Genotoxic agent and their metabolic pathway

Genotoxic agent and their metabolic pathway

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What are the mechanics (set of biochemical reactions) allowing a given genotoxic agent

  • to modify the mutation rate at a given spot?
  • to induce only a given type of mutation (from Gs to Cs for example)?
  • some other consequence of the kind that you think is worth talking about!

I am not necessarily seeking for a very detailed explanation of the biochemical pathway but rather some kind of understanding of how such things are possible (not evolutionary speaking but in terms of physiology and cytology).

This question comes in reaction to this post.

In terms of DNA mutations, it's usually just pure chemistry. The mutagens article gives a brief rundown of some of the usual suspects, but to pick a few of the ones I'm familiar with:

  • UV light can cause pyrimidine dimers, which clearly is a dimerization of Cytosines or Thymines, which can cause replication issues.
  • Deaminases, which remove amine groups, is probably the coolest example. Deamination can occur naturally, turning Cytosine into Uracil, but is often done deliberately as part of bisulfite sequencing to determine methylation status.
  • Alkylation can occur, in particular of Guanine, which can lead to a preference in binding for Thymine; subsequent replication will result in an Guanine to Adenine conversion.

Similarly, there are many base analogs that will fill in for a given nitrogenous base. These analogs often prefer to bind to an "incorrect" base as above (and in the figure below with 5-bromouracil) which will lead to specific errors.

On a more intentional basis, biotechnological tools such as zinc finger nucleases, TALENs, and the (oh-so-sexy) CRISPR system can be used to specifically alter genome sequences of choice. ZFNs are in particular being used as a gene therapy tool for just that reason.

Otherwise, viruses (and transposons) that insert into the genome can cause specific mutations or errors if they do so non-randomly. Figuring that out, though, can be tricky; most oncoviruses cause mutations through specific genes that allow uncontrolled growth and tumorigenesis, not in a site-directed manner. There is, however, a growing hypothesis that certain retroviruses which tend not to cause cancer, in particular HIV, may be inserting into sites with certain characterizations, such as chromatin level. That is far from known, though.

If you're looking for random causes, that's easy. Anything that disrupts DNA repair mechanisms such as p53 or Rb will do that. For chemicals, intercalators such as ethidium bromide and thalidomide insert in between DNA bases and prevent proper DNA repair.


CancerQuest presents a video introduction to chemotherapy . Click on the image below to watch the documentary and patient interviews.

The term chemotherapy, or chemo., refers to a wide range of drugs used to treat cancer. These drugs usually work by killing dividing cells. Since cancer cells have lost many of the regulatory functions present in normal cells, they will continue to attempt to divide when other cells do not. This trait makes cancer cells susceptible to a wide range of cellular poisons.

Many chemotherapy drugs kill cancer cells by causing damage to DNA (their genes). Since cancer cells are already damaged, this extra push can kill them.

The chemotherapy agents work to cause cell death in a variety of ways. Some of the drugs are naturally occurring compounds that have been identified in various plants and some are man-made chemicals. A few different types of chemotherapy drugs are briefly described below. For more information on a particular type of drug, choose from the list below.

    Antimetabolites : Drugs that interfere with the formation of key biomolecules within the cell. These drugs ultimately interfere with cell division.
      : These are also known as antifolates, inhibit dihydrofolate reductase (DHFR), an enzyme involved in the formation of nucleotides. When this enzyme is blocked, nucleotides are not formed, which disrupts DNA replication and cell division Chemicals used to build the nucleotides of DNA and RNA Drugs that act as decoys that block the synthesis of pyrimidine containing nucleotides

    Normal cells are more resistant to the drugs because they often stop dividing when conditions are not favorable. Normal cells are also better at repairing their DNA than cancer cells. Not all normal dividing cells escape however, a fact that contributes to the toxicity of these drugs. Cell types that are normally rapidly dividing, such as those in the bone marrow (making blood cells) and in the lining of the intestine, tend to be hardest hit. Death of the normal cells produces some of the common side-effects of chemotherapy, including hair loss, anemia, immune suppression and stomach/digestive problems.

    Many cancer drugs kill cells by causing DNA damage. Some normal cells also get killed, causing side effects.

    Watch the video to hear how sarcoma survivor Ned Crystal dealt with the side effects of high dose chemotherapy.
    Watch the full interview with Ned Crystal.

