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Molecular Microbiology Dec 2023Cyclic dimeric adenosine monophosphate (c-di-AMP) has been well studied in bacteria, including those of the genus Streptococcus, since the first recognition of this... (Review)
Review
Cyclic dimeric adenosine monophosphate (c-di-AMP) has been well studied in bacteria, including those of the genus Streptococcus, since the first recognition of this dinucleotide in 2008. Streptococci possess a sole diadenylate cyclase, CdaA, and distinct c-di-AMP phosphodiesterases. Interestingly, cdaA is required for viability of some streptococcal species but not all when streptococci are grown in standard laboratory media. Bacteria of this genus also have distinct c-di-AMP effector proteins, diverse c-di-AMP-signaling pathways, and subsequent biological outcomes. In streptococci, c-di-AMP may influence bacterial growth, morphology, biofilm formation, competence program, drug resistance, and bacterial pathogenesis. c-di-AMP secreted by streptococci has also been shown to interact with the mammalian host and induces immune responses including type I interferon production. In this review, we summarize the reported c-di-AMP networks in seven species of the genus Streptococcus, which cause diverse clinical manifestations, and propose future perspectives to investigate the signaling molecule in these streptococcal pathogens.
Topics: Animals; Bacterial Proteins; Second Messenger Systems; Dinucleoside Phosphates; Cyclic AMP; Bacteria; Streptococcus; Mammals
PubMed: 37898560
DOI: 10.1111/mmi.15187 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Sep 2017Bacterial biofilm plays an important role in persistent microbial infection. Delineation of the formation and development of bacterial biofilm would provide a promising... (Review)
Review
Bacterial biofilm plays an important role in persistent microbial infection. Delineation of the formation and development of bacterial biofilm would provide a promising strategy to treat recalcitrant infection. c-di-AMP (Cyclic diadenosine monophosphate) is a recently identified second messenger of bacteria and involved in plethora of bacterial activities, including cell growth, cell wall homeostasis, biofilm formation and microbial pathogenicity. Here we review the recent literature pertinent to the role and molecular mechanisms of c-di-AMP in regulating biofilm formation of bacteria. The potential application of c-di-AMP and its related proteins in the development of novel antimicrobial therapeutics has also been discussed.
Topics: Bacteria; Biofilms; Dinucleoside Phosphates; Second Messenger Systems
PubMed: 28956388
DOI: 10.13345/j.cjb.170078 -
Organic Letters Jul 2016A methodology for the synthesis of oligophosphate conjugates using phosphordiamidites is described. This strategy facilitates the straightforward preparation of...
A methodology for the synthesis of oligophosphate conjugates using phosphordiamidites is described. This strategy facilitates the straightforward preparation of C2-symmetric dinucleoside tri-, penta-, and heptaphosphates. Moreover, unsymmetric compounds such as thiamine adenosine triphosphate and thiamine cytidine triphosphate can be prepared. The material is used to study the inhibitory activity of thiaminylated nucleotides against adenosine diphosphate ribosyltransferases.
PubMed: 27308921
DOI: 10.1021/acs.orglett.6b01466 -
FEMS Microbiology Reviews Nov 2020Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP) is an emerging second messenger in bacteria and archaea that is synthesized from two molecules of ATP by... (Review)
Review
Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP) is an emerging second messenger in bacteria and archaea that is synthesized from two molecules of ATP by diadenylate cyclases and degraded to pApA or two AMP molecules by c-di-AMP-specific phosphodiesterases. Through binding to specific protein- and riboswitch-type receptors, c-di-AMP regulates a wide variety of prokaryotic physiological functions, including maintaining the osmotic pressure, balancing central metabolism, monitoring DNA damage and controlling biofilm formation and sporulation. It mediates bacterial adaptation to a variety of environmental parameters and can also induce an immune response in host animal cells. In this review, we discuss the phylogenetic distribution of c-di-AMP-related enzymes and receptors and provide some insights into the various aspects of c-di-AMP signaling pathways based on more than a decade of research. We emphasize the key role of c-di-AMP in maintaining bacterial osmotic balance, especially in Gram-positive bacteria. In addition, we discuss the future direction and trends of c-di-AMP regulatory network, such as the likely existence of potential c-di-AMP transporter(s), the possibility of crosstalk between c-di-AMP signaling with other regulatory systems, and the effects of c-di-AMP compartmentalization. This review aims to cover the broad spectrum of research on the regulatory functions of c-di-AMP and c-di-AMP signaling pathways.
