-
Biochemistry Sep 2022is the causative parasitic protozoan of the disease trichomoniasis, the most prevalent, nonviral sexually transmitted disease in the world. is a parasite that...
is the causative parasitic protozoan of the disease trichomoniasis, the most prevalent, nonviral sexually transmitted disease in the world. is a parasite that scavenges nucleosides from the host organism via catalysis by nucleoside hydrolase (NH) enzymes to yield purine and pyrimidine bases. One of the four NH enzymes identified within the genome of displays unique specificity toward purine nucleosides, adenosine and guanosine, but not inosine, and atypically shares greater sequence similarity to the pyrimidine hydrolases. Bioinformatic analysis of this enzyme, adenosine/guanosine-preferring nucleoside ribohydrolase (AGNH), was incapable of identifying the residues responsible for this uncommon specificity, highlighting the need for structural information. Here, we report the X-ray crystal structures of , unliganded AGNH and three additional structures of the enzyme bound to fragment and small-molecule inhibitors. Taken together, these structures facilitated the identification of residue Asp231, which engages in substrate interactions in the absence of those residues that typically support the canonical purine-specific tryptophan-stacking specificity motif. An altered substrate-binding pose is mirrored by repositioning within the protein scaffold of the His80 general acid/base catalyst. The newly defined structure-determined sequence markers allowed the assignment of additional NH orthologs, which are proposed to exhibit the same specificity for adenosine and guanosine alone and further delineate specificity classes for these enzymes.
Topics: Adenosine; Animals; Guanosine; Inosine; N-Glycosyl Hydrolases; Parasites; Pyrimidines; Substrate Specificity
PubMed: 35994320
DOI: 10.1021/acs.biochem.2c00361 -
Proceedings of the National Academy of... Sep 2023In the final step of cytokinin biosynthesis, the main pathway is the elimination of a ribose-phosphate moiety from the cytokinin nucleotide precursor by...
In the final step of cytokinin biosynthesis, the main pathway is the elimination of a ribose-phosphate moiety from the cytokinin nucleotide precursor by phosphoribohydrolase, an enzyme encoded by a gene named LONELY GUY (LOG). This reaction accounts for most of the cytokinin supply needed for regulating plant growth and development. In contrast, the LOG-independent pathway, in which dephosphorylation and deribosylation sequentially occur, is also thought to play a role in cytokinin biosynthesis, but the gene entity and physiological contribution have been elusive. In this study, we profiled the phytohormone content of chromosome segment substitution lines of and searched for genes affecting the endogenous levels of cytokinin ribosides by quantitative trait loci analysis. Our approach identified a gene encoding an enzyme that catalyzes the deribosylation of cytokinin nucleoside precursors and other purine nucleosides. The cytokinin/purine riboside nucleosidase 1 (CPN1) we identified is a cell wall-localized protein. Loss-of-function mutations () were created by inserting a -retrotransposon that altered the cytokinin composition in seedling shoots and leaf apoplastic fluid. The mutation also abolished cytokinin riboside nucleosidase activity in leaf extracts and attenuated the -zeatin riboside-responsive expression of cytokinin marker genes. Grain yield of the mutants declined due to altered panicle morphology under field-grown conditions. These results suggest that the cell wall-localized LOG-independent cytokinin activating pathway catalyzed by CPN1 plays a role in cytokinin control of rice growth. Our finding broadens our spatial perspective of the cytokinin metabolic system.
Topics: Oryza; Cytokinins; Purine Nucleosides; N-Glycosyl Hydrolases; Nucleosides; Cell Wall
PubMed: 37639600
DOI: 10.1073/pnas.2217708120 -
Current Topics in Medicinal Chemistry 2011Malaria remains the most serious parasitic diseases affecting humans in the world today, resulting in 1-2 million fatalities each year. Plasmodium falciparum (Pf) and... (Review)
Review
Malaria remains the most serious parasitic diseases affecting humans in the world today, resulting in 1-2 million fatalities each year. Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the predominant causative agents. Both are responsible for widespread mortality and morbidity and are a serious socio-economic burden, especially for countries in the developing world. One of the most important defences against malaria has been the use of chemotherapeutic drugs (e.g. chloroquine, artemisinins, pyrimethamine) but these have mainly been found by serendipity. Their mechanisms was not understood at the time of their discovery and, even today, are still not unequivocal. For many of these compounds, the parasite is now resistant and, hence, there is an urgent need to develop new therapeutic drugs directed to validated targets. One metabolic pathway crucial for the survival and replication and survival of the parasite is the synthesis of the purine nucleoside monophosphates essential for the production of DNA/RNA molecules. A key enzyme in this pathway is the 6-oxopurine phosphoribosyltransferase (PRTase). The focus of this review is on the identification and characterization of inhibitors of the enzymes from both Pf and Pv as antimalarial drug leads. The acyclic nucleoside phosphonates (ANPs) appear to be excellent candidates because they are good inhibitors of the two Plasmodium enzymes, can be selective compared to the human enzyme, can arrest parasitemia in cell based assays, have low cytotoxicity to the human host cell and, because of their stable carbon-phosphorous bond, are stable within the cell.
