scholarly journals Plumbagin, a Natural Product with Potent Anticancer Activities, Binds to and Inhibits Dihydroorotase, a Key Enzyme in Pyrimidine Biosynthesis

2021 ◽  
Vol 22 (13) ◽  
pp. 6861
Author(s):  
Hong-Hsiang Guan ◽  
Yen-Hua Huang ◽  
En-Shyh Lin ◽  
Chun-Jung Chen ◽  
Cheng-Yang Huang
Keyword(s):  
De Novo ◽  
Competitive Inhibitor ◽  
Carnivorous Plant ◽  
Binding Modes ◽  
Anticancer Activities ◽  
Pyrimidine Nucleotides ◽  
Anticancer Chemotherapy ◽  
Key Enzyme ◽  
4T1 Cells ◽  
Induced Apoptosis

Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway for pyrimidine nucleotides, and an attractive target for potential anticancer chemotherapy. By screening plant extracts and performing GC–MS analysis, we identified and characterized that the potent anticancer drug plumbagin (PLU), isolated from the carnivorous plant Nepenthes miranda, was a competitive inhibitor of DHOase. We also solved the complexed crystal structure of yeast DHOase with PLU (PDB entry 7CA1), to determine the binding interactions and investigate the binding modes. Mutational and structural analyses indicated the binding of PLU to DHOase through loop-in mode, and this dynamic loop may serve as a drug target. PLU exhibited cytotoxicity on the survival, migration, and proliferation of 4T1 cells and induced apoptosis. These results provide structural insights that may facilitate the development of new inhibitors targeting DHOase, for further clinical anticancer chemotherapies.

scholarly journals Autophagy-dependent ribosomal RNA degradation is essential for maintaining nucleotide homeostasis during C. elegans development

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yubing Liu ◽  
Wei Zou ◽  
Peiguo Yang ◽  
Li Wang ◽  
Yan Ma ◽  
...  
Keyword(s):  
Ribosomal Rna ◽  
Ribosomal Proteins ◽  
De Novo ◽  
Normal Growth ◽  
Growth Conditions ◽  
Rna Degradation ◽  
Pyrimidine Nucleotides ◽  
C Elegans ◽  
Key Enzyme ◽  
Simultaneous Loss

Ribosome degradation through the autophagy-lysosome pathway is crucial for cell survival during nutrient starvation, but whether it occurs under normal growth conditions and contributes to animal physiology remains unaddressed. In this study, we identified RNST-2, a C. elegans T2 family endoribonuclease, as the key enzyme that degrades ribosomal RNA in lysosomes. We found that loss of rnst-2 causes accumulation of rRNA and ribosomal proteins in enlarged lysosomes and both phenotypes are suppressed by blocking autophagy, which indicates that RNST-2 mediates autophagic degradation of ribosomal RNA in lysosomes. rnst-2(lf) mutants are defective in embryonic and larval development and are short-lived. Remarkably, simultaneous loss of RNST-2 and de novo synthesis of pyrimidine nucleotides leads to complete embryonic lethality, which is suppressed by supplements of uridine or cytidine. Our study reveals an essential role of autophagy-dependent degradation of ribosomal RNA in maintaining nucleotide homeostasis during animal development.

scholarly journals Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

2021 ◽  
Vol 11 (3) ◽  
pp. 1259
Author(s):  
Qiong Wu ◽  
Bo Zhao ◽  
Guangchao Sui ◽  
Jinming Shi
Keyword(s):  
Cancer Cells ◽  
Metabolic Pathways ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Structural Characteristics ◽  
Natural Compounds ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Anticancer Activities ◽  
Substrate Analogs

Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.

scholarly journals Targeting the hallmarks of cancer: the effects of silibinin on proliferation, cell death, angiogenesis, and migration in colorectal cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Saba Sameri ◽  
Chiman Mohammadi ◽  
Mehrnaz Mehrabani ◽  
Rezvan Najafi
Keyword(s):  
Annexin V ◽  
Anticancer Activities ◽  
Scratch Assay ◽  
Anti Cancer ◽  
Different Types ◽  
Colon Cell ◽  
Colon Cell Line ◽  
And Migration ◽  
Induced Apoptosis ◽  
Colony Forming Assay

Abstract Background Silibinin, as a chemopreventive agent, has shown anti-cancer efficacy against different types of cancers. In the present study, we investigated the anti-cancer activities of silibinin on CT26 mouse colon cell line. Methods CT26 cells were treated with different concentrations of silibinin. To examine the cytotoxic effect of silibinin on proliferation, apoptosis, autophagy, angiogenesis, and migration, MTT, colony-forming assay, Annexin V/PI flow cytometry, RT-qPCR, and Scratch assay were used. Results Silibinin was found to significantly reduce CT26 cells survival. Furthermore, silibinin strongly induced apoptosis and autophagy by up-regulating the expression of Bax, Caspase-3, Atg5, Atg7 and BECN1 and down-regulating Bcl-2. Silibinin considerably down-regulated the expression of COX-2, HIF-1α, VEGF, Ang-2, and Ang-4 as well as the expression of MMP-2, MMP-9, CCR-2 and CXCR-4. Conclusions The present study revealed that silibinin shows anticancer activities by targeting proliferation, cell survival, angiogenesis, and migration of CT26 cells.