Topics: Bacteria; Bacterial Physiological Phenomena; Dinucleoside Phosphates; Phylogeny; Research; Signal Transduction
PubMed: 32472931
DOI: 10.1093/femsre/fuaa019 -
Current Opinion in Microbiology Apr 2021Cyclic dinucleotide (cdN) second messengers are essential for bacteria to sense and adapt to their environment. These signals were first discovered with the... (Review)
Review
Cyclic dinucleotide (cdN) second messengers are essential for bacteria to sense and adapt to their environment. These signals were first discovered with the identification of 3'-5', 3'-5' cyclic di-GMP (c-di-GMP) in 1987, a second messenger that is now known to be the linchpin signaling pathway modulating bacterial motility and biofilm formation. In the past 15 years, three more cdNs were uncovered: 3'-5', 3'-5' cyclic di-AMP (c-di-AMP) and 3'-5', 3'-5' cyclic GMP-AMP (3',3' cGAMP) in bacteria and 2'-5', 3'-5' cyclic GMP-AMP (2',3' cGAMP) in eukaryotes. We now appreciate that bacteria can synthesize many varieties of cdNs from every ribonucleotide, and even cyclic trinucleotide (ctN) second messengers have been discovered. Here we highlight our current understanding of c-di-GMP and c-di-AMP in bacterial physiology and focus on recent advances in 3',3' cGAMP signaling effectors, its role in bacterial phage response, and the diversity of its synthase family.
Topics: Bacteria; Bacterial Physiological Phenomena; Bacterial Proteins; Cyclic GMP; Dinucleoside Phosphates; Nucleotides, Cyclic; Oligonucleotides; Second Messenger Systems
PubMed: 33640793
DOI: 10.1016/j.mib.2021.01.017 -
Purinergic Signalling Mar 2021Development of science needs the cooperation of many creative brains. Sometimes, ideas on a specific area get suddenly exhausted and then it is the time for a privileged... (Review)
Review
Development of science needs the cooperation of many creative brains. Sometimes, ideas on a specific area get suddenly exhausted and then it is the time for a privileged mind to think in a different way and reach the turning point to introduce a new paradigm. This happened to Geoffrey Burnstock, a heterodox thinker and nonconformist scientist that has been the paladin of purinergic signalling since 1972, opening neuroscience to the understanding of organs and tissues functioning and development of a new pharmacology. This review summarizes the contribution of our group to the understanding of the role of the diadenosine polyphosphates, ApA, as signalling molecules, describing their tissue and organ distribution, their transport and storage in secretory vesicles and their release and interaction with purinergic receptors. We also have to acknowledge the friendly and kindly support of Professor Burnstock that showed a great interest in the field from our initial findings and actively stimulated our efforts to establish the extracellular roles and biological significance of these dinucleotides.
Topics: Animals; Dinucleoside Phosphates; Humans; Receptors, Purinergic; Secretory Vesicles; Synapses
PubMed: 33025428
DOI: 10.1007/s11302-020-09736-9 -
Bioorganic Chemistry Dec 2023Xeno nucleic acids (XNA) are an increasingly important class of hypermodified nucleic acids with great potential in bioorganic chemistry and synthetic biology. Glycol... (Review)
Review
Xeno nucleic acids (XNA) are an increasingly important class of hypermodified nucleic acids with great potential in bioorganic chemistry and synthetic biology. Glycol nucleic acid (GNA) is constructed from a three-carbon 1,2-propanediol (propylene glycol) backbone attached to a nucleobase entity, representing the simplest known XNA. This review is intended to present GNA nucleosides from a synthetic chemistry perspective-a perspective that serves as a starting point for biological studies. Therefore this account focuses on synthetic methods for GNA nucleoside synthesis, as well as their postsynthetic chemical transformations. The properties and biological activity of GNA constituents are also highlighted. A literature survey shows four major approaches toward GNA nucleoside scaffold synthesis. These approaches pertain to glycidol ring-opening, Mitsunobu, S2, and dihydroxylation reactions. The general arsenal of reactions used in GNA chemistry is versatile and encompasses the Sonogashira reaction, Michael addition, silyl-Hilbert-Johnson reaction, halogenation, alkylation, cyclization, Rh-catalyzed N-allylation, Sharpless catalytic dihydroxylation, and Yb(OTf)-catalyzed etherification. Additionally, various phosphorylation reactions have enabled the synthesis of diverse types of GNA nucleotides, dinucleoside phosphates, phosphordiamidites, and oligos. Furthermore, recent advances in GNA chemistry have resulted in the synthesis of previously unknown redox-active (ferrocenyl) and luminescent (pyrenyl and phenanthrenyl) GNA nucleosides, which are also covered in this review.
Topics: Nucleic Acids; Nucleosides; Glycols; Nucleotides; Propylene Glycol
PubMed: 37871392
DOI: 10.1016/j.bioorg.2023.106921 -
Current Protocols Sep 2023Cyclic diadenosine monophosphate (c-di-AMP) is a bacterial cyclic dinucleotide (CDN) comprising two adenosine monophosphates covalently linked by two...
