Cell Metabolism

Recent inquiry in cell metabolism of SNOs has led to the identification and characterization of enzyme-mediated processes (nitrosylases and denitrosylases) that are implicated in targeted S-nitrosylation or denitrosylation of proteins in physiological settings.

From: Nitric Oxide (Donor/Induced) in Chemosensitizing , 2017

Cellular metabolism

Chaya Gopalan Ph.D., FAPS , Erik Kirk Ph.D. , in Biology of Cardiovascular and Metabolic Diseases, 2022

9.10.1 Krebs cycle/citric acrid cycle/tricarboxylic acrid cycle

The Krebs bicycle is considered one of the master pathways in cellular metabolism. Acetyl CoA enters the Krebs bike past combining with a four-carbon molecule, oxaloacetate, and becomes half-dozen-carbon-molecule citrate, or citric acid. It is the formation of citric acid that gives its proper noun, the citric acid wheel. The citrate molecule is systematically converted to a v-carbon molecule and a four-carbon molecule, catastrophe with oxaloacetate (Fig. nine.11). The ii carbons from citrate to oxaloacetate are released in the course of two molecules of CO2. Each citrate molecule causes the release of ane ATP, ane FADH2, and three NADH coenzymes along the mode. In this reaction, coenzyme A molecule is released, combining with another pyruvate molecule to start a new cycle equally needed. The FADH2 and NADH will enter the oxidative phosphorylation system located in the inner mitochondrial membrane.

Fig. 9.11

Fig. 9.11. Krebs cycle(citric acid cycle or tricarboxylic acid cycle) [viii]. One acetyl CoA is candy in each bike to yield high-free energy NADH, FADH2, and ATP molecules. Ii CO2 molecules are released as waste material products.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128234211000032

Omics Technologies Used in Systems Biology

Delisha Stewart , ... Susan Sumner , in Systems Biological science in Toxicology and Environmental Health, 2015

Metabolic Flux Analysis

Cellular metabolism is complex and consists of many thousands of genes, proteins, and metabolites. These molecules are involved in a network of biochemical reactions. Metabolic flux analysis using stable isotopes such as 2H, 13C, and 15N (due east.g., 13C-labeled glucose) enables identifying and quantitatively estimating the metabolism through metabolic pathways [130] past observing the position of the isotopic characterization along the metabolic pathways. Metabolic flux assay can exist performed past using oneH and 13C NMR methods likewise as mass spectrometry methods [130–133]. Single or multiple tracer applications using prison cell-based [134,135] and in vivo methods in animal models [136,137] and in humans [39] are used in the metabolic flux analysis and will be useful in elucidation cellular mechanisms.

Read total chapter

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B9780128015643000043

Protein Synthesis

David P. Clark , ... Michelle R. McGehee , in Molecular Biological science (Third Edition), 2019

viii Some Ribosomes Become Stalled and Are Rescued

Cellular metabolism is non perfect and cells must allow for errors. Ane problem ribosomes sometimes run across is lacking mRNA that lacks a stop codon. Whether synthesis of the mRNA was never completely finished or whether it was mistakenly snipped short past a ribonuclease, bug ensue. In the normal course of events, a ribosome that is translating a message into protein will, sooner or after, come up across a stop codon. Even if an mRNA molecule comes to an abrupt end, ribosomes may be released only past release factor and this in turn needs a stop codon. If the mRNA is defective and there is no stop codon, a ribosome that reaches the finish could just sit there forever and the ribosomes backside it will all be stalled, too.

Ribosomes that have stalled due to defective mRNA tin be rescued by a special RNA—tmRNA.

Bacterial cells contain a small RNA molecule that rescues stalled ribosomes. This is named tmRNA considering it acts partly like tRNA and partly like mRNA. Like a tRNA, the tmRNA carries alanine, an amino acid. When it finds a stalled ribosome, it binds abreast the defective mRNA (Fig. 13.28). Protein synthesis now continues, offset using the alanine carried past tmRNA, then continuing on to translate the brusk stretch of bulletin that is besides function of the tmRNA. Finally, the tmRNA provides a proper stop codon so that release cistron can disassemble the ribosome and complimentary information technology for continued poly peptide synthesis. The tRNA domain of tmRNA lacks an anticodon loop and a D-loop. A protein known every bit SmpB (non shown in Fig. xiii.28 for clarity) binds to the tRNA domain and makes contacts to the ribosome that would normally exist made by the missing D-loop.

