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Cancer Cell Jul 2017Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine...
Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.
Topics: Carbon; Deoxycytidine; Digoxin; Drug Resistance, Neoplasm; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mucin-1; Pancreatic Neoplasms; Pentose Phosphate Pathway; Prognosis; Pyrimidines; Signal Transduction; Gemcitabine
PubMed: 28697344
DOI: 10.1016/j.ccell.2017.06.004 -
Proceedings of the National Academy of... Jan 2023Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid...
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the rs72613567-A variant in humans and by the knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the -induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.
Topics: Animals; Humans; Mice; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Pyrimidines
PubMed: 36669104
DOI: 10.1073/pnas.2217543120 -
Molecules (Basel, Switzerland) Nov 2019Pyrido[2,3-]pyrimidines () are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our... (Review)
Review
Pyrido[2,3-]pyrimidines () are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-]pyrimidine-7(8)-ones () due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-]pyrimidine-7(8)-ones (), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds.
Topics: Chemistry Techniques, Synthetic; Molecular Structure; Pyrimidines; Pyrimidinones; Structure-Activity Relationship
PubMed: 31744155
DOI: 10.3390/molecules24224161 -
Parasites & Vectors Feb 2018The trypanosomatid parasites continue their killing spree resulting in significant annual mortality due to the lack of effective treatments and the prominence of these... (Review)
Review
The trypanosomatid parasites continue their killing spree resulting in significant annual mortality due to the lack of effective treatments and the prominence of these diseases in poorer countries. These dimorphic parasites thrive unchecked in the host system, outsmarting the immune mechanisms. An understanding of biology of these parasitic forms will help in the management and elimination of these fatal diseases. Investigation of various metabolic pathways in these parasites has shed light in the understanding of the unique biology of the trypansomatids. An understanding of these pathways have helped in tracing the soft targets in the metabolic pathways, which could be used as effective drug targets which would further impact the therupeutic implications. Pyrimidine pathway is a vital metabolic pathway which yields in the formation of pyrimidines, which are then integrated in nucleic acids (DNA and RNA) in sugars (UDP sugars) and lipids (CDP lipids). A wealth of data and information has been generated in the past decades by in-depth analyses of pyrimidine pathway in the trypanosomatid parasites, which can aid in the identification of anomalies between the parasitic and host counterpart which could be further harnessed to develop therapeutic interventions for the treatment of parasitic diseases. This review presents an updated and comprehensive detailing of the pyrimidine metabolism in the trypansomatids, their uniqueness and their distinctions, and its possible outcomes that would aid in the eradication of these parasitic diseases.
Topics: Biosynthetic Pathways; Carbohydrate Metabolism; DNA; Lipid Metabolism; Pyrimidines; Trypanosoma
PubMed: 29422065
DOI: 10.1186/s13071-018-2660-8 -
Molecular Metabolism May 2020Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis, and cellular bioenergetics. Increased... (Review)
Review
BACKGROUND
Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis, and cellular bioenergetics. Increased nucleotide metabolism supports uncontrolled growth of tumors and is a hallmark of cancer. Agents inhibiting synthesis and incorporation of nucleotides in DNA are widely used as chemotherapeutics to reduce tumor growth, cause DNA damage, and induce cell death. Thus, the research on nucleotide metabolism in cancer is primarily focused on its role in cell proliferation. However, in addition to proliferation, the role of purine molecules is established as ligands for purinergic signals. However, so far, the role of the pyrimidines has not been discussed beyond cell growth.
SCOPE OF THE REVIEW
In this review we present the key evidence from recent pivotal studies supporting the notion of a non-proliferative role for pyrimidine metabolism (PyM) in cancer, with a special focus on its effect on differentiation in cancers from different origins.
MAJOR CONCLUSION
In leukemic cells, the pyrimidine catabolism induces terminal differentiation toward monocytic lineage to check the aberrant cell proliferation, whereas in some solid tumors (e.g., triple negative breast cancer and hepatocellular carcinoma), catalytic degradation of pyrimidines maintains the mesenchymal-like state driven by epithelial-to-mesenchymal transition (EMT). This review further broadens this concept to understand the effect of PyM on metastasis and, ultimately, delivers a rationale to investigate the involvement of the pyrimidine molecules as oncometabolites. Overall, understanding the non-proliferative role of PyM in cancer will lead to improvement of the existing antimetabolites and to development of new therapeutic options.
Topics: Animals; Cell Differentiation; Cell Proliferation; Disease Progression; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Pyrimidines
PubMed: 32244187
DOI: 10.1016/j.molmet.2020.02.005 -
Nature Chemistry Nov 2017Understanding the diversity of dynamic structures and functions of DNA and RNA in biology requires tools that can selectively and intimately probe these biomolecules.... (Review)
Review
Understanding the diversity of dynamic structures and functions of DNA and RNA in biology requires tools that can selectively and intimately probe these biomolecules. Synthetic fluorescent nucleobases that can be incorporated into nucleic acids alongside their natural counterparts have emerged as a powerful class of molecular reporters of location and environment. They are enabling new basic insights into DNA and RNA, and are facilitating a broad range of new technologies with chemical, biological and biomedical applications. In this Review, we will present a brief history of the development of fluorescent nucleobases and explore their utility as tools for addressing questions in biophysics, biochemistry and biology of nucleic acids. We provide chemical insights into the two main classes of these compounds: canonical and non-canonical nucleobases. A point-by-point discussion of the advantages and disadvantages of both types of fluorescent nucleobases is made, along with a perspective into the future challenges and outlook for this burgeoning field.
