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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 -
Critical Reviews in Biochemistry and... Feb 2021The focus of this review is the human de novo purine biosynthetic pathway. The pathway enzymes are enumerated, as well as the reactions they catalyze and their physical... (Review)
Review
The focus of this review is the human de novo purine biosynthetic pathway. The pathway enzymes are enumerated, as well as the reactions they catalyze and their physical properties. Early literature evidence suggested that they might assemble into a multi-enzyme complex called a metabolon. The finding that fluorescently-tagged chimeras of the pathway enzymes form discrete puncta, now called purinosomes, is further elaborated in this review to include: a discussion of their assembly; the role of ancillary proteins; their locus at the microtubule/mitochondria interface; the elucidation that at endogenous levels, purinosomes function to channel intermediates from phosphoribosyl pyrophosphate to AMP and GMP; and the evidence for the purinosomes to exist as a protein condensate. The review concludes with a consideration of probable signaling pathways that might promote the assembly and disassembly of the purinosome, in particular the identification of candidate kinases given the extensive phosphorylation of the enzymes. These collective findings substantiate our current view of the de novo purine biosynthetic metabolon whose properties will be representative of how other metabolic pathways might be organized for their function.
Topics: Adenosine Monophosphate; Biosynthetic Pathways; Cyclic AMP; Cyclic GMP; Guanosine Monophosphate; Humans; Microtubules; Mitochondria; Multienzyme Complexes; Phosphoribosyl Pyrophosphate; Phosphorylation; Proteins; Purines; Signal Transduction
PubMed: 33179964
DOI: 10.1080/10409238.2020.1832438 -
Cell Metabolism Jun 2021NAD(H) and NADP(H) have traditionally been viewed as co-factors (or co-enzymes) involved in a myriad of oxidation-reduction reactions including the electron transport in... (Review)
Review
NAD(H) and NADP(H) have traditionally been viewed as co-factors (or co-enzymes) involved in a myriad of oxidation-reduction reactions including the electron transport in the mitochondria. However, NAD pathway metabolites have many other important functions, including roles in signaling pathways, post-translational modifications, epigenetic changes, and regulation of RNA stability and function via NAD-capping of RNA. Non-oxidative reactions ultimately lead to the net catabolism of these nucleotides, indicating that NAD metabolism is an extremely dynamic process. In fact, recent studies have clearly demonstrated that NAD has a half-life in the order of minutes in some tissues. Several evolving concepts on the metabolism, transport, and roles of these NAD pathway metabolites in disease states such as cancer, neurodegeneration, and aging have emerged in just the last few years. In this perspective, we discuss key recent discoveries and changing concepts in NAD metabolism and biology that are reshaping the field. In addition, we will pose some open questions in NAD biology, including why NAD metabolism is so fast and dynamic in some tissues, how NAD and its precursors are transported to cells and organelles, and how NAD metabolism is integrated with inflammation and senescence. Resolving these questions will lead to significant advancements in the field.
Topics: Animals; Energy Metabolism; Humans; Mitochondria; NAD; NADP
PubMed: 33930322
DOI: 10.1016/j.cmet.2021.04.003 -
Signal Transduction and Targeted Therapy Oct 2020Nicotinamide adenine dinucleotide (NAD) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to... (Review)
Review
Nicotinamide adenine dinucleotide (NAD) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP. Prolonged disequilibrium of NAD metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD-regulated physiological responses to stresses, the contribution of NAD deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.
Topics: Aging; Cyclic ADP-Ribose; Humans; Metabolic Diseases; NAD; NADP; Neoplasms; Neurodegenerative Diseases; Oxidation-Reduction
PubMed: 33028824
DOI: 10.1038/s41392-020-00311-7 -
Cell Jan 2020Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We...
Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H and phosphate recycling.
Topics: Adenine; Adenosine; Adenosine Deaminase; Chromatography, Liquid; HEK293 Cells; Hep G2 Cells; Humans; Intracellular Signaling Peptides and Proteins; Mass Spectrometry; Multifunctional Enzymes; Phosphorylation; Proteins; Purine Nucleotides; Purines
PubMed: 31978345
DOI: 10.1016/j.cell.2019.12.017 -
Molecular Cell Feb 2021Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms...
Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD/NADH ratio. This change in NAD/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD is in excess of the demand for ATP.