    The one-carbon metabolism pathway highlights therapeutic targets for gastrointestinal cancer (Review)

    According to central dogma, information flow from the genome is dictated by the transcription of coding genes to mRNA, followed by translation to proteins. Multi-faceted omics information yields high-volume data associated with the whole-genome sequence, epigenome, methylome, transcriptome, proteome and metabolome, all of which have been linked to disease-specific cell phenotypes (1). The metabolome comprises of physiologically active substances such as nutrients (e.g., glucose), lipids, amino acids (e.g., serine and glycine) and nucleic acids. Importantly, in tumor cells, the processes of cell growth and proliferation requires construction of building blocks for new cellular components from substances associated with a redox status (Fig. 1) (2). One-carbon (C1) metabolism encompasses a complex metabolic network based on the chemical reaction of folate compounds (3). The folate cycle couples with the methionine cycle to form a bi-cyclic metabolic pathway that circulates carbon units as part of a process referred to as the C1 metabolism (3). These two cycles also link with the trans-sulfuration pathway, which plays a critical role in the regulation of the redox state by producing glutathione (3). C1 metabolism is critical for the maintenance of genomic stability through nucleotide metabolism as well as for the epigenetic control of DNA and histones, altered expression of which is a characteristic attribute of tumor cells. Ultimately, these findings should unravel new opportunities for translational approaches, drug discovery and studies of cancer pathogenesis. The study and control of C1 metabolism is the foundation for precision medicine in the context of disease prevention, identification of biomarkers, diagnosis, and treatment of various diseases, including cancer (3–5). High expression of C1 metabolic enzymes such as SHMT2, MTHFD2 and ALDH1L2 was shown to be independently associated with RFS. These findings suggest that mitochondrial folate metabolic enzymes could serve as potential therapeutic targets for treatment of colorectal cancer (6). The genomic analysis of clinical samples is an entry point for developments in Precision Medicine. Here we highlight recent developments in C1 metabolism research.

    Figure 1

    Multi-faceted functions of one-carbon metabolism. Three mitochondrial enzymes, SHMT2, MTHFD2 and ALDH1L2, play critical roles in cancer survival and proliferation presumably though purine production, and are thus suggested as potential diagnostic and therapeutic targets in gastrointestinal cancer cells. THF, tetrahydrofolic acid me-THF, N5N10-methylene-tetrahydrofolic acid m-THF, N5-methyl-tetrahydrofolic acid F-THF, N10-formyl-tetrahydrofolic acid MET, methionine SAM, S-adenosylmethionine SAH, S-adenosyhomocysteine hCYS, homocysteine DMG, dimethylglycine ROS, reactive oxygen species.

    2. Therapeutic targets in C1 metabolism

    Naturally, researchers have considered folate metabolism as a plausible target for disease control. Antagonism of folate metabolism has been the principal plank of chemotherapeutic concept for more than 60 years. Farber and colleagues (7) noted that folic acid could stimulate proliferation of acute lymphoblastic leukemia (ALL) cells and wondered whether the intermediates of chemical synthesis could antagonize cell proliferation. They conducted a pioneering study in which they used aminopterin, one of the above-mentioned intermediates, to induce clinical remission in patients with ALL (8). Thereafter, multiple pathways downstream of C1 metabolism were identified and targeted by various cytotoxic chemotherapeutic agents. For example, methotrexate (MTX), an anti-folate agent that targets dihydrofolate reductase, is used to treat various cancer and is an effective therapy for rheumatoid arthritis (RA), despite its associated toxicity (9). The first documented use of 5-fluorouracil (5-FU) was reported by Spears et al (10) it was later approved for the treatment of colorectal cancer. 5-FU is an analogue of the DNA base, uracil, and is a potent thymidine synthase inhibitor that blocks methylation of dUMP to dTMP and disrupts the folate cycle (11). Similarly, gemcitabine, another nucleotide metabolism inhibitor in the C1 metabolic pathway, is used to treat pancreatic cancer (12). A previous study of gemcitabine-resistant pancreatic cancer cells indicated that microRNA-1246, which belongs to a class of non-coding RNAs, is involved in the modulation of chemotherapy resistance and cancer stem cell properties, which suggests a critical role of nucleotide metabolism in cancer cell metabolism (12). The conceptual basis of 5-FU has been used to develop a thymidine analog, trifluorothymidine (TFT), as discussed below.

    Recently, C1 metabolic enzymes were shown to be novel therapeutic targets for cancer. Pandey et al (13) showed that inhibition of SHMT1 with targeted siRNAs reduced tumor size in a mouse xenograft model. Pickman et al (14) demonstrated inhibition of acute myeloid leukemia cells by MTHFD2 knockdown-induced suppression of TCA in vivo . Small compounds for inhibition of SHMT1 or MTHFD2 have already been identified (15–18). These compounds may undergo further development as novel drugs for cancer therapy in the foreseeable future.

    Regarding nucleotide medicine, microRNAs have been shown to exert various effects on cells, such as epigenetic reprogramming via modulation of the methylation pathway (19,20). Later studies indicated that specific microRNAs, such as microRNA-302, could induce reprogramming in cancer cells, thus, identifying these as candidate moieties for treatment of refractory cancer cells from a nucleotide medicine perspective (21–23). Furthermore, microRNA-369 was shown to modulate the activity of a splicing factor of pyruvate kinase (PK), which induces metabolic reprogramming (24). Taken together, nucleotide metabolism plays a critical role in C1 metabolism and allows the generation of useful tools for mechanistic studies and therapeutic tools with which to target cancer cells.

