ChemInform Abstract: 2,4-Dinitrophenol: A Novel Activating Reagent in Nucleotide Synthesis via the Phosphoramidite Route. Design of New Effective Phosphitylating Reagents.

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

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Synthesis and In Vitro Enzymatic Studies of New 3-Aryldiazenyl Indoles as Promising Helicobacter pylori IMPDH Inhibitors

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190227212334 ◽

2019 ◽

Vol 19 (5) ◽

pp. 376-382 ◽

Cited By ~ 4

Author(s):

Sachin Jangra ◽

Gayathri Purushothaman ◽

Kapil Juvale ◽

Srimadhavi Ravi ◽

Aishwarya Menon ◽

...

Keyword(s):

Helicobacter Pylori ◽

Bacterial Infections ◽

Immunosuppressive Drugs ◽

Multi Drug Resistance ◽

Metabolic Enzyme ◽

World Population ◽

Inhibitor Molecule ◽

Nucleotide Synthesis ◽

H Pylori

Background & Objective:Helicobacter pylori infection is one of the primary causes of peptic ulcer followed by gastric cancer in the world population. Due to increased occurrences of multi-drug resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against H. pylori. Inosine 5′-monophosphate dehydrogenase (IMPDH), a metabolic enzyme plays a significant role in cell proliferation and cell growth. It catalyses guanine nucleotide synthesis. IMPDH enzyme has been exploited as a target for antiviral, anticancer and immunosuppressive drugs. Recently, bacterial IMPDH has been studied as a potential target for treating bacterial infections. Differences in the structural and kinetic parameters of the eukaryotic and prokaryotic IMPDH make it possible to target bacterial enzyme selectively.Methods:In the current work, we have synthesised and studied the effect of substituted 3-aryldiazenyl indoles on Helicobacter pylori IMPDH (HpIMPDH) activity. The synthesised molecules were examined for their inhibitory potential against recombinant HpIMPDH.Results:In this study, compounds 1 and 2 were found to be the most potent inhibitors amongst the database with IC50 of 0.8 ± 0.02µM and 1 ± 0.03 µM, respectively.Conclusion:When compared to the most potent known HpIMPDH inhibitor molecule C91, 1 was only four-fold less potent and can be a good lead for further development of selective and potent inhibitors of HpIMPDH.

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Transcriptome profiling of developing leaf and shoot apices to reveal the molecular mechanism and co-expression genes responsible for the wheat heading date

BMC Genomics ◽

10.1186/s12864-021-07797-7 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuxin Yang ◽

Xueying Zhang ◽

Lifen Wu ◽

Lichao Zhang ◽

Guoxiang Liu ◽

...

Keyword(s):

Transcription Factor ◽

Flowering Time ◽

Heading Date ◽

Yield Component ◽

Potential Candidate ◽

Rna Seq ◽

Nucleotide Synthesis ◽

Light Reaction ◽

Grain Number Per Spike ◽

Double Ridge

Abstract Background Wheat is one of the most widely planted crops worldwide. The heading date is important for wheat environmental adaptability, as it not only controls flowering time but also determines the yield component in terms of grain number per spike. Results In this research, homozygous genotypes with early and late heading dates derived from backcrossed progeny were selected to conduct RNA-Seq analysis at the double ridge stage (W2.0) and androgynous primordium differentiation stage (W3.5) of the leaf and apical meristem, respectively. In total, 18,352 differentially expressed genes (DEGs) were identified, many of which are strongly associated with wheat heading date genes. Gene Ontology (GO) enrichment analysis revealed that carbohydrate metabolism, trehalose metabolic process, photosynthesis, and light reaction are closely related to the flowering time regulation pathway. Based on MapMan metabolic analysis, the DEGs are mainly involved in the light reaction, hormone signaling, lipid metabolism, secondary metabolism, and nucleotide synthesis. In addition, 1,225 DEGs were annotated to 45 transcription factor gene families, including LFY, SBP, and MADS-box transcription factors closely related to flowering time. Weighted gene co-expression network analysis (WGCNA) showed that 16, 336, 446, and 124 DEGs have biological connections with Vrn1-5 A, Vrn3-7B, Ppd-1D, and WSOC1, respectively. Furthermore, TraesCS2D02G181400 encodes a MADS-MIKC transcription factor and is co-expressed with Vrn1-5 A, which indicates that this gene may be related to flowering time. Conclusions RNA-Seq analysis provided transcriptome data for the wheat heading date at key flower development stages of double ridge (W2.0) and androgynous primordium differentiation (W3.5). Based on the DEGs identified, co-expression networks of key flowering time genes in Vrn1-5 A, Vrn3-7B, WSOC1, and Ppd-1D were established. Moreover, we discovered a potential candidate flowering time gene, TraesCS2D02G181400. Taken together, these results serve as a foundation for further study on the regulatory mechanism of the wheat heading date.

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Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity

Nature Metabolism ◽

10.1038/s42255-021-00385-9 ◽

2021 ◽

Author(s):

Hans-Georg Sprenger ◽

Thomas MacVicar ◽

Amir Bahat ◽

Kai Uwe Fiedler ◽

Steffen Hermans ◽

...

