DOCSLIB.ORG

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses life Review Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses Inseok Choi , Hyewon Son and Jea-Hyun Baek * School of Life Science, Handong Global University, Pohang, Gyeongbuk 37554, Korea; [email protected] (I.C.); [email protected] (H.S.) * Correspondence: [email protected]; Tel.: +82-54-260-1347 Abstract: The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation of acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In the eukaryotic system, the TCA cycle occurs completely in mitochondria, while the intermediates of the TCA cycle are retained inside mitochondria due to their polarity and hydrophilicity. Under cell stress conditions, mitochondria can become disrupted and release their contents, which act as danger signals in the cytosol. Of note, the TCA cycle intermediates may also leak from dysfunctioning mitochondria and regulate cellular processes. Increasing evidence shows that the metabolites of the TCA cycle are substantially involved in the regulation of immune responses. In this review, we aimed to provide a comprehensive systematic overview of the molecular mechanisms of each TCA cycle intermediate that may play key roles in regulating cellular immunity in cell stress and discuss its implication for immune activation and suppression. Keywords: Krebs cycle; tricarboxylic acid cycle; cellular immunity; immunometabolism 1. Introduction The tricarboxylic acid cycle (TCA, also known as the Krebs cycle or the citric acid Citation: Choi, I.; Son, H.; Baek, J.-H. Tricarboxylic Acid (TCA) Cycle cycle) is a series of chemical reactions used in aerobic organisms (pro- and eukaryotes) to Intermediates: Regulators of Immune generate energy via the oxidation of acetyl-coenzyme A (CoA) derived from carbohydrates, Responses. Life 2021, 11, 69. fatty acids and proteins. In the eukaryotic system, the TCA cycle occurs exclusively in the https://doi.org/10.3390/life11010069 matrix of the mitochondria, which are surrounded by two lipid bilayers and impermeable to polar solutes. The mitochondrial membrane separates energy-producing reactions from Received: 31 December 2020 energy-consuming ones and retains the TCA cycle intermediates, which are small, highly Accepted: 18 January 2021 polar, and electrophilic organic carboxylic acids, inside mitochondria. The intermediates of Published: 19 January 2021 the TCA cycle take several roles as metabolites in metabolisms, such as insulin secretion and fatty acid synthesis (FAS) within mitochondria. In addition, they can be transported out Publisher’s Note: MDPI stays neutral of mitochondria through various shuttle mechanisms to participate in various biological with regard to jurisdictional claims in processes. Of note, increasing evidence suggests that the TCA cycle intermediates play published maps and institutional affil- crucial roles in regulating cellular immunity. In cell stress conditions, the mitochondrial iations. membrane may be disrupted and release the TCA cycle intermediates into the cytosol, thereby impacting the cellular immunity (Figure1). Mitochondria are multifunctional organelles. First, they are known as the power- houses of the cell. Mitochondria are the organelles staging the most efficient metabolic Copyright: © 2021 by the authors. pathways, including the TCA cycle and oxidative phosphorylation supplying the entire Licensee MDPI, Basel, Switzerland. cell with energy in form of adenosine triphosphate (ATP) [1]. In addition, mitochondria This article is an open access article are critical in many other processes, such as detoxification, iron-sulfur cluster biogenesis, distributed under the terms and intracellular calcium homeostasis. Importantly, mitochondria are the central regulators of conditions of the Creative Commons intracellular innate immune responses to pathogens [2–7]. In line with this, they provide Attribution (CC BY) license (https:// stress mediators initiating cell death and autophagy, present adaptor molecules required creativecommons.org/licenses/by/ for the transduction of cellular innate immune signals [2,3], and release mitochondrial 4.0/). Life 2021, 11, 69. https://doi.org/10.3390/life11010069 https://www.mdpi.com/journal/life LifeLife 20212021,, 1111,, 69x FOR PEER REVIEW 22 of 1919 components (e.g. (e.g.,, mitochondrial DNA, mitochondrial RNA, RNA, cytochrome c, c, reactive