    Control of methylation events might be plausible, given the significance of epigenetic events with regard to the malignant phenotype of cancer (25,26). Previous research has shown that a temporarily distinct subpopulation of slow-cycling melanoma cells in which the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) play a role is required for continuous tumor growth (27). These slow-cycling cells, which exhibit slow DNA replication and are likely resistant to chemotherapeutic reagents (e.g., genotoxic agents) and radiation, may be instrumental in tumor relapse and metastasis. In solid cancers, KDM family members are implicated in carcinogenesis, and knockdown of associated genes has been shown to inhibit tumorigenicity and elicit cellular senescence (28,29). Several reagents, such as dimethyl sulfoxide (DMFO), have been developed to target methylation donors, ornithine decarboxylation (ODC), and polyamine metabolism and have been evaluated in clinical trials (30).

    3. Application of nucleotide analogues in C1 metabolism

    Nucleoside analogues, including deoxyadenosine analogues, adenosine analogues (31), deoxycytidine analogues, guanosine and deoxyguanosine analogues, thymidine and deoxythymidine analogues, and deoxyuridine analogues, can be used to target hepatitis B or C virus (HBV and HCV), herpes simplex virus (HSV) and human immunodeficiency virus (HIV). The uracil analogue, 5-FU, contains a fluorine atom in place of hydrogen at the C-5 position (32). 5-FU is the cornerstone of treatment for various malignancies, including colon, gastric and pancreatic cancers. Current strategy for cancer treatment usually includes a combination of cytotoxic drugs and more targeted drugs that affect, for example, signal transduction pathways. Furthermore, the efficacy of the combination drug tegafur/gimeracil/oteracil (TS-1 in Japan) in patients with advanced gastric cancer has been reported in an adjuvant setting (33). Gimeracil has been reported to inhibit tegafur degradation, thus, increasing the effect of tegafur. More recently, the thymidine analog TFT has been shown to be a potent inhibitor of DNA replication. Originally, the effects of TFT were evaluated in tumors transplanted into mice in the 1960s (34). However, the short half-life of TFT, which limits its clinical use as a chemotherapeutic agent, is yet to be overcome. TFT is an antiviral drug that interferes with DNA replication. This agent is thought to overcome signaling pathways involved in resistance to 5-FU derivatives (S-1) in several model settings. 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI) is a potent inhibitor of thymidine phosphorylase, the enzyme that degrades FTD, and thereby potentiates the efficacy of TF in viv o. A TFT:TPI molecular ratio of 2:1 was used in TAS-102. Evaluation of this combination demonstrated that the cytotoxicity of TFT is enhanced by TPI. Furthermore, TPI also possesses antiangiogenic properties specifically, this agent inhibits thymidine phosphorylase (TP). Evaluation of these drugs in combination with other cytotoxic agents for treatment of various cancers has also yielded consistent results. The combinatorial use of these agents with other targeted agents synergistically downregulates signal transduction pathways responsible for tumor growth, progression and metastasis. In patients with refractory colorectal cancer, TAS-102 was associated with a significant improvement in overall survival relative to the placebo in both phase II and phase III trials (35,36). Further studies to assess the efficacy of S-1 or TAS-102 in a neoadjuvant setting are underway (37–39). The above-described results clearly demonstrate that in the future, these agents will alter the effectiveness of anti-metabolite agents used for cancer chemotherapy.

    4. Polyamines in C1 metabolism

    The methionine cycle produces S-adenocyl methionine (SAM), which acts as a methyl donor in methylation reactions (40). SAM is involved in the methylation of histones, DNA and RNA, as well as of lysine and arginine in general proteins. SAM is coupled with ornithine metabolic pathway. In a study of PK, which catalyzes the last step of glycolysis, PKM2 knock-down in the allele contributed to the generation of SAM in mice (24), which suggests an important role of PKM2 in the modulation of cancer phenotypes via SAM-mediated control of methylation. PKM2, which results from alternative splicing of the PK gene, was preferentially expressed in tumors relative to PKM1, which is expressed in differentiated cells. PK contributes to the production and transportation of pyruvate in the mitochondria and is thus, associated with folate production in C1 metabolism. This gateway function of PK is altered in colorectal cancer, wherein the translocation of PKM2 protein into the nucleus via TGF-β stimulation has been observed in metastatic cancer cells (41) notably, pyruvate dehydrogenase is also affected in cancer cells (42).

    SAM production is associated with polyamine metabolism in which ornithine decarboxylation (ODC) functions as a restricting step in the metabolic flow (43). Studies of an ODC enzyme revealed the characteristic cancer stem cell properties of fluorescent cancer cells harboring a GFP-ODC enzyme fusion cassette (44–46). These GFP-ODC labeled cancer cells exhibited the most aggressive tumorigenicity in immunodeficient mice, were resistant to chemotherapy and radiation therapy and exhibited reduced production of reactive oxygen species (ROS). A trans-omics mathematical analysis that linked metabolome data with transcriptome data revealed novel functions of the ornithine metabolic pathway in cancer stem cells (47). Given that ornithine is located upstream of polyamine metabolism, the polyamine flow might play a role in the maintenance of cancer stemness. Thus, C1 metabolism helps to control treatment-refractory cancer stem cells.