Figure 13.28. Stalled Ribosome Liberated by tmRNA

Binding of a tmRNA carrying alanine allows the translation of a damaged bulletin to continue. First, alanine is added, and then a short sequence of most ten amino acids encoded by the tmRNA. Finally, the terminate codon of the tmRNA allows proper termination of the polypeptide concatenation.

Clearly, the poly peptide that has just been made is defective and should be degraded. As might be supposed, the tmRNA has signaled that the protein that was fabricated is defective. The brusque stretch of eleven amino acids specified by the bulletin part of tmRNA and added to the end of the defective protein acts every bit a bespeak, known as the ssrA tag. (SsrA stands for small stable RNA A, a name used for tmRNA earlier its office was elucidated.) The ssrA tag is recognized by several proteases (originally referred to as " tail specific proteases "), which dethrone all proteins conveying this point. These include the Clp proteases and the HflB protease involved in the estrus shock response (see Chapter 16: Regulation of Transcription in Prokaryotes). Eukaryotic cells lack tmRNA, merely practice have a process chosen nonsense-mediated decay that degrades defective mRNA (encounter Affiliate 12: Processing of RNA).

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128132883000136

Neuroendocrine Aging: Pituitary Metabolism

W.Eastward. Sonntag , ... R.Chiliad. Goya , in Encyclopedia of Neuroscience, 2009

TSH: Tri-iodothyronine, Thyroxine, and Thyroid Function

Cellular metabolism is regulated by the secretion of TSH release from the anterior pituitary gland. This hormone enters the apportionment and stimulates the thyroid gland to produce both tri-iodothyronine (T3) and thyroxine (T4). These hormones circulate spring to thyroid binding globulin and after transport are taken upward by the prison cell. T3 is the more potent thyroid hormone, just Tiv tin be converted to T3 with the enzyme deiodinase. Levels of these hormones regulate basal metabolic activity throughout the torso. T3 and T4 are controlled by negative feedback regulation, primarily at the level of the anterior pituitary gland, by suppression of TSH release although the hypothalamus besides produces thyroid-releasing hormone (TRH) that tin can stimulate TSH release. TRH has merely a minor role in the regulation of TSH release under normal atmospheric condition, merely in response to common cold stress or other challenges, TRH exerts an of import influence. In improver to prominent furnishings on cellular metabolism and temperature regulation, thyroid hormones accept a permissive role in the regulation of many organs and tissues, including reproductive office, os metabolism, and glucose metabolism. Therefore, changes in the secretion or response to thyroid hormones would be expected to have wide-ranging effects on the wellness of the organism.

Autonomously from the appearance of specific thyroid diseases that increment with age, just subtle changes in the levels of thyroid hormones seem to occur in otherwise healthy older animals or humans. Investigators have reported a reduction in deiodinase activity that leads to reduced levels of T3 within target organs, just the significance of these changes for the development of physiological changes in tissue office have non been well defined. Similarly, it is of interest that numerous animal models that showroom increased life span also exhibit a decrease in thyroid hormone levels, only the significance of these changes remains to be adamant.

Read total affiliate

URL:

https://www.sciencedirect.com/science/article/pii/B9780080450469001133

Fundamentals of jail cell metabolism and cancer

Ragunathan Devendran , ... Prabu Gnanasekaran , in Agreement Cancer, 2022

8.11 Conclusion

Cellular metabolism is comprehensively governed past the interaction of several cistron products and the conversion of metabolites [63]. While matured omics such every bit genomics and proteomics occupy every bit the major components, the unanswered questions in "-omics" tin can be answered by metabolomics every bit the metabolites are the end products and intermediates of biochemical reactions, cellular interactions, and processes [64,65]. Thus, metabolomics in-hand with other '-omics' approaches will bridge the gap of genotype-phenotype relations in systems biological science [66]. Therefore, it is necessary to unravel the metabolic processes in disease atmospheric condition to brand progress in functional genomics [67]. Numerous studies employed the metabolomics approach in diverse cancer types to identify the contradistinct metabolite levels [68–71]. Thus, metabolomics is a useful approach in understanding the biological status and to employ the information to predict the cancer condition in biological and clinical contexts.