oxy- gen species (ROS))(ROS)) into the cytosol as dangerdanger signalssignals [[4]4] (Figure(Figure1 1).). MitochondrialMitochondrial DNADNA and RNA may activate intracellular sensors sensing pathogenic DNA and RNA (e.g., the retinoicretinoic-acid-inducible-acid-inducible gene ( (RIG)-I-likeRIG)-I-like proteins, protein kinase R (PKR),(PKR), thethe stimulatorstimulator of interferon genes (STING),(STING), mitochondrial antiviral signaling protein (MAVS),(MAVS), cycliccyclic guanine monophosphate monophosphate (GMP (GMP)—adenosine) - adenosine monophosphate monophosphate (AMP (AMP)) synthase synthase [cGAS] [cGAS] and interferonand interferon--γ-inducibleγ-inducible protein protein 16 (IFI16 16 (IFI16)))) to detect to detect intracellular intracellular pathogens pathogens [2,3,8– [132,3]., 8Stud-–13]. iesStudies have havefound found that mitochondrial that mitochondrial DNADNA leaking leaking from fromdysfunctioning dysfunctioning or disrupted or disrupted mito- chondriamitochondria directly directly activate activatess STING STING providing providing a direct a direct pot potentialential link link between between mitochon- mitochon- drial disease andand inflammatoryinflammatory response response [3 [3,14,15],14,15]. A. A more more recent recent study study showed showed that, that, under un- pathologicder pathologic conditions, conditions, mitochondrial mitochondrial RNA RNA is released is released from from dysfunctioning dysfunctioning mitochondria, mitochon- driin turn,a, in turn, triggering triggering immune immune activation activation [13]. [13]. Under Under conditions conditions of cell of cell stress, stress, mitochondria mitochon- drireleasea release cytochrome cytochrome c and c and ROS ROS inducing inducing apoptosis apoptosis and and cell cell and and tissue tissue destruction destruction [4]. [4]. In Inaddition, addition, TCA TCA cycle cycle intermediates intermediates may may also also leak leak from from mitochondria mitochondria upon upon cell stresscell stress and regulate cellular immune and stress responses (Figure1). and regulate cellular immune and stress responses (Figure 1). Figure 1. Mitochondrial danger signals in cell stress.stress. In the the last last ten ten years, years, it ithas has been been increasingly increasingly recognized recognized that that cellular cellular metabolism metabolism con- trolscontrols immune immune cell functions, cell functions, and it and became it became evident evident that some that metabolic some metabolic pathways pathways activate, andactivate, others and suppress others suppress immune immuneresponses. responses. Innovative Innovative systems systemsbiology biologytools have tools revolu- have tionizedrevolutionized metabolic metabolic research research and andare arecurrently currently providing providing us us with with an an overwhelming amount of of data data and and new new insights, insights, which which need need to be to put be together put together to form to a form coherent a coherent whole. whole.In this review, In this review, we present we present findings findings from studies from studies focusing focusing on the onrole the of role TCA of cycle TCA inter- cycle mediatesintermediates in cellular in cellular immunity immunity and andprovide provide a comprehensive a comprehensive systematic systematic overview overview of the of immunthe immunologicologic features features of each of each TCA TCA cycle cycle intermediate intermediate (Figure (Figure 2). 2). 2. Acetyl-CoA Acetyl-CoA is a molecule produced in the breakdown of carbohydrates, proteins, and fatty acids. It feeds into the TCA cycle by combining with oxaloacetate to citrate. Ac- etyl-CoA is, strictly speaking, not an intermediate of the TCA cycle, Nonetheless, the in- tramitochondrial levels of acetyl-CoA are essential for sustaining TCA cycle activity. Fur- thermore, acetyl-CoA is a precursor for fatty acids, steroids, and certain amino acids, such as glutamate, proline, and arginine [16] and has the important function of providing an acetyl group for histone acetylation in the nucleus. Elevated histone acetylation was found to upregulate the expression of glycolytic enzymes, which are related to immune activa- tion [17]. Of note, acetyl-CoA is generated in multiple compartments, including cytosol. Therefore, it is difficult to estimate to what extent the mitochondrial portion of acetyl-CoA contributes