Topics: A549 Cells; Adenosine Triphosphate; Aerobiosis; Glucose; Glycolysis; HeLa Cells; Humans; NAD; Oxidation-Reduction
PubMed: 33382985
DOI: 10.1016/j.molcel.2020.12.012 -
Profiles of Drug Substances,... 2023Remdesivir, marketed under the brand name Veklury, is an antiviral drug with a broad spectrum of activity. There were various countries where the use of Remdesivir for... (Review)
Review
Remdesivir, marketed under the brand name Veklury, is an antiviral drug with a broad spectrum of activity. There were various countries where the use of Remdesivir for the treatment of COVID-19 was authorized during the pandemic. Remdesivir was first designed to treat hepatitis C, but it was later tested for Ebola virus sickness and Marburg virus infections. Remdesivir is a prodrug designed to facilitate the intracellular transport of GS-441524 monophosphate and its subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase. The objective of this chapter is to provide a comprehensive review of Remdesivir (GS-5734), including its nomenclature, physiochemical properties, preparation methods, identification procedures, numerous qualitative and quantitative analytical techniques, ADME profiles, and pharmacological effects. In addition, the chapter provides a variety of chromatographic and spectroscopic techniques for separating brimonidine from other drugs in combination formulations.
Topics: Humans; COVID-19; SARS-CoV-2; COVID-19 Drug Treatment; Adenosine Monophosphate
PubMed: 37061276
DOI: 10.1016/bs.podrm.2022.11.003 -
Science Immunology Jul 2023The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the... (Review)
Review
The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
Topics: Humans; Neoplasms; Adenosine; Adenosine Triphosphate; Adenosine Monophosphate; DNA Damage; Tumor Microenvironment
PubMed: 37418547
DOI: 10.1126/sciimmunol.abq3015 -
Molecules (Basel, Switzerland) Dec 2023In addition to comprising monomers of nucleic acids, nucleotides have signaling functions and act as second messengers in both prokaryotic and eukaryotic cells. The most... (Review)
Review
In addition to comprising monomers of nucleic acids, nucleotides have signaling functions and act as second messengers in both prokaryotic and eukaryotic cells. The most common example is cyclic AMP (cAMP). Nucleotide signaling is a focus of great interest in bacteria. Cyclic di-AMP (c-di-AMP), cAMP, and cyclic di-GMP (c-di-GMP) participate in biological events such as bacterial growth, biofilm formation, sporulation, cell differentiation, motility, and virulence. Moreover, the cyclic-di-nucleotides (c-di-nucleotides) produced in pathogenic intracellular bacteria can affect eukaryotic host cells to allow for infection. On the other hand, non-cyclic nucleotide molecules pppGpp and ppGpp are alarmones involved in regulating the bacterial response to nutritional stress; they are also considered second messengers. These second messengers can potentially be used as therapeutic agents because of their immunological functions on eukaryotic cells. In this review, the role of c-di-nucleotides and cAMP as second messengers in different bacterial processes is addressed.
Topics: Second Messenger Systems; Cyclic GMP; Signal Transduction; Bacteria; Cyclic AMP; Nucleotides, Cyclic; Bacterial Proteins
PubMed: 38138485
DOI: 10.3390/molecules28247996 -
Frontiers in Endocrinology 2022Adenosine triphosphate (ATP) serves as the essential source of cellular energy. Over the last two decades, however, ATP has also attracted increasing interest as an... (Review)
Review
Adenosine triphosphate (ATP) serves as the essential source of cellular energy. Over the last two decades, however, ATP has also attracted increasing interest as an extracellular signal that activates purinergic plasma membrane receptors of the P2 family. P2 receptors are divided into two types: ATP-gated nonselective cation channels (P2X) and G protein-coupled receptors (P2Y), the latter being activated by a broad range of purine and pyrimidine nucleotides (ATP, ADP, UTP, and UDP, among others). Purinergic signaling mechanisms are involved in numerous physiological events and pathophysiological conditions. Here, we address the growing body of evidence implicating purinergic signaling in male reproductive system functions. The life-long generation of fertile male germ cells is a highly complex, yet mechanistically poorly understood process. Given the relatively sparse innervation of the testis, spermatogenesis relies on both endocrine control and multi-directional paracrine communication. Therefore, a detailed understanding of such paracrine messengers, including ATP, is crucial to gain mechanistic insight into male reproduction..
Topics: Adenosine Triphosphate; Endocrine System; Humans; Male; Receptors, Purinergic; Signal Transduction; Spermatogenesis
PubMed: 35480481
DOI: 10.3389/fendo.2022.867011