Read full chapter

URL:

https://world wide web.sciencedirect.com/science/article/pii/B9780323998833000019

Reconstruction of Genome-Calibration Metabolic Networks

Hooman Hefzi , ... Nathan E. Lewis , in Handbook of Systems Biological science, 2013

Cellular Metabolism

Cellular metabolism is organized around a large network of enzyme-catalyzed and spontaneous chemical reactions. These reactions involve a ready of diverse metabolites, and all of the reactions role together to produce and recycle the materials for cell maintenance and growth (eastward.g.. amino acids, lipids, ATP), signaling molecules (due east.g., cAMP and H2S), waste products, and molecules that affect the growth of surrounding organisms (e.yard., antibiotics, quorum-sensing molecules, hormones, etc.). Metabolism is important in about cell and organism phenotypes. For example, it has been implicated equally a contributing gene of human being diseases such every bit diabetes [1] and cancer [2], making it an auspicious surface area for research. However, the size of these metabolic networks has made the written report of their functions hard, since they contain hundreds or thousands of reactions. Thus, systems-level methods have been developed to gain insight into how thousands of cellular components function together as a whole to provide the phenotypes we observe in living organisms.

Read total chapter

URL:

https://world wide web.sciencedirect.com/science/article/pii/B9780123859440000125

Prison cell preparation for 3D bioprinting

A. Al-Sabah , ... C. Thornton , in 3D Bioprinting for Reconstructive Surgery, 2018

four.5 Metabolic assessment

Cell metabolism provides a reflection of the health status of the prison cell. The mitochondrion is the main powerhouse of the cell in which bioenergetic processes occur by the uptake of fuel sources such every bit glucose and fatty acids and converts them into energy in a series of enzymatic reactions [ 73,74]. Bioenergetics processes are tightly regulated as they are essential for prison cell viability. Deregulation of cellular bioenergetics has been previously associated with numerous pathologies such as cancer, diabetes, and neurodegenerative diseases [75].

Measurement of cellular bioenergetics will present a clearer picture for understanding alterations in cell phenotype and physiology. Bioenergetics of cells is quantified via measurement of extracellular flux and the alteration in oxygen and protons concentrations in the media. The charge per unit of oxygen consumption rate (OCR)—an indicator of mitochondrial respiration and rate of acid efflux (ECAR)—the amount of lactic acid germination during glycolytic metabolism are parameters which decide prison cell physiology and their metabolic state [76–78]. Measurement of OCR and ECAR simultaneously provides unique bioenergetic profiles that occur due to culture atmospheric condition or specific treatments.

It is well established that the environmental growth conditions influence cellular bioenergetics. Studies examining the culture of stalk cells in nonphysiological levels of oxygen have shown that it is detrimental to cell viability and genetic stability. With college oxygen levels, the bioenergetic mechanisms of stem cells have shifted from glycolytic to mitochondrial respiration (oxidative phosphorylation) [79]. Consequently, the increased consumption of oxygen results in the generation of reactive oxidative species (ROS) which is implicated in promoting cellular senescence, cell decease, and genetic instability [80,81]. Physiological oxygen levels were shown to enhance prison cell stemness in prolonged civilisation of stem cells thus emphasizing the necessity to restate the microenvironment of the jail cell [82]. In addition to increasing stemness, low oxygen levels have resulted in increased stem cell proliferation and extension of cellular life span [83]. In vivo jail cell bioenergetics is dependent on the microenvironment of the cell such as available vascularization and oxygen tension of the tissues. Well-nigh stalk cells reside in a hypoxic environment which have enabled them to utilize glycolysis every bit their preferred means of energy production [84]. As a result, information technology is relatively uncomplicated to confirm whether the cells of involvement have retained their metabolic phenotype by assessing the extracellular flux after prolonged expansion.

Culture media composition and, in item, glucose concentration is additionally a potential source which can alter cellular bioenergetics. Every bit mentioned previously, stem cells primarily utilise glycolysis for energy production, whereas it is suggested that differentiated cells shift toward oxidative phosphorylation [85]. This miracle was observed with embryonic stalk cells cultured in high glucose concentrations which have shown to consequence in formation of ROS promoting cell differentiation [86]. A report past Rogers et al. have identified that culturing endothelial cells in either low or high glucose accelerated prison cell senescence [87]. These findings must be considered when selecting the optimal concentration of glucose supplementation for cell culture media. Using the glucose concentration that is not physiologically relevant for the cell of interest could atomic number 82 to dedifferentiation of cells and premature cell aging.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780081011034000065

