Authors: Panu K Luukkonen, Ikki Sakuma, Rafael C Gaspar...

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

Authors: Surendra K Shukla, Vinee Purohit, Kamiya Mehla...

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

Authors: Ola A Elgamal, Sydney Fobare, Sandip Vibhute...

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.

Topics: Leukemia, Myeloid, Acute; Humans; Pyrimidines; Mice; Animals; Dihydroorotate Dehydrogenase; Immunotherapy; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female

PubMed: 38646934
DOI: 10.1172/jci.insight.173646

Authors: Jianfei Yan, Junjie Wu, Mingyue Xu...

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

Topics: Humans; Animals; Mice; Pyridoxine; Aldehyde Dehydrogenase; Seizures; Pyrimidines; Cognition; Epilepsy; 2-Aminoadipic Acid

PubMed: 38579001
DOI: 10.1126/sciadv.adl2764

Review

Authors: Guillem Jubete, Raimon Puig de la Bellacasa, Roger Estrada-Tejedor...

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

Authors: Dongwon Shin, Renatus W Sinkeldam, Yitzhak Tor...

A fluorescent ribonucleoside alphabet consisting of highly emissive purine ((th)A, (th)G) and pyrimidine ((th)U, (th)C) analogues, all derived from thieno[3,4-d]pyrimidine as the heterocyclic nucleus, is described. Structural and biophysical analyses demonstrated that the emissive analogues are faithful isomorphic nucleoside surrogates. Photophysical analysis established that the nucleosides offer highly desirable qualities, including visible emission, high quantum yield, and responsiveness to environmental perturbations, traits entirely lacking in their native counterparts.

Topics: Crystallography, X-Ray; Fluorescence; Models, Molecular; Molecular Conformation; Pyrimidines; RNA; Stereoisomerism

PubMed: 21866967
DOI: 10.1021/ja206095a

Authors: Mei-Hui Hou, Chao-Jung Chen, Chia-Shin Yang...

3',5'-cyclic uridine monophosphate (cUMP) and 3',5'-cyclic cytidine monophosphate (cCMP) have been established as bacterial second messengers in the phage defense system, named pyrimidine cyclase system for anti-phage resistance (Pycsar). This system consists of a pyrimidine cyclase and a cyclic pyrimidine receptor protein. However, the molecular mechanism underlying cyclic pyrimidine synthesis and recognition remains unclear. Herein, we determine the crystal structures of a uridylate cyclase and a cytidylate cyclase, revealing the conserved residues for cUMP and cCMP production, respectively. In addition, a distinct zinc-finger motif of the uridylate cyclase is identified to confer substantial resistance against phage infections. Furthermore, structural characterization of cUMP receptor protein PycTIR provides clear picture of specific cUMP recognition and identifies a conserved N-terminal extension that mediates PycTIR oligomerization and activation. Overall, our results contribute to the understanding of cyclic pyrimidine-mediated bacterial defense.

Topics: Pyrimidines; Bacterial Proteins; Crystallography, X-Ray; Bacteriophages; Uridine Monophosphate; Escherichia coli; Models, Molecular; Amino Acid Sequence; Zinc Fingers

PubMed: 38965224
DOI: 10.1038/s41467-024-49861-2

Review

Authors: Aarif Siddiqui, Paolo Ceppi

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

Authors: Omobolanle Janet Jesumoroti, Richard M Beteck, Audrey Jordaan...

Tuberculosis (TB) is one of the leading causes of death worldwide. Developing new anti-TB compounds using cost-effective processes is critical to reduce TB incidence and accomplish the End TB Strategy milestone. Herein, we describe the synthesis and structure-activity relationships of a library of thirty 7H-Pyrrolo[2,3-d]pyrimidine derivatives providing insights into the contributions of different aromatic, aryl and alkyl substitution at the C-4 position of the 7-deazapurine ring. The minimum inhibitory concentration (MIC) of the compounds against the green fluorescent protein (GFP) reporter strain of Mycobacterium tuberculosis was assayed using the standard broth microdilution method, and cell toxicity was determined using the MTT assay. Sixteen compounds displayed in vitro activity against the GFP reporter strain of Mycobacterium tuberculosis with MIC values of 0.488-62.5 µM. This study highlights the most potent derivative, N-(4-phenoxy phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine with a MIC value of 0.488 µM and was non-cytotoxic to the Vero cell line. Moreover, all the potent compounds from this series have a ClogP value less than 4 and molecular weight < 400; thus, likely to maintain drug-likeness during lead optimisation.

Topics: Antitubercular Agents; Mycobacterium tuberculosis; Structure-Activity Relationship; Pyrimidines; Cell Line; Microbial Sensitivity Tests

PubMed: 35598185
DOI: 10.1007/s11030-022-10453-1

Review

Authors: Peng Zhang, Congcong Shi, Tongbao Dong...

Cancer as a devastating malignancy, seriously threatens human life and health, but most chemotherapeutics have long been criticized for unsatisfactory therapeutic efficacy due to drug resistance and severe off-target toxicity. Pyrimidines, including fused pyrimidines, are privileged scaffolds for various biological cancer targets and are the most important class of metalloenzyme carbonic anhydrase inhibitors. Pyrimidine-sulfonamide hybrids can act on different targets in cancer cells simultaneously and possess potent activity against various cancers, revealing that hybridization of pyrimidine with sulfonamide is a promising approach to generate novel effective anticancer candidates. This review aims to summarize the recent progress of pyrimidine-sulfonamide hybrids with anticancer potential, covering papers published from 2020 to present, to facilitate further rational design of more effective candidates.

Topics: Humans; Sulfonamides; Pyrimidines; Antineoplastic Agents; Neoplasms; Carbonic Anhydrase Inhibitors; Molecular Structure; Animals

PubMed: 38624011
DOI: 10.4155/fmc-2024-0010