scholarly journals Apoptosis Induced by Tanshinone IIA and Cryptotanshinone Is Mediated by Distinct JAK/STAT3/5 and SHP1/2 Signaling in Chronic Myeloid Leukemia K562 Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Ji Hoon Jung ◽  
Tae-Rin Kwon ◽  
Soo-Jin Jeong ◽  
Eun-Ok Kim ◽  
Eun Jung Sohn ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Biological Effects ◽  
K562 Cells ◽  
Tanshinone Iia ◽  
Anticancer Activities ◽  
Caspase 9 ◽  
Anticancer Effects ◽  
Induced Apoptosis ◽  
Better Than

Though tanshinone IIA and cryptotanshinone possess a variety of biological effects such as anti-inflammatory, antioxidative, antimetabolic, and anticancer effects, the precise molecular targets or pathways responsible for anticancer activities of tanshinone IIA and cryptotanshinone in chronic myeloid leukemia (CML) still remain unclear. In the present study, we investigated the effect of tanshinone IIA and cryptotanshinone on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. We found that both tanshinone IIA and cryptotanshinone induced apoptosis by activation of caspase-9/3 and Sub-G1 accumulation in K562 cells. However, they have the distinct JAK/STAT pathway, in which tanshinone IIA inhibits JAK2/STAT5 signaling, whereas cryptotanshinone targets the JAK2/STAT3. In addition, tanshinone IIA enhanced the expression of both SHP-1 and -2, while cryptotanshinone regulated the expression of only SHP-1. Both tanshinone IIA and cryptotanshinone attenuated the expression of bcl-xL, survivin, and cyclin D1. Furthermore, tanshinone IIA augmented synergy with imatinib, a CML chemotherapeutic drug, better than cryptotanshinone in K562 cells. Overall, our findings suggest that the anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct the JAK/STAT3/5 and SHP1/2 signaling, and tanshinone IIA has the potential for combination therapy with imatinib in K562 CML cells.

scholarly journals Repression of the pyr Operon in Lactobacillus plantarum Prevents Its Ability To Grow at Low Carbon Dioxide Levels

2005 ◽  
Vol 187 (6) ◽  
pp. 2093-2104 ◽  
Author(s):  
Hervé Nicoloff ◽  
Aram Elagöz ◽  
Florence Arsène-Ploetze ◽  
Benoît Kammerer ◽  
Jan Martinussen ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Lactobacillus Plantarum ◽  
De Novo ◽  
Site Directed Mutagenesis ◽  
Low Carbon ◽  
Wild Type ◽  
Carbamoyl Phosphate ◽  
Phosphoribosyl Pyrophosphate ◽  
Pyrimidine Nucleotides ◽  
Transcription Attenuation

ABSTRACT Carbamoyl phosphate is a precursor for both arginine and pyrimidine biosynthesis. In Lactobacillus plantarum, carbamoyl phosphate is synthesized from glutamine, ATP, and carbon dioxide by two sets of identified genes encoding carbamoyl phosphate synthase (CPS). The expression of the carAB operon (encoding CPS-A) responds to arginine availability, whereas pyrAaAb (encoding CPS-P) is part of the pyrR1BCAaAbDFE operon coding for the de novo pyrimidine pathway repressed by exogenous uracil. The pyr operon is regulated by transcription attenuation mediated by a trans-acting repressor that binds to the pyr mRNA attenuation site in response to intracellular UMP/phosphoribosyl pyrophosphate pools. Intracellular pyrimidine triphosphate nucleoside pools were lower in mutant FB335 (carAB deletion) harboring only CPS-P than in the wild-type strain harboring both CPS-A and CPS-P. Thus, CPS-P activity is the limiting step in pyrimidine synthesis. FB335 is unable to grow in the presence of uracil due to a lack of sufficient carbamoyl phosphate required for arginine biosynthesis. Forty independent spontaneous FB335-derived mutants that have lost regulation of the pyr operon were readily obtained by their ability to grow in the presence of uracil and absence of arginine; 26 harbored mutations in the pyrR1-pyrB loci. One was a prototroph with a deletion of both pyrR1 and the transcription attenuation site that resulted in large amounts of excreted pyrimidine nucleotides and increased intracellular UTP and CTP pools compared to wild-type levels. Low pyrimidine-independent expression of the pyr operon was obtained by antiterminator site-directed mutagenesis. The resulting AE1023 strain had reduced UTP and CTP pools and had the phenotype of a high-CO2-requiring auxotroph, since it was able to synthesize sufficient arginine and pyrimidines only in CO2-enriched air. Therefore, growth inhibition without CO2 enrichment may be due to low carbamoyl phosphate pools from lack of CPS activity.