to the expression of glycolytic enzymes. Particularly, the role of mitochondrial Life 2021, 11, x FOR PEER REVIEW 3 of 19 acetyl-CoA leaking from mitochondria during cellular stress in cellular immunity has re- mained elusive [18]. Interestingly, the cytosolic and nucleic levels of acetyl-CoA can in- crease, when citrate is transported from mitochondria into the cytosol by the dicarboxylate antiporter solute carrier family 25 (SLC25A1; mitochondrial citrate carrier, CIC) and con- verted into oxaloacetate and acetyl-CoA by ATP citrate lyase (ACLY). ACLY-derived cy- tosolic and nucleic acetyl-CoA, in turn, may drive histone acetylation affecting cellular functions [19–21]. The acetylation of lysine residues on
Load more

Recommended publications
  • Spectroscopy of Porphyrins
    BORIS F. KIM and JOSEPH BOHANDY SPECTROSCOPY OF PORPHYRINS Porphyrins are an important class of compounds that are of interest in molecular biology because of the important roles they play in vital biochemical systems such as biochemical energy conversion in animals, oxygen transport in blood, and photosynthetic energy conversion in plants. We are studying the physical properties of the energy states of porphyrins using the techniques of ex­ perimental and theoretical spectroscopy with the aim of contributing to a basic understanding of their biochemical behavior. INTRODUCTION Metalloporphin Porphyrins are a class of complex organic chemical compounds found in such diverse places as crude oil, plants, and human beings. They are, in most cases, tailored to carry out vital chemical transformations in intricate biochemical or biophysical systems. They are the key constituents of chlorophyll in plants and of hemoglobin in animals. Without them, life would y be impossible. t Free base porphin These molecules display a wide range of chemical and physical properties that depend on the structural details of the particular porphyrin molecule. All por­ ~x phyrins are vividly colored and absorb light in the visible and ultraviolet regions of the spectrum. Some exhibit luminescence, paramagnetism, photoconduc­ tion, or semiconduction. Spme are photosensitizers Wavelength (nanometers) or catalysts. Scientists from several disciplines have been interested in unraveling the principles that cause Fig. 1-The chemical structures for the two forms of por· this diversity of properties. phin are shown on the left. A carbon atom and a hydrogen The simplest compound of all porphyrins is por­ atom are understood to be at each apex not attached to a nitrogen atom.
    [Show full text]
  • Emerging Role of the Hexosamine Biosynthetic Pathway in Cancer Neha M
    Akella et al. BMC Biology (2019) 17:52 https://doi.org/10.1186/s12915-019-0671-3 REVIEW Open Access Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer Neha M. Akella, Lorela Ciraku and Mauricio J. Reginato* “ ” Abstract conditions [2]. This switch, termed the Warburg effect , funnels glycolytic intermediates into pathways that produce Altered metabolism and deregulated cellular energetics nucleosides, amino acids, macromolecules, and organelles are now considered a hallmark of all cancers. Glucose, required for rapid cell proliferation [3]. Unlike normal cells, glutamine, fatty acids, and amino acids are the primary cancer cells reprogram cellular energetics as a result of drivers of tumor growth and act as substrates for the oncogenic transformations [4]. The hexosamine biosyn- hexosamine biosynthetic pathway (HBP). The HBP thetic pathway utilizes up to 2–5% of glucose that enters a culminates in the production of an amino sugar uridine non-cancer cell and along with glutamine, acetyl- diphosphate N-acetylglucosamine (UDP-GlcNAc) that, coenzyme A (Ac-CoA) and uridine-5′-triphosphate (UTP) along with other charged nucleotide sugars, serves as the are used to produce the amino sugar UDP-GlcNAc [5]. basis for biosynthesis of glycoproteins and other The HBP and glycolysis share the first two steps and di- glycoconjugates. These nutrient-driven post-translational verge at fructose-6-phosphate (F6P) (Fig. 1). Glutamine modifications are highly altered in cancer and regulate fructose-6-phosphate amidotransferase (GFAT) converts protein functions in various cancer-associated processes. F6P and glutamine to glucosamine-6-phosphate and glu- In this review, we discuss recent progress in tamate in the rate-limiting step of HBP [6].