Stem Cell Proliferation and Differentiation

Logeshwaran Somasundaram , ... Hannele Ruohola-Baker , in Electric current Topics in Developmental Biology, 2020

two Stem cell energetics

Cellular metabolism is the set of all biochemical reactions that produce the energy, and irrespective of cell type or differentiation state, it is required to support the intricate molecular mechanism that keeps the jail cell alive. Metabolic processes can exist broken downwards into either synthesis of new biomolecules (anabolism) or breaking downwards of molecules and existing biomolecules (catabolism) to generate energy. Several pathways are involved in the building up and breaking downwards of biomolecules and cellular components. In this review, we consider glycolysis, pentose phosphate pathway, tricarboxylic acrid (TCA) cycle, fatty acid β-oxidation and oxidative phosphorylation (Fig. 1). Glycolysis is a metabolic pathway that converts glucose into pyruvate while generating ATP and NADPH. Biosynthetic intermediates from glycolysis tin can be directed into the pentose phosphate pathway (PPP) for jail cell growth and proliferation. PPP is shown to be an essential metabolic pathway for pluripotent stalk cells (Filosa et al., 2003; Varum et al., 2011) because information technology generates metabolites that are needed for lipid and nucleotide biosynthesis. Some adult stem cells also require this pathway since the PPP enzyme hexose-6-phosphate dehydrogenase (H6PD) was found to exist required for the self-renewal of myoblast in vitro during muscle regeneration (Bracha et al., 2010). In the presence of oxygen, pyruvate generated from glycolysis can exist transported into mitochondria and converted into acetyl-CoA. However, in low oxygen conditions (hypoxia) pyruvate will exist reduced to lactate and a gratuitous energy carrier, NAD+ is generated.

Fig. 1

Fig. 1. Overview of the major cellular metabolic pathways (indicated in blue): Glycolysis, pentose phosphate pathway (PPP), TCA (Krebs) cycle, β-oxidation and oxidative phosphorylation (OXPHOS). Metabolites from glycolysis tin move to PPP to generate NADPH and precursors for lipid and nucleotide synthesis. In improver to generating ATP, glycolysis generates pyruvate which is oxidized in the TCA cycle. OXPHOS generates the most ATP in the electron transport chain (ETC). Adult and pluripotent stem cells both apply these metabolic pathways (come across text for details). ADP, adenosine diphosphate; ATP, adenosine triphosphate; ATPase, ATP synthase; ETC, electron ship chain; F6P, fructose vi phosphate; G6P, glucose vi phosphate; G3P, glyceraldehyde-3-phosphate; FAD, Flavin adenine dinucleotide; NAD, Nicotinamide adenine dinucleotide; TCA, tricarboxylic acid.

 The figure was created with Biorender.com.

In addition to glucose, lipids are a major source of energy in cells. Free energy is generated from lipid breakdown through fat acid β-oxidation, producing acetyl-CoA. Long chain fat acids are transported to mitochondria by the carnitine acyl transferase, CAT, system, besides known as the carnitine shuttle. The charge per unit limiting enzyme in this step is CAT1. Fatty Acyl-CoA is then dehydrogenated to acetyl-CoA utilizing the mitochondrial trifunctional protein (TFP) consisting of enoyl-CoA hydratase, hydroxyacyl-CoA dehydrogenase A and B (HADHA and HADHB) and ketoacyl-CoA thiolase. Defects in components of this pathway are causative for LCHAD deficiency, resulting in sudden babe death syndrome (SIDS) in humans (Miklas et al., 2019). Each cycle in the TFP complex results in a fatty acyl-CoA moiety that is shorter past two carbons and an acetyl-CoA that tin enter the TCA cycle.

Acetyl-CoA produced either from glucose or from fatty acid β-oxidation is oxidized in the TCA cycle in a series of reactions that ultimately generate ATP and CO2. TCA wheel generates important metabolic intermediates and electron carriers, FADH2 and NADH. Electrons carried past NADH and FADHii into the electron transport chain will generate a proton gradient across the inner mitochondrial membrane. The free energy from this proton gradient is finally captured in the form of ATP by the conversion of ADP and phosphate to ATP by ATP-β-synthase, a rotating molecular machine that taps its energy from utilizing the chemiosmotic proton [H   +] slope to ability its motility. The rotating movement is critical for catalytic site to access ADP and phosphate to generate ATP. The synthesis of ATP by ATP-β synthase is a process known as oxidative phosphorylation (OXPHOS) (Fig. 1).