    5. Diadenosine phosphate hydrolases in C1 metabolism

    Although genetic alterations are not the sole pathogenetic mechanism of carcinogenesis, these factors undoubtedly play a significant role in disease initiation and progression (48–50). Studies of hereditary diseases that are known to predispose to cancer have indicated the involvement of ectopically activated oncogenes and the inhibition of tumor suppressor genes (51). In the 1990s, numerous studies suggested that in cancer patients, commonly deleted genomic regions might contain tumor suppressor genes (52) accordingly, introduction of these missing genes to cancer cells might inactivate tumor cell proliferation and cell cycle progression and thus suppress tumorigenicity (53). Positional cloning approaches to the identification of critical genes in the common fragile sites on chromosome 3p14 led to the identification of the fragile histidine triad ( FHIT ) gene, which encodes an enzyme with dinucleotide hydrolase activity (diadenosine tri-phosphate hydrolase) and a role in purine metabolism (54). A subsequent biochemical study indicated the importance of His96 as a catalyst for the hydrolysis of phosphoanhydrides such as Ap3A (55). More than 50% of human tumors exhibit focal deletion of this gene (56). Experiments in mice have indicated a deficiency in FHIT -induced genomic instability and spontaneous tumor formation, both of which were suppressed by the introduction of FHIT (3,57).

    Studies of the FHIT loci genomic structure identified LINE-1, a human transposable element that is presumably involved in genomic deletion breakpoints associated with cancer (58,59). Since aphidicholine, an inhibitor of DNA polymerase α and δ, is known to affect the fragility of the above-mentioned common fragile sites (56), fragility in cancer cells might involve processes such as replication, recombination and DNA repair. Indeed, studies of gene function have indicated the involvement of Fhit protein in checkpoint system activation in response to genomic damage (60). In cancer, alterations to this checkpoint response have been linked to the activation of an Akt-survivin pathway-mediated cell survival mechanism (61). The mechanism by which the above-mentioned phenomenon occurs in tumors remains to be elucidated however, DNA repair presumably requires the repair enzymes to appropriately incorporate nucleotide bases into DNA (3). Therefore, this historically important discovery of FHIT from the most active common fragile sites in the human genome indicates the homology of the encoded protein with dinucleotide hydrolase (62) and suggests that C1 metabolism leads to nucleotide metabolism in cancer cells.

    6. ROS in C1 metabolism

    Mitochondrial quality is known to influence cellular differentiation. For example, certain mutations in mitochondrial DNA (mtDNA) affect cellular reprogramming. Reprogramming induction in fibroblasts harboring mtDNA mutations revealed drastically reduced reprogramming efficiency of these cells relative to that of wild-type fibroblast cells (63). Reduced reprogramming efficiency has also been observed in human cells that harbor large mtDNA deletions (64), as well as in clonal human fibroblast cells with very high frequency of mt-tRNA point mutations. In addition, mtDNA has been suggested to affect reprogramming efficiency (57,58). However, the induced pluripotent stem cell lines showed different pathological mtDNA point mutations (20,25,63–66). In these cells, no significant difference in reprogramming efficiency was observed between the normal and mutated lines. Many studies have associated heteroplasmic mtDNA mutations with specific segregation patterns during reprogramming. This phenomenon was not only observed in the induced pluripotent stem cells, but also in mouse germ cells and during epiblast differentiation in monkey embryos (11,67).

    Furthermore, tDNA mutation was found to induce ROS. ROS signaling determines cell fate. For example, mitochondrial ROS was shown to induce differentiation of hematopoietic stem cells (HSCs) (9,30). Therefore, ROS was thought to mediate signaling and thus affect cell differentiation. Induced pluripotent stem cells with mtDNA mutations retain high levels of ROS (63), although this phenotype can be rescued via treatment with antioxidants such as n-acetyl-l-cysteine (NAC). Altered ROS signaling is thought to induce the mtDNA mutation phenotype in stem cells (63). Therefore, the mitochondria is an organelle involved in signal transduction (Fig. 2).

    Figure 2

    One-carbon metabolism in mitochondria. One-carbon metabolism comprises three critical reactions: the folate and methionine cycles and the trans-sulfuration pathway. In the folate cycle, glycine and serine fuel mitochondrial enzymes via purine production. In the methionine cycle, S-adenocyl methionine (SAM) serves both hydrocarbons and polyamines. The trans-sulfuration pathway is critical for the synthesis of glutathione, which is involved in the production of reactive oxygen species. Acting in unison, these molecules promote the survival and maintenance of gastrointestinal cancer cells. NAD, nicotinamide adenine dinucleotide NADH, reduced nicotinamide adenine dinucleotide ETC, electron transport chain GSH, glutathione PHGDH, 3-phosphoglycerate dehydrogenase SOD1, superoxide dismutase 1 SOD1, superoxide dismutase 2 TRX, thioredoxin VDAC, voltage dependent anion channel 1.