Acetylenic antifolates as anticancer agents

Pteridines ◽  
2015 ◽  
Vol 26 (3) ◽  
pp. 85-92
Author(s):  
Filiz Esra Önen Bayram ◽  
Hande Sipahi ◽  
Hülya Akgün
Keyword(s):  
Thymidylate Synthase ◽  
Anticancer Agents ◽  
Reductase Inhibitor ◽  
De Novo ◽  
Cell Lymphoma ◽  
Terminal Alkyne ◽  
Anticancer Activities ◽  
Peripheral T Cell Lymphoma ◽  
Structural Analogues ◽  
The U.S

AbstractFolates are crucial cofactors involved in the de novo generation of purine and deoxythymidine monophosphate, which are essential for DNA synthesis. Antifolates are structural analogues of folate derivatives that act as inhibitors of folate-dependent enzymes and constitute the oldest antimetabolite class of anticancer agents. This review focuses on antifolates with remarkable anticancer activities that include a terminal alkyne function in their molecular structure. The properties of CB3717, a tremendous inhibitor of thymidylate synthase, are described, and the development of raltitrexed and pralatrexate, a dihydrofolate reductase inhibitor approved by the U.S. Food and Drug Administration (FDA) as the first drug for the treatment of relapsed and refractory peripheral T cell lymphoma are presented.

scholarly journals Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Marcus O. W. Grimm ◽  
Sven Grösgen ◽  
Tatjana L. Rothhaar ◽  
Verena K. Burg ◽  
Benjamin Hundsdörfer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Physiological Function ◽  
Proteolytic Processing ◽  
Sphingolipid Metabolism ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Coa Transferase ◽  
Key Enzyme

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipidde novosynthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic ADpostmortembrains, suggesting that SPT is involved in AD pathology.

scholarly journals Chemical Stability of Ascorbic Acid Integrated into Commercial Products: A Review on Bioactivity and Delivery Technology

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 153
Author(s):  
Xin Yin ◽  
Kaiwen Chen ◽  
Hao Cheng ◽  
Xing Chen ◽  
Shuai Feng ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Active Site ◽  
De Novo ◽  
Food Matrix ◽  
De Novo Synthesis ◽  
Nutritional Characteristics ◽  
Gulonolactone Oxidase ◽  
Key Enzyme ◽  
Commercial Applications ◽  
Delivery Technology

The L-enantiomer of ascorbic acid is commonly known as vitamin C. It is an indispensable nutrient and plays a key role in retaining the physiological process of humans and animals. L-gulonolactone oxidase, the key enzyme for the de novo synthesis of ascorbic acid, is lacking in some mammals including humans. The functionality of ascorbic acid has prompted the development of foods fortified with this vitamin. As a natural antioxidant, it is expected to protect the sensory and nutritional characteristics of the food. It is thus important to know the degradation of ascorbic acid in the food matrix and its interaction with coexisting components. The biggest challenge in the utilization of ascorbic acid is maintaining its stability and improving its delivery to the active site. The review also includes the current strategies for stabilizing ascorbic acid and the commercial applications of ascorbic acid.

scholarly journals Distinct histone H3–H4 binding modes of sNASP reveal the basis for cooperation and competition of histone chaperones

2021 ◽  
Author(s):  
Chao-Pei Liu ◽  
Wenxing Jin ◽  
Jie Hu ◽  
Mingzhu Wang ◽  
Jingjing Chen ◽  
...  
Keyword(s):  
De Novo ◽  
Critical Role ◽  
Histone H3 ◽  
Coiled Coil ◽  
Dynamic Network ◽  
Histone Chaperones ◽  
Binding Modes ◽  
Nucleosome Assembly ◽  
Partially Unfolded

Chromosomal duplication requires de novo assembly of nucleosomes from newly synthesized histones, and the process involves a dynamic network of interactions between histones and histone chaperones. sNASP and ASF1 are two major histone H3–H4 chaperones found in distinct and common complexes, yet how sNASP binds H3–H4 in the presence and absence of ASF1 remains unclear. Here we show that, in the presence of ASF1, sNASP principally recognizes a partially unfolded Nα region of histone H3, and in the absence of ASF1, an additional sNASP binding site becomes available in the core domain of the H3–H4 complex. Our study also implicates a critical role of the C-terminal tail of H4 in the transfer of H3–H4 between sNASP and ASF1 and the coiled-coil domain of sNASP in nucleosome assembly. These findings provide mechanistic insights into coordinated histone binding and transfer by histone chaperones.

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