Cyclic diadenosine monophosphate (c-di-AMP) is a bacterial cyclic dinucleotide (CDN) comprising two adenosine monophosphates covalently linked by two 3',5'-phosphodiester bonds. c-di-AMP works as a second messenger, regulating many biological processes in bacteria such as cell wall homeostasis, DNA integrity, and sporulation via specific protein and/or RNA receptors. Moreover, c-di-AMP can function as an immunomodulatory agent in eukaryote cells via the stimulator of interferon genes (STING) signaling pathway. This protocol describes the chemical synthesis of two c-di-AMP analogs with a sulfur atom at the 4'-position of the furanose ring instead of an oxygen atom: c-di-4'-thioAMP (1) and cAMP-4'-thioAMP (2). Analogs 1 and 2 have resistance to phosphodiesterase-mediated degradation and are therefore useful for understanding the diverse biological phenomena regulated by c-di-AMP. In this protocol, two 4'-thioadenosine monomers are initially prepared via a Pummerer-like reaction assisted by hypervalent iodine. The CDN skeleton is then constructed through two key reactions based on phosphoramidite chemistry: dimerization of two appropriately protected nucleoside monomers to produce a linear dinucleotide, followed by macrocyclization of the resulting linear dinucleotide to form the CDN skeleton. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Preparation of 4'-thioadenosine monomers 13 and 14 Basic Protocol 2: Preparation of c-di-4'-thioAMP (1) and cAMP-4'-thioAMP (2).
Topics: Dinucleoside Phosphates; Thionucleosides; Homeostasis; Cyclic AMP
PubMed: 37725690
DOI: 10.1002/cpz1.892 -
Critical Reviews in Eukaryotic Gene... 2016Nucleotide-based second messengers transduce signals originating from both outside and inside the cell to adaptive responses accordingly. c-di-AMP is a newly established... (Review)
Review
Nucleotide-based second messengers transduce signals originating from both outside and inside the cell to adaptive responses accordingly. c-di-AMP is a newly established second messenger employed by many organisms. We summarize recent advances in bacterial c-di-AMP-mediated signaling, especially the interaction between c-di-AMP signaling and the host.
Topics: Bacteria; Dinucleoside Phosphates; Second Messenger Systems
PubMed: 27910745
DOI: 10.1615/CritRevEukaryotGeneExpr.2016016642 -
Bioorganic Chemistry Jul 2024Adenylate kinase (AK) plays a crucial role in the metabolic monitoring of cellular adenine nucleotide homeostasis by catalyzing the reversible transfer of a phosphate...
Adenylate kinase (AK) plays a crucial role in the metabolic monitoring of cellular adenine nucleotide homeostasis by catalyzing the reversible transfer of a phosphate group between ATP and AMP, yielding two ADP molecules. By regulating the nucleotide levels and energy metabolism, the enzyme is considered a disease modifier and potential therapeutic target for various human diseases, including malignancies and inflammatory and neurodegenerative disorders. However, lacking approved drugs targeting AK hinders broad studies on this enzyme's pathological importance and therapeutic potential. In this work, we determined the effect of a series of dinucleoside polyphosphate derivatives, commercially available (11 compounds) and newly synthesized (8 compounds), on the catalytic activity of human adenylate kinase isoenzyme 1 (hAK1). The tested compounds belonged to the following groups: (1) diadenosine polyphosphates with different phosphate chain lengths, (2) base-modified derivatives, and (3) phosphate-modified derivatives. We found that all the investigated compounds inhibited the catalytic activity of hAK1, yet with different efficiencies. Three dinucleoside polyphosphates showed IC values below 1 µM, and the most significant inhibitory effect was observed for P-(5'-adenosyl) P-(5'-adenosyl) pentaphosphate (ApA). To understand the observed differences in the inhibition efficiency of the tested dinucleoside polyphosphates, the molecular docking of these compounds to hAK1 was performed. Finally, we conducted a quantitative structure-activity relationship (QSAR) analysis to establish a computational prediction model for hAK1 modulators. Two PLS-regression-based models were built using kinetic data obtained from the AK1 activity analysis performed in both directions of the enzymatic reaction. Model 1 (AMP and ATP synthesis) had a good prediction power (R = 0.931, Q = 0.854, and MAE = 0.286), while Model 2 (ADP synthesis) exhibited a moderate quality (R = 0.913, Q = 0.848, and MAE = 0.370). These studies can help better understand the interactions between dinucleoside polyphosphates and adenylate kinase to attain more effective and selective inhibitors in the future.
Topics: Humans; Quantitative Structure-Activity Relationship; Dinucleoside Phosphates; Kinetics; Molecular Structure; Adenylate Kinase; Dose-Response Relationship, Drug; Protein Kinase Inhibitors; Enzyme Inhibitors
PubMed: 38744169
DOI: 10.1016/j.bioorg.2024.107432