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/S0070215320300296

Metabolomics and Lipidomics

Priscilla L. Yang , in Viral Pathogenesis (Third Edition), 2016

one Introduction

Cellular metabolism is comprised of the chemical reactions that occur in living cells. Broadly, these reactions can be divided into catabolic reactions that convert nutrients to energy and anabolic reactions that lead to the synthesis of larger biomolecules. The reactants and products of these chemical reactions are metabolites. The flow of genetic information from Deoxyribonucleic acid (genome) to RNA (transcriptome) to poly peptide (proteome) described by the Central Dogma leads to production of the metabolome. The composition of the metabolome is dynamic and reflects expression of the genome nether specific weather condition. Metabolomic changes induced by viral infection are the integration of virus-induced changes in both host cistron expression and host poly peptide function.

As early as the 1950s, Seymour Southward. Cohen advanced the idea of viral replication as a serial of biochemical reactions whose reactants and products are amenable to autopsy, writing: "Many of the well-nigh important biological questions have been rephrased every bit chemical problems. Questions at present are being posed concerning the nature of the edifice blocks and the pathways of their biosynthesis. The time course of infection, duplication, and virus liberation is being dissected minute by minute in terms of the molecular transformations occurring in these systems." Cohen advocated that the tools of chemical science would enable understanding of viral processes at the molecular level. In the sixty-odd years since Cohen first referred to this expanse of investigation as "chemic virology," advances in analytical methods have facilitated increasingly precise knowledge of the interaction of viruses with host metabolism.

The major classes of metabolites include amino acids, carbohydrates, nucleotides, lipids, coenzymes, and cofactors. These classes of compounds encompass an enormous variety of molecular structures, physicochemical properties, functions, and abundances. Due to the analytical challenges posed by this diverseness, most studies require segmentation of the metabolome into subsets of metabolites. The most common distinction is that between hydrophilic (polar) metabolites and hydrophobic (nonpolar) metabolites. Polar metabolites are soluble in aqueous solutions and include most sugars, purines and pyrimidines, nucleotides and nucleosides, acyl carnitines, organic acids, hydrophilic acids, amino acids, and phosphorylated compounds. These metabolites include most of the reactants and products involved in cellular respiration (due east.g., glycolysis, the TCA wheel, or the pentose phosphate pathway) and in the production of edifice blocks for synthesis of big biopolymers such as DNA, RNA, proteins, and oligosaccharides. The nonpolar or hydrophobic metabolites are traditionally referred to as lipids. These metabolites function in energy storage, membrane structure, and signal transduction. Reflecting the diversity and complexity of lipid structures and functions (Table 1), the written report of lipid metabolites has developed every bit a subfield within metabolomics. Thus, the complete metabolome formally includes both hydrophilic and hydrophobic metabolites, but the term "metabolome" is now frequently used to refer to the hydrophilic metabolome and the term "lipidome" is used to refer to hydrophobic metabolites. This affiliate provides background and a framework for examining the function of lipid metabolites in viral processes and highlights general themes in our current understanding of the office of lipids in viral replication and pathogenesis.

