DOCSLIB.ORG

Structure–Function Relationships of Human Jmjc Oxygenases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Structure–Function Relationships of Human Jmjc Oxygenases Available online at www.sciencedirect.com ScienceDirect Structure–function relationships of human JmjC oxygenases — demethylases versus hydroxylases 1,3 1,2,3 Suzana Markolovic , Thomas M Leissing , 1 1 2 Rasheduzzaman Chowdhury , Sarah E Wilkins , Xin Lu and 1 Christopher J Schofield The Jumonji-C (JmjC) subfamily of 2-oxoglutarate (2OG)- response [1]. Of these, the Jumonji-C domain-containing dependent oxygenases are of biomedical interest because of oxygenases (JmjC oxygenases) have attracted attention, their roles in the regulation of gene expression and protein including from a pharmaceutical perspective [2], principally biosynthesis. Human JmjC 2OG oxygenases catalyze oxidative because of their roles in histone demethylation [3 ,4 ,5 ,6], modifications to give either chemically stable alcohol products, though they have wider roles in protein hydroxylation e or in the case of N -methyl lysine demethylation, relatively [7 ,8 ,9]. The JmjC oxygenases are a subfamily of 2OG unstable hemiaminals that fragment to give formaldehyde and oxygenases that share sequence homology and structural the demethylated product. Recent work has yielded conflicting similarities (as detailed below). Most JmjC oxygenases reports as to whether some JmjC oxygenases catalyze (>20) have been assigned as histone lysine demethylases e N-methyl group demethylation or hydroxylation reactions. We (KDMs), which catalyze N -methyl lysine residue demeth- e review JmjC oxygenase-catalyzed reactions within the context ylation reactions (Figure 1a), proceeding via initial N - of structural knowledge, highlighting key differences between methyl group hydroxylation followed by fragmentation to hydroxylases and demethylases, which have the potential to give the demethylated product and formaldehyde. Other inform on the possible type(s) of reactions catalyzed by partially members of the JmjC subfamily catalyze oxidation of characterized or un-characterized JmjC oxygenases in humans proteins (and, in one case, tRNA) to give a stable hydroxyl- and other organisms. ated product; we refer to these as ‘JmjC hydroxylases’. This Addresses dual functionality within the JmjC subfamily has led to 1 Chemistry Research Laboratory, University of Oxford, Mansfield Road, conflicting reports regarding the assignment of some JmjC Oxford OX1 3TA, UK oxygenases. To date, several JmjC oxygenases have been 2 Ludwig Institute for Cancer Research, Nuffield Department of Clinical reported to catalyze both demethylation and hydroxylation. Medicine, Old Road Campus Research Building, Old Road Campus, Here, we review JmjC oxygenases from structural and University of Oxford, Headington, Oxford OX3 7DQ, UK biochemical perspectives, focusing on members that have Corresponding author: Schofield, Christopher J been structurally characterized. We discuss structural (christopher.schofi[email protected]) 3 features common to different types of JmjC oxygenases These authors contributed equally to this work. (i.e. hydroxylases versus demethylases) and correlate these with the types of reactions that they catalyze. Current Opinion in Structural Biology 2016, 41:62–72 This review comes from a themed issue on Catalysis and regulation History and overview of the JmjC oxygenases Edited by David Christianson and Nigel Scrutton The JmjC domain is named after the ‘Jumonji’ protein in which it was first identified [10]. The name ‘Jumonji’ http://dx.doi.org/10.1016/j.sbi.2016.05.013 (meaning ‘cruciform’ in Japanese) is based on the abnor- mal ‘cross-like’ appearance of neural grooves in Jumonji 0959-440/# 2016 The Authors. Published by Elsevier Ltd. This is an (Jmj)-null mice. The Jmj gene was proposed to encode for open access article under the CC BY license (http://creativecom- mons.org/licenses/by/4.0/). a putative Jumonji protein (corresponding to human JARID2) [10], which contains a DNA-binding domain (AT-rich interaction domain, ARID), JmjC, and Jumonji- N (JmjN) domains [11]. The latter two were proposed to co-occur [11], though later work revealed they are sepa- rate structural and functional units [12]. Bioinformatics Introduction indicated that the JmjC domain is widely distributed in Interest in human Fe(II)- and 2-oxoglutarate (2OG)-de- eukaryotes [11,12]. Since many of the proteins containing pendent oxygenases has been stimulated by the discovery JmjN and JmjC domains had been previously linked with of their roles in regulation of gene expression and protein transcriptional control and contained known DNA bind- biosynthesis. More than 60 human 2OG oxygenases have ing domains (e.g. plant homeobox domain (PHD), ARID, been identified, with roles in diverse processes such as or Zn fingers), they were collectively termed the Jumonji fatty acid metabolism (including carnitine biosynthesis), family of transcription factors [11]. Bioinformatics identi- collagen biosynthesis, development, and the hypoxic fied that the JmjC domain shared considerable similarity Current Opinion in Structural Biology 2016, 41:62–72 www.sciencedirect.com Structure–function relationships of JmjC oxygenases Markolovic et al. 63 Figure 1 (a) Histone demethylases RNA hydroxylase H + + N N+ NH O + 2 NH3 OH H2N O KDM4-6 KDM2-7 KDM2-7 N N N N N N H 2OG succinate H 2OG succinate H 2OG succinate H N N N O CO O CO O CO O O2 2 O2 2 O 2 H CO H CO 2 Kme3 2 Kme2 2 Kme1 H2CO Iysine yW-72 + Protein hydroxylases TYW5, Fe(II) NH3 2OG HO O2 NH NH + OH NH N MINA53/NO66/FIH, Fe(II) N 3 JMJD6, Fe(II) succinate N N N H 2OG succinate H 2OG succinate H CO2 O O O CO2 O CO 2 O2 2 histidine 3S-hydroxyhistidine 5S-hydroxylysine N O H + O JMJD4, F NH OH 3 H2N Iysine e(II) O O O 2OG HO OH O N R FIH, Fe(II) R for R = OH 2 OH N 3S-hydroxyaspartate succinate CO N N N N N for R = NH2 2 N H 2OG succinate H H O 3S-hydroxyasparagine O O CO O 2 2 4-hydroxylysine aspartate OHyW* (b) Extended loop at N-terminus of DSBH characteristic of basic residue LysLys JmjC KDMs coordinating 2OG DDSBHSBH C-5 carboxylate I IIII VIIIVIII VIIVII IIIIII IVIV VIVI V N-terminally-terminally extendedextended Fe anti-parallelanti-parallel β-strands-strands C N N HxD/E...H C iron-coordinating residues βIV-V insert β involved in N-terminal-terminal extraextra IV-V insert substrate binding β-strands-strands Current Opinion in Structural Biology Characteristic features of JmjC domain architecture and reaction catalysis. (a) Demethylation and hydroxylation reactions catalyzed by human JmjC oxygenases. (b) (Left) View from a crystal structure of an FIH monomer (PBD ID: 1H2K, [14 ]) as a representative JmjC oxygenase, and (right) two dimensional domain topology of a generalized JmjC domain (generated using TopDraw). The JmjC domain fold contains a distorted double-stranded b-helix (DSBH; b-strands I–VIII; blue) fold, additional N-terminal anti-parallel b-strands that extend the DSBH (grey), and a bIV-V insert (red). Fe(II) (orange sphere) and 2OG (cyan sticks) are bound in the active site. Abbreviations are defined in Table 1. with enzymes containing a cupin or double-stranded b- factor (FIH), reveal the JmjC domain indeed adopts a helix (DSBH) fold, leading to the proposal that JmjC DSBH fold [7 ,8 ,13 ,14 ,15 ]. Rather than supporting a proteins act as Zn(II)-dependent transcriptional regula- Zn(II)-binding active site, FIH is an Fe(II)- and 2OG- tors, since phosphomannose isomerase is a Zn(II)-utiliz- dependent oxygenase like many JmjC enzymes. This work ing DSBH fold enzyme [12]. identified roles for JmjC oxygenases in transcriptional reg- ulation via FIH-catalyzed asparaginyl hydroxylation of Studies on the first biochemically and structurally charac- hypoxia inducible factor-a (HIF-a) isoforms [7 ,8 ], a reac- terized JmjC oxygenase, factor inhibiting hypoxia inducible tion important in the hypoxic response; FIH regulates HIF www.sciencedirect.com Current Opinion in Structural Biology 2016, 41:62–72 64 Catalysis and regulation activity by reducing its binding to transcriptional coactiva- ‘distal’ His is positioned at the start of bVII, spatially tors (CBP/p300) [16]. These discoveries were followed by adjacent to bII (Figure 1b). 