Topics: DNA; Fluorescent Dyes; Purines; Pyrimidines; RNA
PubMed: 29064490
DOI: 10.1038/nchem.2859 -
Cells Feb 2022Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids... (Review)
Review
Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids and glucose, the salvage pathway recovers nucleosides or bases formed during DNA or RNA degradation. In contrast to high proliferating non-malignant cells, which are highly dependent on the de novo synthesis, cancer cells can switch to the nucleoside salvage pathways to maintain efficient DNA replication. Pyrimidine de novo synthesis remains the target of interest in cancer therapy and several inhibitors showed promising results in cancer cells and in vivo models. In the 1980s and 1990s, poor responses were however observed in clinical trials with several of the currently existing pyrimidine synthesis inhibitors. To overcome the observed limitations in clinical trials, targeting pyrimidine salvage alone or in combination with pyrimidine de novo inhibitors was suggested. Even though this approach showed initially promising results, it received fresh attention only recently. Here we discuss the re-discovery of targeting pyrimidine salvage pathways for DNA replication alone or in combination with inhibitors of pyrimidine de novo synthesis to overcome limitations of commonly used antimetabolites in various preclinical cancer models and clinical trials. We also highlight newly emerged targets in pyrimidine synthesis as well as pyrimidine salvage as a promising target in immunotherapy.
Topics: Neoplasms; Nucleosides; Nucleotides; Pyrimidines
PubMed: 35203388
DOI: 10.3390/cells11040739 -
International Journal of Molecular... Apr 2021At the focus of abiotic chemical reactions is the synthesis of ribose. No satisfactory explanation was provided as to the missing link between the prebiotic synthesis of... (Review)
Review
At the focus of abiotic chemical reactions is the synthesis of ribose. No satisfactory explanation was provided as to the missing link between the prebiotic synthesis of ribose and prebiotic RNA (preRNA). Hydrogen cyanide (HCN) is assumed to have been the principal precursor in the prebiotic formation of aldopentoses in the formose reaction and in the synthesis of ribose. Ribose as the best fitting aldopentose became the exclusive sugar component of RNA. The elevated yield of ribose synthesis at higher temperatures and its protection from decomposition could have driven the polymerization of the ribose-phosphate backbone and the coupling of nucleobases to the backbone. RNA could have come into being without the involvement of nucleotide precursors. The first nucleoside monophosphate is likely to have appeared upon the hydrolysis of preRNA contributed by the presence of reactive 2'-OH moieties in the preRNA chain. As a result of phosphorylation, nucleoside monophosphates became nucleoside triphosphates, substrates for the selective synthesis of genRNA.
Topics: Metabolic Networks and Pathways; Nucleotides; Phosphorylation; Polymerization; Purines; Pyrimidines; RNA; Ribose
PubMed: 33917807
DOI: 10.3390/ijms22083857 -
Molecules (Basel, Switzerland) May 2021Pyrazolo[1,5-]pyrimidine () derivatives are an enormous family of -heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great... (Review)
Review
Pyrazolo[1,5-]pyrimidine () derivatives are an enormous family of -heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015-2021) in the synthesis and functionalization of diverse pyrazolo[1,5-]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-]pyrimidine core.
Topics: Animals; Antineoplastic Agents; Catalysis; Enzyme Inhibitors; Humans; Pyrazoles; Pyrimidines
PubMed: 34063043
DOI: 10.3390/molecules26092708 -
Nature Communications Aug 2023Purine-containing nucleotide second messengers regulate diverse cellular activities. Cyclic di-pyrimidines mediate anti-phage functions in bacteria; however, the...
Purine-containing nucleotide second messengers regulate diverse cellular activities. Cyclic di-pyrimidines mediate anti-phage functions in bacteria; however, the synthesis mechanism remains elusive. Here, we determine the high-resolution structures of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases (CD-NTases) in clade E (CdnE) in its apo, substrate-, and intermediate-bound states. A conserved (R/Q)xW motif controlling the pyrimidine specificity of donor nucleotide is identified. Mutation of Trp or Arg from the (R/Q)xW motif to Ala rewires its specificity to purine nucleotides, producing mixed purine-pyrimidine cyclic dinucleotides (CDNs). Preferential binding of uracil over cytosine bases explains the product specificity of cyclic di-pyrimidine-synthesizing CdnE to cyclic di-UMP (cUU). Based on the intermediate-bound structures, a synthetic pathway for cUU containing a unique 2'3'-phosphodiester linkage through intermediate pppU[3'-5']pU is deduced. Our results provide a framework for pyrimidine selection and establish the importance of conserved residues at the C-terminal loop for the specificity determination of CD-NTases.
Topics: Pyrimidines; Nucleotidyltransferases; Nucleotides; Chromogranin A; Purine Nucleotides
PubMed: 37604815
DOI: 10.1038/s41467-023-40787-9