Table ane. Classes and Functions of Lipids

Lipid Class Examples Part
Fatty Acids/Fatty Acyls
Carboxylic acids and their derivatives
Energy storage
Hydrophobic tail varies in length and degrees of unsaturation Building block for other lipids
Glycerolipids
Glycerol cadre (blue) with one, two, or three fatty acyl groups to form mono-, di-, and tri-acylglycerides (Magazine, DAG, TAG)
Free energy storage
DAG are also 2d messengers in indicate transduction and pre-cursors for prostaglandin synthesis
TAG are used for energy transport
Glycerophospholipids
DAG backbone (blue) with phosphate at third alcohol (ruby)
PC, PE, PS are structural components of membranes
Phosphate (red) esterified with choline, ethanolamine, serine, or inositol (green) results in phosphatidylcholines (PC), phosphatidylethanolamines (PE), phosphatidylserines (PS), and phosphatidylinositols (PI), respectively PE and PS induce membrane curvature, as do MAGs like BMP
Acyl groups are represented as "Rone" and "R2" and vary in length and degree of unsaturation
 PS and PI serve as docking sites in membranes for signaling proteins
PI are precursors of secondary messengers and course a "lipid code" signifying membrane identity
Sphingolipids
Sphingosine base is the long-concatenation aliphatic amine backbone (R1)
S1P are extracellular signaling molecules
Ceramides (CER) are the sphingosine base acylated at the amine (R2)
 CER and SM are structural components of membranes that tin can induce formation of lipid-ordered domains ("rafts") and membrane curvature
Sphingomyelin (SM) corresponds to a ceramide conjugated to phosphatidyl-choline (greenish) at the 2d alcohol
R2 varies in length and saturation
Sterols
Sterols are defined by a four-ringed structure
Cholesterol is the structural component of membranes
Rings are labeled A, B, C, D Packing of cholesterol with SM induces lipid-ordered domains important for bespeak transduction and viral assembly
Sterol esters are formed by esterification with fat acids Sterols are too signaling molecules
Sterol esters are used for energy storage
Bioactive Lipids
Bioactive lipids are derived from arachidonic acid and related molecules
Point transduction via 1000-poly peptide-coupled and peroxisome proliferator-activated receptors
These include prostaglandins, thromboxanes, lipoxins, leukotrienes, resolvins, protectins, and maresins Pro- or anti-inflammatory effects

Viruses require hydrophilic and lipid metabolites from the host. Starting time, viruses are unable to manufacture the primary metabolites required for synthesis of new virions. The nucleotides, amino acids, and lipids that are structural components of the viral particle are all commandeered from the host cell. Likewise, cellular respiration provides the fuel required to drive the energetically costly procedure of viral replication. The effects of many viruses on metabolic pathways that produce the edifice blocks and energy needed for viral replication are well-documented. Although these perturbations are thought to support viral replication, the underlying molecular mechanisms are still the subject of much investigation. Second, many viruses utilise specialized membranes for viral entry, gene expression, genome replication, and assembly. The distinct morphology and functional properties of these membranes presumably reflects their specialized limerick, which has been optimized for the viral process that they support. Assay of the chemical limerick and biophysical backdrop of these membranes, every bit well every bit the molecular mechanisms underlying their biogenesis, is therefore cardinal to understanding their role in viral processes. Third, signal transduction by bioactive lipid metabolites plays a major role in the host response to viral infection and, in many cases, in pathogenesis. Identification of bioactive lipids associated with viral replication or the host inflammatory response holds promise for the identification of biomarkers of infection and disease progression likewise equally for identifying potential points for pharmacological intervention (Box 1).

Box i

Metabolomics for the discovery of antiviral targets

Metabolic enzymes and other metabolite-bounden proteins are an attractive source of potential antiviral targets. Get-go, metabolic reactions are essential to the infectious cycle of all viruses. Synthesis of new virions is itself comprised by the chemical conversion of nucleotides, amino acids, and lipids into progeny virions. Host-catalyzed chemic reactions that lead to the synthesis of these bones building blocks, and to the release of energy, have directly impacts on viral replication. Second, since the natural function of metabolite-binding sites on proteins is to bind to small molecules, these sites are generally reasonable molecular targets for drug discovery efforts. Indeed, many existing drugs mimic the interaction of naturally occurring metabolites with their respective enzymes and receptors. These "anti-metabolites" human action by preventing utilization of the natural metabolite. Traditional antivirals targeting viral polymerase and protease activities are good examples of drugs that act past this mode. They inhibit the natural catalytic function of these enzymes by binding to the active site or to allosteric sites. These antiviral drugs are selective because they target metabolic reactions unique to the virus. Although this approach has produced some of the virtually successful drugs on the market place today, information technology is inherently express because viral genomes encode a very express number of metabolite-bounden proteins, and because resistance can develop through mutations that affect drug binding without affecting catalytic function. In addition, the selectivity of these drugs for their specific viral targets usually limits their use to a narrow spectrum of closely related viruses.

Targeting essential metabolic reactions catalyzed past host factors offers an alternative antiviral strategy. Viruses are fully dependent upon host metabolism and exercise not themselves encode the enzymes needed to produce the metabolites required for their ain replication. Inhibition of a metabolic reaction critical for viral replication is therefore unlikely to be overcome by direct mutations of the viral genome. Also, the centrality of host metabolism to the viral infectious cycle makes information technology likely that phylogenetically related viruses take shared dependencies on specific metabolic pathways. Although the host proteome is replete with enzymes and proteins that bind to minor-molecule metabolites, the challenge is to identify those that can mediate antiviral activity without affecting normal host cell function. Every bit advances in belittling methods have enabled both broader and deeper surveys of virus-induced perturbations of host metabolism, identification of targets that mediate fairly selective antiviral effects has come closer to reality.