    7. Roles in cancer stem cell control

    ROS such as superoxide (O 2 − ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical (OH.), are highly chemically reactive species derived from molecular oxygen (68,69). ROS are generated in the mitochondria (69). ROS can also be produced by various oxidases (e.g., NADPH oxidases and peroxidases) in different cellular compartments or organelles, such as the cell membranes, peroxisomes and the endoplasmic reticulum (70). Furthermore, chemotherapy, radioactivity, and even smoking can increase cellular ROS levels (66,71,72). A low level of ROS promotes cell proliferation and growth and increases cell survival (73). In contrast, a high level of ROS can cause cellular toxicity and trigger apoptosis (74,75). Cellular antioxidant systems can scavenge ROS and prevent irreversible cellular oxidative damage (76). It is important for cells to balance ROS generation and antioxidant activity, and redox regulation of cellular processes is essential for growth and development. ROS levels are increased in many cancer cells, and this is in part due to the higher metabolism rate (65,77). Aberrant ROS levels can elicit cancer cell apoptosis and necrosis (78). Cancer cells have a high antioxidant capacity to counteract and scavenge ROS. Because this high antioxidant capacity enhances cell survival and impairs cellular responses to anticancer therapy (79), induction of ROS-mediated damage in cancer cells with use of appropriate pharmacological agents that either promote ROS generation beyond the cellular anti-oxidative capacity or disable the cellular antioxidant system, has been considered as a radical therapeutic strategy for preferential targeting of cancer cells (79). Recently, cancer stem cells (CSCs) have gained attention as a subpopulation of cancer cells with stem cell-like properties and characteristics these cells have been identified in the context of various cancers, including leukemia (80), breast (64) and pancreatic cancer (81). CSCs have the capacity to self-renew and differentiate and are thought to be responsible for cancer recurrence after chemotherapy or radiotherapy because of their ability to survive treatment and quickly generate new tumors (82,83). Characterization of CSCs have led to a perspective in which cancer therapeutic strategies should target not only normal cancer cells, but also CSCs. Given the importance of redox balance in cancer cells, conventional therapies (chemotherapy or radiotherapy) that target the redox balance could kill most cancer cells (67,79,84). However, the unique redox balance in CSCs and the underlying mechanisms that protect CSCs from ROS-mediated cell killing have not been fully elucidated (63,85,86).


    The present review was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology a Grant-in-Aid from the Third Comprehensive 10-year Strategy for Cancer Control, Ministry of Health, Labor and Welfare a grant from the Kobayashi Cancer Research Foundation a grant from the Princess Takamatsu Cancer Research Fund, Japan a grant from the National Institute of Biomedical Innovation and a grant from the Osaka University Drug Discovery Funds. A.H. is a research fellow of the Japan Society for the Promotion of Science. Partial support was received from Taiho Pharmaceutical, Co., Ltd., (H.I., J.K. and M.M.), Chugai, Co., Ltd., Yakult Honsha, Co., Ltd., Merck, Co., Ltd., Takeda Science Foundation and Takeda Medical Research Foundation (M.K., M.M., N.N. and H.I.) through institutional endowments.


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    A. MP1: An Overview of Metabolic Pathways - Catabolism

    • Contributed by Henry Jakubowski
    • Professor (Chemistry) at College of St. Benedict/St. John's University

    Biological cells have a daunting task. They must carry out 1000s of different chemical reactions required to carry out cell function. These reactions can include opposing goals such as energy production and energy storage, macromolecule degradation and synthesis, and breakdown and synthesis of small molecules. All of these reactions are catalyzed by proteins and RNAs enzymes whose activities must be regulated, again through chemical reactions, to avoid a futile and energy wasting scenario of having opposing pathways functioning simultaneously in a cell.

    Metabolism can be divided into two main parts, catabolism, the degradation of molecules, usually to produce energy or small molecules useful for cell function, and anabolism, the synthesis of larger biomolecules from small precursors.

    CATBOLISM: Catabolic reactions involve the breakdown of carbohydrates, lipids, proteins, and nucleic acids to produce smaller molecules and biological energy in the form of heat or small thermodynamically reactive molecules like ATP whose further degradation can drive endergonic process such as biosynthesis. Our whole world is reliant on the oxidation of organic hydrocarbons to water and carbon dioxide to produce energy (at the expense of releasing a potent greenhouse gas, CO2). In the biological world, reduced molecules like fatty acids and partially oxidized molecules such as glucose polymers (glycogen, starch), as well as simple sugars, can be partially or fully oxidized to ultimately produce CO2 as well. Energy released from oxidative reactions is used to produce molecules like ATP as well as heat. Oxidative pathways include glycolysis, the tricarboxylic acid cycle (aka Kreb's cycle) and mitochondrial oxidative phosphorylation/electron transport. To fully oxidize carbon in glucose and fatty acids to carbon dioxide requires splitting C-C bonds and the availability of series of oxidizing agents that can perform controlled, step-wise oxidation reactions, analogous to the sequential oxidation of methane, CH4 to methanol (CH3OH), formaldehyde (CH2O) and carbon dixoxide.