    [Show full text]
  • Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
    Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent
    [Show full text]
  • ATP—The Free Energy Carrier
    ATP—The Free Energy Carrier How does the ATP molecule capture, store, and release energy? Why? A sporting goods store might accept a $100 bill for the purchase of a bicycle, but the corner store will not take a $100 bill when you buy a package of gum. That is why people often carry smaller denominations in their wallets—it makes everyday transactions easier. The same concept is true for the energy transactions in cells. Cells need energy (their “currency”) to take care of everyday functions, and they need it in many denominations. As humans we eat food for energy, but food molecules provide too much energy for our cells to use all at once. For quick cellular transactions, your cells store energy in the small molecule of ATP. This is analogous to a $1 bill for your cells’ daily activities. Model 1 – Adenosine Triphosphate (ATP) NH2 N N O– O– O– CH OP OP OP O– N N O 2 ADENINE O O O TRI-PHOSPHATE GROUP OH OH RIBOSE 1. The diagram of ATP in Model 1 has three parts. Use your knowledge of biomolecules to label the molecule with an “adenine” section, a “ribose sugar” section, and a “phosphate groups” section. 2. Refer to Model 1. a. What is meant by the “tri-” in the name adenosine triphosphate? 3 PHOSPHATES b. Discuss with your group what the structure of adenosine diphosphate (ADP) might look like. Draw or describe your conclusions. SAME AS ABOVE, BUT WITH ONLY 2 PHOSPHATES IN PHOSPHATE GROUP. ATP— The Free Energy Carrier 1 Model 2 – Hydrolysis of ATP H2O NH2 NH2 Energy N – – – N – – N O O O N O O O– CH OPOPOPO– CH O P O P OH HO P O– N N O 2 N N O 2 + O O O O O O Inorganic OH OH OH OH Phosphate (Pi) 3.
    [Show full text]
  • ROS Production Induced by BRAF Inhibitor Treatment Rewires
    Cesi et al. Molecular Cancer (2017) 16:102 DOI 10.1186/s12943-017-0667-y RESEARCH Open Access ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells Giulia Cesi, Geoffroy Walbrecq, Andreas Zimmer, Stephanie Kreis*† and Claude Haan† Abstract Background: Most melanoma patients with BRAFV600E positive tumors respond well to a combination of BRAF kinase and MEK inhibitors. However, some patients are intrinsically resistant while the majority of patients eventually develop drug resistance to the treatment. For patients insufficiently responding to BRAF and MEK inhibitors, there is an ongoing need for new treatment targets. Cellular metabolism is such a promising new target line: mutant BRAFV600E has been shown to affect the metabolism. Methods: Time course experiments and a series of western blots were performed in a panel of BRAFV600E and BRAFWT/ NRASmut human melanoma cells, which were incubated with BRAF and MEK1 kinase inhibitors. siRNA approaches were used to investigate the metabolic players involved. Reactive oxygen species (ROS) were measured by confocal microscopy and AZD7545, an inhibitor targeting PDKs (pyruvate dehydrogenase kinase) was tested. Results: We show that inhibition of the RAS/RAF/MEK/ERK pathway induces phosphorylation of the pyruvate dehydrogenase PDH-E1α subunit in BRAFV600E and in BRAFWT/NRASmut harboring cells. Inhibition of BRAF, MEK1 and siRNA knock-down of ERK1/2 mediated phosphorylation of PDH. siRNA-mediated knock-down of all PDKs or the use of DCA (a pan-PDK inhibitor) abolished PDH-E1α phosphorylation. BRAF inhibitor treatment also induced the upregulation of ROS, concomitantly with the induction of PDH phosphorylation.
    [Show full text]
  • Effect of Citric Acid Cycle Genetic Variants and Their Interactions With
    cancers Article Effect of Citric Acid Cycle Genetic Variants and Their Interactions with Obesity, Physical Activity and Energy Intake on the Risk of Colorectal Cancer: Results from a Nested Case-Control Study in the UK Biobank Sooyoung Cho 1 , Nan Song 2,3 , Ji-Yeob Choi 2,4,5 and Aesun Shin 1,2,* 1 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea; [email protected] 2 Cancer Research Institute, Seoul National University, Seoul 03080, Korea; [email protected] (N.S.); [email protected] (J.-Y.C.) 3 Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA 4 Department of Biomedical Sciences, Graduate School of Seoul National University, Seoul 03080, Korea 5 Medical Research Center, Institute of Health Policy and Management, Seoul National University, Seoul 03080, Korea * Correspondence: [email protected]; Tel.: +82-2-740-8331; Fax: +82-2-747-4830 Received: 18 August 2020; Accepted: 9 October 2020; Published: 12 October 2020 Simple Summary: The citric acid cycle has a central role in the cellular energy metabolism and biosynthesis of macromolecules in the mitochondrial matrix. We identified the single nucleotide polymorphisms (SNPs) of the citrate acid cycle with colorectal cancer susceptibility in UK population. Furthermore, we found the significant interaction of SNPs in the citric acid cycle with the contributors to energy balance and SNP-SNP interactions. Our findings provide clues to the etiology in cancer development related to energy metabolism and evidence on identification of the population at high risk of colorectal cancer.