Metabolomic profiling enables the systematic identification of perturbations of metabolism that arise from the interaction of viral pathogens with the host. Differences in metabolomic profiles reverberate changes in poly peptide function. This contrasts and complements the changes in factor expression and protein abundance detected by transcriptomic and proteomic studies. The combination of these approaches provides the fullest moving-picture show of virus–host interactions occurring at both the molecular and pathway levels.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128009642000148

Stem Cells in Development and Affliction

Ana Mafalda Baptista Tadeu , Valerie Horsley , in Current Topics in Developmental Biology, 2014

5.one Intrinsic regulation of stalk prison cell office

Cellular metabolism and ecology assaults can result in Deoxyribonucleic acid damage, especially in the skin, which direct receives UV irradiation from the sunday and environmental mutagens that can induce genomic instability. Interestingly, HFSCs are more resistant to radiation-induced damage compared to other epithelial skin cells (Sotiropoulou et al., 2010). To achieve this resistance, HFSCs express high levels of the antiapoptotic protein B-cell lymphoma ii (Bcl2) and transiently express p53 to promote survival. In addition, chest cancer 1 (Brca1) is essential for DNA harm repair (Gudmundsdottir & Ashworth, 2006; Moynahan & Jasin, 2010) and epidermal deletion of Brca1 leads to defects in HF formation as well as induction of caspase-dependent apoptosis that leads to hyperproliferation and subsequent exhaustion of developed SCs (Sotiropoulou et al., 2013). The differential regulation of DNA damage in SCs as well exists within other tissues (Mandal, Blanpain, & Rossi, 2011) and may be similar to the mechanisms that act in SCs in the IFE and other epidermal appendages.

Several transcriptional regulators of SC role in the HF have been identified and are shared among SCs of other tissues including transcription factor 3 and 4 (TCF3/4), nuclear factor of activated T-cells 1 (NFATc1) and sexual practice determining region Y-box 9 (Sox9) (Blanpain & Fuchs, 2006; Nguyen et al., 2009; Nguyen, Rendl, & Fuchs, 2006; Nowak, Polak, Pasolli, & Fuchs, 2008). In improver, Lgr5 (Barker et al., 2007) and the singular HOP homeobox protein Hopx are expressed by an intestinal SC epithelial pool at the base of the catacomb (Takeda, Jain, LeBoeuf, Wang, & Lu, 2011). In the HF, Hopx is expressed within burl cells and tin contribute to all HF lineages upon HF growth as well as to IFE cells upon wounding (Takeda, Jain, LeBoeuf, & Padmanabhan, 2013). Lower burl cells expressing the SC marking Lgr5 likewise express Hopx, are able to escape apoptosis during the HF death phase and contribute long-term to bulge cell maintenance (Takeda et al., 2013).

The transcription factor LIM homeobox poly peptide 2 (Lhx2) is some other homeobox protein that has been implicated in regulating morphogenesis and patterning of ectodermal derivatives and in SC maintenance and quiescence inside the HF SC niche (Mardaryev et al., 2011; Rhee, Polak, & Fuchs, 2006; Törnqvist, Sandberg, Hägglund, & Carlsson, 2010). Lhx2 is expressed in the bulge and secondary hair germ where information technology co-localizes with the SC markers Sox9, Tcf4, and Lgr5. In response to pare injury, Lhx2+ cells within the bulge and secondary pilus germ proliferate and contribute to peel re-epithelialization via positive regulation of Sox9 and Tcf4 while inhibiting HF cycling through negatively regulating Lgr5 ( Mardaryev et al., 2011). These and many other studies have provided novel insights of how Wnt and BMP signaling pathways and transcriptional regulation networks modulate activity of epithelial SCs during normal homeostasis and in response to injury (Blanpain & Fuchs, 2006; Lee & Tumbar, 2012; Sennett & Rendl, 2012).