    Glycolysis: This most primitive of metabolic pathways is found in perhaps all organisms. In glycolysis, glucose (C6H12O6), a 6C molecule, is split (or lysed) into two, 3C carbon molecules, glyceraldehyde-3-phosphate, which are then partially oxidized under anaerobic conditions (without O2) to form two molecules of pyruvate (CH3COCO2-). Instead of the very strong oxidizing agent, O2, a weaker one, NAD+ is used, which is reduced in the process to form NADH. Since none of the carbon atoms is oxidized to the state of CO2, little energy is released compared to the complete oxidation to CO2. This pathway comes to a screeching halt if all cellular NAD+ is converted to NADH as NAD+ is not replenished by the simple act of breathing as is the case with O2 in aerobic oxidation. To prevent the depletion of NAD+ from inhibiting the cycle and to allow the cycle to continue under anaerobic conditions, excess NADH is reconverted to NAD+ when the other product of glycolysis, pyruvate is converted to lactate by the enzyme lactate dehydrogenase. Glycolysis occurs in the cytoplasm of the cell.

    Figure: Summary of Glycolysis

    Tricarboxylic Acid (Kreb's) Cycle: The TCA cycle is an aerobic pathway which takes place in an intracellular organelle called the mitochondria. It takes pyruvate, the incompletely oxidized product from glycolysis, and finishes the job of oxidizing the 3C atoms all the way to CO2. First the pyruvate moves into the mitochondria where is is oxidized to the 2C molecule acetylCoA with the release of one CO2 by the enzyme pyruvate dehydrogenase. The acetyl-CoA then enters the TCA cycle where two more CO2 are released. As in glycolysis, C-C bonds are cleaved and C is oxidized by NAD+ and another related oxidizing agent, FAD. What is very different about this pathway is that instead of being a series of linear, sequential reactions with one reactant (glucose) and one product (two pryuvates), it is a cyclic pathway. This has significant consequences since if any of the reactants within the pathways becomes depleted, the whole cyclic pathway can slow down and stop. To see how this happens consider the molecule oxaloacetate (OAA) which condenses with acetyl-CoA to form citrate (see diagram below). In this reaction, one OAA is consumed. However, when the cycle returns, one malate is converted to OAA so there is no net loss of OAA, unless OAA is pulled out of the TCA cycle for other reactions, which happens.

    Figure: Pyruvate Dehydrogenase (mitochondrial) and the TCA Cycle

    Mitochondrial Oxidative Phosphorylation/Electron Transport: The TCA cycle accomplishes what glycolysis didn't, that is the cleavage of all C-C bonds in glucose (in the form of pyruvate and acetyl-CoA, and the complete oxidation of all C atoms to CO2. Yet two problem remains. The pool of oxidizing molecules, NAD+ and FAD get converted to their reduced forms, NADH and FADH2. Unless NAD+ and FAD are regenerated, as was the case in anaerobic conditions when pyruvate gets converted to lacate, the pathway would again come to a grinding halt. In addition, not much ATP is made in the cycle (in the form of a related molecule GTP). Both these problems are resolved as the resulting NADH and FADH2 formed are reoxidized by mitochondrial membrane enzyme complexes which pass electrons from the oxidized NADH and FADH2 to increasingly potent oxidizing agents until they are accepted by the powerful oxidant O2,which is converted reduced to water. The net oxidation of NADH and FADH2 by dioxygen is greatly exergonic, and the energy released by the process drives the synthesis of ATP from ADP and Pi by an mitochondrial enzyme complex, the F0F1ATPase.

    Figure: Mitochondrial Electron Transport/Oxidative Phosphorylation

    Feeder Pathways: Other catabolic pathways produce products that can enter glycolysis or the TCA cycle. Two examples are given below.

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    These studies were supported by the Susan and John Freeman Research Grant from Cancer Council NSW. MTL was supported by a Cancer Institute New South Wales early career fellowship, and GGN is supported by an NHMRC career development fellowship II CDF1111940. SG is supported by Judith and David Coffey Life Lab at the Charles Perkins Centre, the University of Sydney. In vivo studies were funded by the Cancer Australia project grant (APP1100722 MP), Cancer Institute New South Wales career development fellowship (MP), and early career fellowship (AC). MP acknowledges fellowship support from the NHMRC 1162556, Cancer Institute NSW, and Philip Hemstritch philanthropic fellowship, with project grant support from the NHMRC 1162860 and Cancer Australia, Cancer Council NSW 1143699.


    Transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses were combined to determine the role of pregnane X receptor (PXR) in nongenotoxic signaling and energy homeostasis in liver after rats were repeatedly orally dosed with the PXR agonist pregnenolone carbonitrile (PCN) for 7 days. Analyses of mRNAs and proteins in the supernatant, membrane, and cytosolic fractions of enlarged liver homogenates showed diverse expression profiles. Gene set enrichment analysis showed that the synchronous increase in mRNAs and proteins involved in chemical carcinogenesis and the response to drug was possibly mediated by the PXR pathway and proteasome core complex assembly was possibly mediated by the Nrf2 pathway. In addition, levels of proteins in the endoplasmic reticulum lumen and involved in the acute-phase response showed specific increase with no change in mRNA level, and those composed of the mitochondrial inner membrane showed specific decrease. The analysis of phosphorylated peptides of poly(A) RNA binding proteins showed a decrease in phosphorylation, possibly by casein kinase 2, which may be related to the regulation of protein expression. Proteins involved in insulin signaling pathways showed an increase in phosphorylation, possibly by protein kinase A, and those involved in apoptosis showed a decrease. Metabolomic analysis suggested the activation of the pentose phosphate and anaerobic glycolysis pathways and the increase of amino acid and fatty acid levels, as occurs in the Warburg effect. In conclusion, the results of combined analyses suggest that PXR’s effects are due to transcriptional and post-transcriptional regulation with alteration of nongenotoxic signaling pathways and energy homeostasis.

