloroplasts; Detergents; Escherichia coli; Mitochondria; Protein Binding; Protein Subunits; Proton-Translocating ATPases; Thermodynamics
PubMed: 30472953
DOI: 10.1134/S0006297918100012