    [Show full text]
  • Nutrition and Metabolism
    NUTRITION AND METABOLISM Metabolism - the sum of the chemical changes that occur in the cell and involve the breakdown (catabolism) and synthesis (anabolism) of stored energy sources. Basal Metabolic Rate is dened as the rate of energy production by the body measured under a dened set of conditions which is usually at rest (physical and mental), room temperature, 12 hours after a meal. The result is produced as a percentage of a standard value which is derived from studies of normal healthy people. Measurement of the metabolic rate takes place using a method called calorimetry. This may be done directly by measuring the amount of heat produced by the body in an Atwater chamber, the metabolic rate is the amount of heat produced per hour. More commonly the metabolic rate is determined indirectly by putting people on a closed circuit breathing system, with CO2 removed by a soda lime scrubber and the rate of oxygen consumption measured by change in volume. Oxygen consumption is proportional to the metabolic rate because most of the energy in the body is derived from oxidative phosphorylation, which uses a set amount of oxygen to produce a set amount of energy. For every litre of oxygen consumed the body produces (uses) 4.82 kcals of energy. If the oxygen consumption is 250ml/min (15L/hr) then the metabolic rate is 72.3 kcals/hr. This is often further rened by dividing the gure by the body surface area which for a 70kg male is 1.73m2. This gives an average BMR of approximately 40 kcal/m2/hr.
    [Show full text]
  • Corticosteroid Treatment, Serum Lipids and Coronary Artery Disease D. B. JEFFERYS M
    Postgrad Med J: first published as 10.1136/pgmj.56.657.491 on 1 July 1980. Downloaded from Postgraduate Medical Journal (July 1980) 56, 491-493 Corticosteroid treatment, serum lipids and coronary artery disease D. B. JEFFERYS M. H. LESSOF B.Sc., M.R.C.P. M.D., F.R.C.P. M. B. MATTOCK Ph.D. Department of Medicine, Guy's Hospital, London Bridge SE] 9RT Summary cholesterol out of the tissue and back into the general Serum lipids and the cholesterol concentrations in the metabolic pool, where it may be catabolized. high density lipoprotein (HDL) fractions were meas- In this study the authors have looked at the long- ured in patients receiving long-term corticosteroid term effects of corticosteroids on HDL cholesterol. treatment for connective tissue disorders and asthma. They have studied 3 groups: patients who are receiv- Patients who were not receiving corticosteroid ing corticosteroids; age-, sex- and disease-matched treatment had blood lipid levels which did not differ patients who are not receiving such treatment; and from those of healthy people. However, female (but healthy age- and sex-matched controls. not male) patients who had received prednisolone for a mean period of 3-1 years had a significant elevation Patients and methods in total cholesterol and a large decrease in HDL Subjects cholesterol. It seems possible that high levels of The serum total cholesterol, triglycerides and copyright. corticosteroids may increase the incidence of pre- HDL cholesterol were measured for 16 pre-meno- menopausal ischaemic heart disease in females. pausal female patients (age range 18-34 years) and 15 males (ages 24-38 years) who were all receiving Introduction long-term corticosteroid treatment.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Electronic Spectroscopy of Free Base Porphyrins and Metalloporphyrins
    Absorption and Fluorescence Spectroscopy of Tetraphenylporphyrin§ and Metallo-Tetraphenylporphyrin Introduction The word porphyrin is derived from the Greek porphura meaning purple, and all porphyrins are intensely coloured1. Porphyrins comprise an important class of molecules that serve nature in a variety of ways. The Metalloporphyrin ring is found in a variety of important biological system where it is the active component of the system or in some ways intimately connected with the activity of the system. Many of these porphyrins synthesized are the basic structure of biological porphyrins which are the active sites of numerous proteins, whose functions range from oxygen transfer and storage (hemoglobin and myoglobin) to electron transfer (cytochrome c, cytochrome oxidase) to energy conversion (chlorophyll). They also have been proven to be efficient sensitizers and catalyst in a number of chemical and photochemical processes especially photodynamic therapy (PDT). The diversity of their functions is due in part to the variety of metals that bind in the “pocket” of the porphyrin ring system (Fig. 1). Figure 1. Metallated Tetraphenylporphyrin Upon metalation the porphyrin ring system deprotonates, forming a dianionic ligand (Fig. 2). The metal ions behave as Lewis acids, accepting lone pairs of electrons ________________________________ § We all need to thank Jay Stephens for synthesizing the H2TPP 2 from the dianionic porphyrin ligand. Unlike most transition metal complexes, their color is due to absorption(s) within the porphyrin ligand involving the excitation of electrons from π to π* porphyrin ring orbitals. Figure 2. Synthesis of Zn(TPP) The electronic absorption spectrum of a typical porphyrin consists of a strong transition to the second excited state (S0 S2) at about 400 nm (the Soret or B band) and a weak transition to the first excited state (S0 S1) at about 550 nm (the Q band).