    View All Pathways

    Cell signaling pathways can be generally categorized into groups based on area of biology. Here, you can explore all available pathways, including those that fall under a variety of areas of biology—from angiogenesis and apoptosis to bone biology, metabolism, transcription factors, and others.

    AKT Signaling Pathway

    AKT is a serine/threonine kinase that is involved in mediating various biological responses, such as inhibition of apoptosis.

    Angiopoietin-TIE2 Signaling

    The angiopoietins are a new family of growth factor ligands that bind to TIE2/TEK RTK (Receptor Tyrosine Kinase).

    Antigen Processing and Presentation by MHCs

    Antigen processing and presentation are the processes that result in association of proteins with major histocompatibility complex (MHC) molecules for recognition by a T-cell.

    Apoptosis Through Death Receptors

    Certain cells have unique sensors, termed death receptors (DRs), which detect the presence of extracellular death signals and rapidly ignite the cell's intrinsic apoptosis machinery.

    APRIL Pathway

    In immune responses, APRIL acts as a co-stimulator for B-cell and T-cell proliferation and supports class switch.

    B-Cell Development Pathway

    In immune responses, APRIL acts as a co-stimulator for B-cell and T-cell proliferation and supports class switch.

    B-Cell Receptor Complex

    The B-cell receptor (BCR) complex usually consists of an antigen-binding subunit that is composed of two Ig heavy chains, two Ig light chains, and a signaling subunit.

    BMP Pathway

    Bone morphogenetic proteins (BMPs) are a large subclass of the transforming growth factor-beta (TGF-beta) superfamily.

    Cancer Immunoediting

    The immune system attempts to constrain tumor growth, but sometimes tumor cells might escape or attenuate this immune pressure.

    CCR5 Pathway in Macrophages

    C-C motif chemokine receptor type 5 (CCR5) is a member of the chemokine receptor subclass of the G protein–coupled receptor (GPCR) superfamily.

    CD4 and CD8 T-Cell Lineage

    Each mature T-cell generally retains expression of the co-receptor molecule (CD4 or CD8) that has a major histocompatibility complex (MHC)-binding property that matches that of its T-cell receptor (TCR).

    Cellular Apoptosis Pathway

    Apoptosis is a naturally occurring process by which a cell is directed to programmed cell death.

    CTL-Mediated Apoptosis

    The cytotoxic T lymphocytes (CTLs), also known as killer T-cells, are produced during cell-mediated immunity designed to remove body cells displaying a foreign epitope.

    CTLA4 Signaling Pathway

    The co-stimulatory CTLA4 pathway attenuates or down-regulates T-cell activation. CTLA4 is designed to remove body cells displaying a foreign epitope.

    Cytokine Network

    Cytokines have been classified on the basis of their biological responses into pro- or anti-inflammatory cytokines, depending on their effects on immunocytes.

    ErbB Family Pathway

    The ErbB family of transmembrane receptor tyrosine kinases (RTKs) plays an important role during the growth and development of organs.

    Fas Signaling

    FAS (also called APO1 or CD95) is a death domain–containing member of the tumor necrosis factor (TNF) receptor superfamily.

    FGF Pathway

    One of the most well characterized modulators of angiogenesis is the heparin-binding fibroblast growth factor (FGF).

    Granulocyte Adhesion and Diapedesis

    Adhesion and diapedesis of granulocytes have mostly been analyzed in context to non-lymphoid endothelium.

    Granzyme Pathway

    Granzyme A (GzmA) activates a caspase-independent cell death pathway with morphological features of apoptosis.

    GSK3 Signaling

    GSK3 is a ubiquitously expressed, highly conserved serine/threonine protein kinase found in all eukaryotes.

    Hematopoiesis from Multipotent Stem Cells

    Hematopoietic stem cells are classified into long-term, short-term and multipotent progenitors, based on the extent of their self-renewal abilities.

    Hematopoiesis from Pluripotent Stem Cells

    Pluripotent stem cells are capable of forming virtually all of the possible tissue types found in human beings.

    ICos-ICosL Pathway in T-Helper Cells

    IL-2 is a cytokine that stimulates the growth, proliferation, and differentiation of T-cells, B-cells, NK cells, and other immune cells.

    IL-2 Gene Expression in Activated and Quiescent T-Cells

    IL-2 is a cytokine that stimulates the growth, proliferation, and differentiation of T-cells, B-cells, NK cells, and other immune cells.