Keyword(s):

Mitochondrial Dna ◽

Cultured Cells ◽

De Novo ◽

Metabolic Response ◽

Interferon Response ◽

Type I ◽

Nucleotide Synthesis ◽

Pyrimidine Synthesis ◽

Pyrimidine Nucleotide ◽

De Novo Pyrimidine Synthesis

AbstractCytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

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Nicotinamide Nucleotide Transhydrogenase as a Novel Treatment Target in Adrenocortical Carcinoma

Endocrinology ◽

10.1210/en.2018-00014 ◽

2018 ◽

Vol 159 (8) ◽

pp. 2836-2849 ◽

Cited By ~ 8

Author(s):

Vasileios Chortis ◽

Angela E Taylor ◽

Craig L Doig ◽

Mark D Walsh ◽

Eirini Meimaridou ◽

...

Keyword(s):

Oxidative Stress ◽

Adrenocortical Carcinoma ◽

Reduced Form ◽

Polyamine Metabolism ◽

Metabolome Analysis ◽

Nucleotide Synthesis ◽

Treatment Target ◽

Nicotinamide Nucleotide Transhydrogenase ◽

Response To Chemotherapy

Abstract Adrenocortical carcinoma (ACC) is an aggressive malignancy with poor response to chemotherapy. In this study, we evaluated a potential new treatment target for ACC, focusing on the mitochondrial reduced form of NAD phosphate (NADPH) generator nicotinamide nucleotide transhydrogenase (NNT). NNT has a central role within mitochondrial antioxidant pathways, protecting cells from oxidative stress. Inactivating human NNT mutations result in congenital adrenal insufficiency. We hypothesized that NNT silencing in ACC cells will induce toxic levels of oxidative stress. To explore this, we transiently knocked down NNT in NCI-H295R ACC cells. As predicted, this manipulation increased intracellular levels of oxidative stress; this resulted in a pronounced suppression of cell proliferation and higher apoptotic rates, as well as sensitization of cells to chemically induced oxidative stress. Steroidogenesis was paradoxically stimulated by NNT loss, as demonstrated by mass spectrometry–based steroid profiling. Next, we generated a stable NNT knockdown model in the same cell line to investigate the longer lasting effects of NNT silencing. After long-term culture, cells adapted metabolically to chronic NNT knockdown, restoring their redox balance and resilience to oxidative stress, although their proliferation remained suppressed. This was associated with higher rates of oxygen consumption. The molecular pathways underpinning these responses were explored in detail by RNA sequencing and nontargeted metabolome analysis, revealing major alterations in nucleotide synthesis, protein folding, and polyamine metabolism. This study provides preclinical evidence of the therapeutic merit of antioxidant targeting in ACC as well as illuminating the long-term adaptive response of cells to oxidative stress.

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An efficient route design for solid waste collection using graph theory and the algorithm of the traveling agent in dynamic programming

Environmental Monitoring and Assessment ◽

10.1007/s10661-021-09003-3 ◽

2021 ◽

Vol 193 (5) ◽

Author(s):

Moisés Filiberto Mora Murillo ◽

Walter Alfredo Mora Murillo ◽

Luis Xavier Orbea Hinojosa ◽

Arlys Michel Lastre Aleaga ◽

Gabriel Estuardo Cevallos Uve ◽

...

Keyword(s):

Dynamic Programming ◽

Graph Theory ◽

Solid Waste ◽

Waste Collection ◽

Solid Waste Collection ◽

Route Design ◽

Efficient Route

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Escherichia coli gene purR encoding a repressor protein for purine nucleotide synthesis. Cloning, nucleotide sequence, and interaction with the purF operator.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)77686-8 ◽

1988 ◽

Vol 263 (36) ◽

pp. 19653-19661

Author(s):

R J Rolfes ◽

H Zalkin

Keyword(s):

Escherichia Coli ◽

Nucleotide Sequence ◽

Purine Nucleotide ◽

Nucleotide Synthesis ◽

Repressor Protein

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Pyridine nucleotide synthesis by rat adipose tissue in vitro

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)38939-2 ◽

1967 ◽

Vol 8 (1) ◽

pp. 30-37

Author(s):

Richard W. Hanson ◽

Zigmund Z. Ziporin

Keyword(s):

Adipose Tissue ◽

Pyridine Nucleotide ◽

Nucleotide Synthesis ◽

Adipose Tissue In Vitro ◽

Rat Adipose Tissue

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Antiproliferative Activity and Potential Mechanism of Marine-Sourced Streptoglutarimide H against Lung Cancer Cells

Marine Drugs ◽

10.3390/md19020079 ◽

2021 ◽

Vol 19 (2) ◽

pp. 79

Author(s):

Hengju Ge ◽

Di Zhang ◽

Muran Shi ◽

Xiaoyuan Lian ◽

Zhizhen Zhang

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Antiproliferative Activity ◽

Lung Cancer Cells ◽

Potential Mechanism ◽

Nucleotide Synthesis ◽

Factor C ◽

Antiglioma Activity

In 2019, streptoglutarimide H (SGH) was characterized as a new glutarimide from the secondary metabolites produced by a marine-derived actinomycete Streptomyces sp. ZZ741 and shown to have in vitro antiglioma activity. However, the antiproliferative activity and potential mechanism of SGH against lung cancer cells have not yet been characterized. This study demonstrated that SGH significantly inhibited the proliferation of different lung cancer cells. In terms of mechanism of action, SGH downregulated cell cycle- and nucleotide synthesis-related proteins to block cell cycle at G0/G1 phase, reduced the expression levels of glycolytic metabolic enzymes to inhibit glycolysis, and downregulated the important cancer transcription factor c-Myc and the therapeutic target deubiquitinase USP28. Potent anticancer activity and multiple mechanisms indicated SGH to be a novel antitumor compound against lung cancer cells.

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