    [Show full text]
  • Adenosine Triphosphate Turnover in Humans. Decreased Degradation During Relative Hyperphosphatemia
    Adenosine triphosphate turnover in humans. Decreased degradation during relative hyperphosphatemia. M A Johnson, … , S P Schmaltz, I H Fox J Clin Invest. 1989;84(3):990-995. https://doi.org/10.1172/JCI114263. Research Article The regulation of ATP metabolism by inorganic phosphate (Pi) was examined in five normal volunteers through measurements of ATP degradation during relative Pi depletion and repletion states. Relative Pi depletion was achieved through dietary restriction and phosphate binders, whereas a Pi-repleted state was produced by oral Pi supplementation. ATP was radioactively labeled by the infusion of [8(14)C]adenine. Fructose infusion was used to produce rapid ATP degradation during Pi depletion and repletion states. Baseline measurements indicated a significant decrease of Pi levels during phosphate depletion and no change in serum or urinary purines. Serum values of Pi declined 20 to 26% within 15 min after fructose infusion in all states. Urine measurements of ATP degradation products showed an eightfold increase within 15 min after fructose infusion in both Pi-depleted and -supplemented states. Urinary radioactive ATP degradation products were fourfold higher and urinary purine specific activity was more than threefold higher during Pi depletion as compared with Pi repletion. Our data indicate that there is decreased ATP degradation to purine end products during a relative phosphate repletion state as compared to a relative phosphate depletion state. These data show that ATP metabolism can be altered through manipulation of the relative Pi state in humans. Find the latest version: https://jci.me/114263/pdf Adenosine Triphosphate Turnover in Humans Decreased Degradation during Relative Hyperphosphatemia Marcia A.
    [Show full text]
  • Crystallization of Malonic and Succinic Acids on Sams: Toward the General Mechanism of Oriented Nucleation on Organic Monolayers†
    pubs.acs.org/Langmuir © 2009 American Chemical Society Crystallization of Malonic and Succinic Acids on SAMs: Toward the General Mechanism of Oriented Nucleation on Organic Monolayers† Boaz Pokroy,‡ Victoria Fay Chernow, and Joanna Aizenberg* School of Engineering and Applied Sciences, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138. ‡ Current address: Department of Materials Engineering, Israel Institute of Technology, Haifa 32000, Israel. Received July 25, 2009. Revised Manuscript Received September 2, 2009 Self-assembled monolayers (SAMs) were shown to induce very specific oriented growth of simple organic and inorganic crystals. Here we present a detailed study of the mechanism by which SAMs control the oriented nucleation by examining a more complex case of crystallization of bifunctional organic molecules. Malonic and succinic acids were grown on the SAMs of HS(CH2)10CO2H and HS(CH2)11CO2H supported on gold films. Each SAM induced a very controlled, specific orientation of the crystals. The preferred nucleating planes always exhibited an alignment of one of the carboxylic acid groups in the molecules of the growing crystal with the carboxylic acid groups on the surface of the SAMs. These results suggest that the translation of the structural information through the interface occurs by stereochemical registry such that the functional groups in the SAM play the role of an oriented surrogate layer for the nucleating crystal. These findings are very important to the understanding of the underlying principles by which various organic surfaces;and most probably also biological templates;control the crystallization process. Introduction templates to control the formation of both organic and inorganic An understanding of crystal nucleation and growth and the materials.
    [Show full text]