    IL-6 Pathway

    IL-6 is a pleiotropic cytokine that affects the immune system and many physiological events in various organs.

    IL-10 Pathway

    IL-10 is a pleiotropic cytokine with important immunoregulatory functions and whose activities influence many immune cell types.

    IL-22 Pathway

    IL-22 is a member of the IL-10 family of cytokines and exerts multiple effects on the immune system.

    Interferon Pathway

    Interferons are pleiotropic cytokines best known for their ability to induce cellular resistance to viral infection.

    JAK/STAT Pathway

    The JAK/STAT pathway is a signaling cascade whose evolutionarily conserved roles include cell proliferation and hematopoiesis.

    MAPK Family Pathway

    Mitogen-activated protein kinases (MAPKs) belong to a large family of serine/threonine protein kinases that are conserved in organisms as diverse as yeast and humans.

    Nanog in Mammalian ESC Pluripotency

    NANOG is a transcription factor transcribed in pluripotent stem cells and is down-regulated upon cell differentiation.

    P53-Mediated Apoptosis Pathway

    Tumor protein p53 is a nuclear transcription factor that regulates the expression of a wide variety of genes involved in apoptosis, growth arrest, or senescence in response to genotoxic or cellular stress.

    Pathogenesis of Rheumatoid Arthritis

    Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet.

    PI3K Signaling in B Lymphocytes

    The phosphoinositide 3-kinases (PI3Ks) regulate numerous biological processes, including cell growth, differentiation, survival, proliferation, migration, and metabolism.

    RANK Pathway

    RANKL and its receptor RANK are key regulators of bone remodeling, and are essential for the development and activation of osteoclasts.

    RANK Signaling in Osteoclasts

    RANKL induces the differentiation of osteoclast precursor cells and stimulates the resorption function and survival of mature osteoclasts.

    TGF-Beta Pathway

    Members of the transforming growth factor (TGF)-beta family play an important role in the development, homeostasis, and repair of most tissues.

    THC Differentiation Pathway

    T-helper cells of type 1 (TH1) and type 2 (TH2) are derived from T-helper cells and provide help to cells of both the innate and adaptive immune systems.

    TNF Signaling Pathway

    Tumor necrosis factor (TNF) is a multifunctional pro-inflammatory cytokine with effects on lipid metabolism, coagulation, insulin resistance, and endothelial function.

    TNF Superfamily Pathway

    The tumor necrosis factor (TNF) superfamily consists of 19 members that signal through 29 receptors that are members of the TNF receptor (TNFR) superfamily.

    Transendothelial Migration of Leukocytes

    Transport of plasma proteins and solutes across the endothelium involves two different routes: transcellular and paracellular junctions.

    Tumoricidal Effects of Hepatic NK Cells

    The liver is a major site for the formation and metastasis of tumors.

    TWEAK Pathway

    TWEAK is a cell surface-associated protein belonging to the tumor necrosis factor (TNF) superfamily and has multiple biological activities.

    VEGF Family of Ligands and Receptor Interactions

    Vascular endothelial growth factor (VEGF) is a highly-conserved genetic pathway that has evolved from simple to complex systems.

    Antibodies Resource Library

    Access a targeted collection of scientific application notes, methods, and cell signaling charts.

    Targeting apoptotic pathways and ROS homeostasis

    (i) Targeting Bcl-2 family proteins

    Bcl-2, Bcl-xL, Bax, and Bak are important in the intrinsic apoptotic pathway. Venetoclax, currently approved for use in patients with chronic lymphocytic leukemia [18], navitoclax, TW-37, GX15-070 and BM-1197, are Bcl-2 or Bcl-xL inhibitors with anticancer activity in a broad range of cancer types [8]. Compounds such as Gossypol, Navitoclax, ABT-737 and α-TOS act as mimetics of the Bcl-2 homology-3 domains to kill cancer cells through the activation of post-mitochondrial apoptotic signaling [17].

    (ii) Targeting redox-regulating enzymes and ROS production

    Electron transport chain is the major site of ROS production, and high level of ROS released due to interference with the ECT complexes cause cellular damage. Oxymatrine was reported to efficiently kill human melanoma cells by generating high levels of ROS. Capsaicin, casticin, and myricetin display anticancer activity by increasing ROS generation, leading to the disruption of mitochondrial transmembrane potential in cancer cells [8]. Promoting mitochondrial ROS production to induce cancer cell death may enhance the activity of chemotherapy [15]. By coupling triphenylamine (TPA) with the fluorophore BODIPY, a novel mitochondrial-targeted fluorescent probe BODIPY-TPA was shown to induce apoptosis in gastric cancer via disruption of the mitochondrial redox balance and ROS accumulation [19].

    In summary, mitochondria play a key role in cell survival and apoptosis. Mitochondrial respiration supports ATP production and is also essential for tumorigenesis. Targeting mitochondrial metabolism presents a new concept to effective cancer therapeutics.

    Watch the video: Animes -Dere Archetypes, Explained. Do You Know Them ALL?! (August 2022).