Topics: Amino Acid Sequence; Antimalarials; Drug Stability; Enzyme Inhibitors; Humans; Malaria, Falciparum; Malaria, Vivax; Models, Molecular; Molecular Sequence Data; Organophosphonates; Pentosyltransferases; Phosphates; Plasmodium falciparum; Plasmodium vivax; Protozoan Proteins; Purine Nucleosides; Sequence Homology, Amino Acid; Substrate Specificity
PubMed: 21619515
DOI: 10.2174/156802611796575911 -
Molecules (Basel, Switzerland) Apr 2020Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including... (Review)
Review
Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compounds remains a topic of significant interest and necessity. Herein, we discuss recent advances in the chemical synthesis and biological evaluation of nucleoside analogues as potential anticancer agents. Focus is paid to 4'-heteroatom substitution of the furanose oxygen, 2'-, 3'-, 4'- and 5'-position ring modifications and the development of new prodrug strategies for these materials.
Topics: Adenosine; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Furans; Humans; K562 Cells; Mice; Molecular Structure; Nucleosides; Oxygen; Prodrugs; Purine Nucleosides; Pyrimidinones; Thionucleosides; Vitamin E
PubMed: 32354007
DOI: 10.3390/molecules25092050 -
Theranostics 2020More than a hundred chemical modifications in coding and non-coding RNAs have been identified so far. Many of the RNA modifications are dynamic and reversible, playing... (Review)
Review
More than a hundred chemical modifications in coding and non-coding RNAs have been identified so far. Many of the RNA modifications are dynamic and reversible, playing critical roles in gene regulation at the posttranscriptional level. The abundance and functions of RNA modifications are controlled mainly by the modification regulatory proteins: writers, erasers and readers. Modified RNA bases and their regulators form intricate networks which are associated with a vast array of diverse biological functions. RNA modifications are not only essential for maintaining the stability and structural integrity of the RNA molecules themselves, they are also associated with the functional outcomes and phenotypic attributes of cells. In addition to their normal biological roles, many of the RNA modifications also play important roles in various diseases particularly in cancer as evidenced that the modified RNA transcripts and their regulatory proteins are aberrantly expressed in many cancer types. This review will first summarize the most commonly reported RNA modifications and their regulations, followed by discussing recent studies on the roles of RNA modifications in cancer, cancer stemness as wells as functional RNA modification machinery as potential cancer therapeutic targets. It is concluded that, while advanced technologies have uncovered the contributions of many of RNA modifications in cancer, the underlying mechanisms are still poorly understood. Moreover, whether and how environmental pollutants, important cancer etiological factors, trigger abnormal RNA modifications and their roles in environmental carcinogenesis remain largely unknown. Further studies are needed to elucidate the mechanism of how RNA modifications promote cell malignant transformation and generation of cancer stem cells, which will lead to the development of new strategies for cancer prevention and treatment.
Topics: Antineoplastic Agents; Drug Design; Forecasting; Gene Expression Regulation, Neoplastic; Humans; Methyltransferases; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Neoplastic Stem Cells; Oxidoreductases, N-Demethylating; Pseudouridine; Purine Nucleosides; RNA Processing, Post-Transcriptional; RNA, Neoplasm
PubMed: 32194861
DOI: 10.7150/thno.41687 -
Purinergic Signalling Dec 2012Adenosine and its metabolite, inosine, have been described as molecules that participate in regulation of inflammatory response. The aim of this study was to investigate...