Epithelial SCs are likewise regulated post-transcriptionally and translationally in part by microRNAs (miRNAs), which are pocket-size noncoding RNAs that alter RNA translation or stability to control cistron expression. Complete ablation of miRNA product by deletion of the upstream processing enzyme Dicer in mice results in perinatal lethality and severe HF defects (Andl et al., 2006; Yi et al., 2006). Among these defects are undeveloped and misaligned HFs, increased apoptosis and lack of K15+ and CD34+ cells within the bulge compartment suggesting that miRNAs, in full general, are of import for HF SC maintenance (Andl et al., 2006).

Several miRNAs are spatiotemporally regulated within the IFE and the HFSCs. MiR203 was shown to be preferentially enriched in the IFE versus the HF (Andl et al., 2006; Yi, Poy, Stoffel, & Fuchs, 2008) and is sufficient to promote IFE differentiation and suppress cocky-renewal in the IFE by controlling the expression of p63 (Andl et al., 2006; Yi et al., 2008).Additionally, miR203 is transcriptionally activated during asymmetric prison cell partitioning in the developing epidermis, localizing to the differentiated girl prison cell, where it promotes jail cell cycle exit and abolishes self-renewal in a process involving co-suppression of p63, Southward-stage kinase-associated protein two (Skp2), and musashi RNA-bounden poly peptide 2 (Msi2) (Jackson et al., 2013).

An additional miRNA, miR125b is sufficient to alter IFE homeostasis and countervail hair specification (Zhang, Stokes, Polak, & Fuchs, 2011).MiR31 tin also alter HFSC action by targeting fibroblast growth factor 10 (Fgf10), distal-less homeobox 3 (Dlx3), several keratin genes and too components of the Wnt and BMP signaling pathways (Mardaryev et al., 2010). The differential regulation of several miRNAs in the epithelium of the pare suggests that roles for additional miRNAs will be defined every bit this burgeoning field continues to expand.

Another level of regulation of skin SCs occurs through modification of histones and Dna to epigenetically regulate transcription (Calo & Wysocka, 2013). Several epigenetic factors play a role in epidermal differentiation (Mulder et al., 2012). Histone acetylation and methylation through histone deacetylase and methyltransferase activity, respectively, regulate IFE development (Driskell et al., 2012; LeBoeuf et al., 2010) and homeostasis (Driskell et al., 2012). Maintenance of repressive histone modifications via the polycomb repressor circuitous, enhancer of zeste homolog i (Ezh1) and Ezh2 are essential for IFE differentiation and for HF morphogenesis and maintenance (Bardot et al., 2013; Ezhkova et al., 2011). Merkel cells also crave Ezh2 proteins for their maintenance through the regulation of the transcription factor Sox2 (Bardot et al., 2013). Histone methylation controlled by the demethylase Jumonji domain containing 3 (JmjD3) is essential for IFE differentiation (Sen, Webster, Barragan, Chang, & Khavari, 2008), while the demethylase Jumonji/jmjc domain-containing protein 2 (Jarid2) is required to maintain IFE basal progenitors (Mejetta et al., 2011). In addition, the Deoxyribonucleic acid methyltransferase one (DNMT1) and the ubiquitin like, containing PHD and Band finger domain-1 (UHRF1) are expressed in basal cells and are downregulated once cells enter the differentiation program suggesting that they are also involved in regulating stemness. Deletion of DNMT1 in homo peel regeneration assays induced premature differentiation of progenitors and progressive tissue loss farther demonstrating its importance for cocky-renewal (Sen, Reuter, Webster, Zhu, & Khavari, 2010).

Boosted control of SC function occurs through the regulation of gene expression past altering nucleosome positioning through the action of chromatin remodeling complexes such as the SWI/SNF circuitous (Kidder, Palmer, & Knott, 2009). Past rearranging nucleosome positions inside the chromatin, these complexes regulate RNA polymerase 2 occupancy and thus transcriptional initiation in an ATP-dependent manner (Liu, Balliano, & Hayes, 2011). At the crux of these complexes, brahma-related gene ane (Brg1) acts equally a catalytic subunit and regulates SC proliferation and differentiation. In the HF, it was recently shown that Brg1 is dynamically activated after SC activation in the peel. Deletion of Brg1 with the bulge-specific NFATc1-Cre induced precocious HF regression, loss of HFSCs, and progressive hair loss (Xiong et al., 2013). Molecularly, Brg1 and Shh act in a molecular loop, where Brg1 regulates Shh expression and Shh activates Brg1 expression within the follicle (Xiong et al., 2013). Whether Brg1 regulates additional genes to control HFSC function will be an interesting area of future investigation.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780124160224000044