Adenosine and its metabolite, inosine, have been described as molecules that participate in regulation of inflammatory response. The aim of this study was to investigate the effect of adenosine and inosine in a mouse model of carrageenan-induced pleurisy as well as the participation of adenosine receptors in this response. Injection of carrageenan into the pleural cavity induced an acute inflammatory response characterized by leukocyte migration, pleural exudation, and increased release of interleukin-1β and tumor necrosis factor-α in pleural exudates. The treatment with adenosine (0.3-100 mg/kg, i.p.) and inosine (0.1-300 mg/kg, i.p.) 30 min before carrageenan injection reduced significantly all these parameters analyzed. Our results also demonstrated that A(2A) and A(2B) receptors seem to mediate the adenosine and inosine effects observed, since pretreatment with selective antagonists of adenosine A(2A) (ZM241385) and A(2B) (alloxazine) receptors, reverted the inhibitory effects of adenosine and inosine in pleural inflammation. The involvement of A(2) receptors was reinforced with adenosine receptor agonist CGS21680 treatment, since its anti-inflammatory effects were reversed completely and partially with ZM241385 and alloxazine injection, respectively. Moreover, the combined treatment with subeffective dose of adenosine (0.3 mg/kg) and inosine (1.0 mg/kg) induced a synergistic anti-inflammatory effect. Thus, based on these findings, we propose that inosine contributes with adenosine to exert anti-inflammatory effects in pleural inflammation, reinforcing the notion that endogenous nucleosides play an important role in controlling inflammatory diseases. This effect is likely mediated by the activation of adenosine A(2) subtype receptors and inhibition of production or release of pro-inflammatory cytokines.
Topics: Adenosine; Animals; Anti-Inflammatory Agents; Carrageenan; Cytokines; Disease Models, Animal; Female; Inosine; Leukocytes; Mice; Pleurisy; Purine Nucleosides; Receptors, Adenosine A2
PubMed: 22456813
DOI: 10.1007/s11302-012-9299-2 -
International Journal of Molecular... Feb 2023Purine nucleotides and nucleosides are involved in various human physiological and pathological mechanisms. The pathological deregulation of purinergic signaling... (Review)
Review
Purine nucleotides and nucleosides are involved in various human physiological and pathological mechanisms. The pathological deregulation of purinergic signaling contributes to various chronic respiratory diseases. Among the adenosine receptors, A2B has the lowest affinity such that it was long considered to have little pathophysiological significance. Many studies suggest that A2BAR plays protective roles during the early stage of acute inflammation. However, increased adenosine levels during chronic epithelial injury and inflammation might activate A2BAR, resulting in cellular effects relevant to the progression of pulmonary fibrosis.
Topics: Humans; Adenosine; Idiopathic Pulmonary Fibrosis; Inflammation; Receptors, Purinergic P1; Disease Progression
PubMed: 36901855
DOI: 10.3390/ijms24054428 -
Molecules (Basel, Switzerland) Mar 2009For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in... (Review)
Review
For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs) plays an important role. Three of them: pentostatin (DCF), cladribine (2-CdA) and fludarabine (FA) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. Recently three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. These agents seem to be useful mainly for the treatment of human T-cell proliferative disorders and they are currently undergoing clinical trials in lymphoid malignancies. However, there are also several studies suggesting the role of these drugs in B-cell malignancies. This review will summarize current knowledge concerning the mechanism of action, pharmacologic properties, clinical activity and toxicity of PNAs accepted for use in clinical practice, as well as new agents available for clinical trials.
Topics: Antineoplastic Agents; Humans; Lymphoproliferative Disorders; Purine Nucleosides; Treatment Outcome
PubMed: 19325518
DOI: 10.3390/molecules14031183 -
Journal of Neurochemistry Apr 2009Axonal degeneration is a key component of many neurodegenerative diseases. Injured axons undergo a program of self-destruction termed Wallerian degeneration that is an... (Comparative Study)
Comparative Study
Axonal degeneration is a key component of many neurodegenerative diseases. Injured axons undergo a program of self-destruction termed Wallerian degeneration that is an active, well-regulated process. The pathways leading to axon fragmentation are uncharacterized, but experiments with wld(s) mutant mice led to the discovery that over-expression of NMN adenylyltransferase 1 or treatment with NAD(+) can inhibit axonal degeneration. In this study, we show that the purine nucleosides adenosine and guanosine, but not inosine, inhibit injury-induced axonal degeneration in cultured dorsal root ganglia neurons. Axons can be preserved by adding adenosine within 6 h of the axonal injury. The presence of adenosine was required continuously after the injury to maintain axonal protection. Together these results suggest that adenosine does not alter the neuronal response to injury, but instead inhibits a local axonal pathway necessary for the commitment and/or execution of the axon destructive program.
Topics: Adenosine; Animals; Axons; Cells, Cultured; Ganglia, Spinal; Guanosine; Mice; Nerve Degeneration; Purine Nucleosides; Wallerian Degeneration
PubMed: 19245660
DOI: 10.1111/j.1471-4159.2009.06002.x -
Molecules (Basel, Switzerland) Mar 2021The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides...
The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.
Topics: Adenine; Adenosine; Magnetic Resonance Spectroscopy; Molecular Conformation; Nucleosides; Piperidines; Purine Nucleosides; Pyrimidinones; Pyrrolidines; Structure-Activity Relationship
PubMed: 33809603
DOI: 10.3390/molecules26061652