2OG binds to Fe(II) in a important work identifying the first JmjC domain-contain- bidentate manner via its C-2 keto and C-1 carboxylate ing KDMs, that is the KDM2, 3, and 4 subfamilies [3 ,4 ,5 ]. groups (Supplementary Figure 2A); its binding is stabi- These studies expanded roles of JmjC oxygenase catalysis lized by electrostatic and hydrogen bonding interactions, to ‘epigenetic’ regulation and identified JmjC KDMs as the including between its C-5 carboxylate and a basic residue largest class of histone KDMs [6], with the flavin-depen- located deeper in the DSBH. For human JmjC oxyge- dent lysine specific KDMs constituting a smaller class [17]. nases, this residue is typically a lysine located at the bIV Structural studies of the JmjC catalytic core of KDM4A N-terminus. Exceptions to this include the KDM6 sub- provided the first insights into KDM structure–function family [37–39], where the lysine is on bI, and KDM3B, relationships [18 ,19 ,20 ]. Since the identification of FIH where the lysine is on bVIII (PBD ID: 4LXL). The and the first JmjC KDMs, the substrate repertoire of JmjC bacterial JmjC hydroxylase ycfD is the only structurally oxygenases has expanded to include other KDMs acting on characterized JmjC oxygenase with an arginine rather histone tails [6], multiple non-HIF-a FIH substrates (most- than a lysine residue on the bIV strand [40,41 ], a differ- ly ankyrin repeat domain proteins) [21], mRNA splicing ence proposed to reflect changes in JmjC evolution [41 ]. factors [22 ], tRNA [23 ], ribosomal proteins [24 ], and As for other 2OG oxygenases, the JmjC oxygenases other proteins involved in translation [25 ] (Table 1). These appear to use an ordered sequential mechanism, where discoveries reveal 2OG oxygenase-catalyzed hydroxylation 2OG binding is followed by substrate and, finally, O2 of proteins is more extensive than was perceived before the (Supplementary Figure 2B) [42].
Load more

Recommended publications
  • A Common X-Linked Inborn Error of Carnitine Biosynthesis May Be a Risk Factor for Nondysmorphic Autism
    A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism Patrícia B. S. Celestino-Sopera,1, Sara Violanteb,c,1, Emily L. Crawfordd, Rui Luoe, Anath C. Lionelf, Elsa Delabyg, Guiqing Caih, Bekim Sadikovica, Kwanghyuk Leea, Charlene Loa, Kun Gaoe, Richard E. Persona, Timothy J. Mossa, Jennifer R. Germana, Ni Huangi, Marwan Shinawia,j,2, Diane Treadwell-Deeringj,k, Peter Szatmaril, Wendy Robertsm, Bridget Fernandezn, Richard J. Schroero, Roger E. Stevensono, Joseph D. Buxbaumh, Catalina Betancurg, Stephen W. Schererf,m, Stephan J. Sandersp, Daniel H. Geschwinde, James S. Sutcliffed, Matthew E. Hurlesi, Ronald J. A. Wandersb, Chad A. Shawa, Suzanne M. Leala, Edwin H. Cook, Jr.q, Robin P. Goin-Kochela,j,r, Frédéric M. Vazb,1, and Arthur L. Beaudeta,j,r,1,3 Departments of aMolecular and Human Genetics, kPsychiatry, and rPediatrics, Baylor College of Medicine, Houston, TX 77030; jTexas Children’s Hospital, Houston, TX 77030; bLaboratory Genetic Metabolic Disease, Departments of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands; cMetabolism and Genetics Group, Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal; dDepartment of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232; eDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles,
    [Show full text]
  • An Overview of Ascorbic Acid Biochemistry
    Ankara Ecz. Fak. Derg. J. Fac. Pharm, Ankara 38 (3) 233-255, 2009 38 (3) 233-255, 2009 AN OVERVIEW OF ASCORBIC ACID BIOCHEMISTRY ASKORBĐK ASĐT BĐYOKĐMYASINA BĐR BAKIŞ Aysun HACIŞEVKĐ Gazi University, Faculty of Pharmacy, Department of Biochemistry, 06330 Etiler-Ankara, TURKEY ABSTRACT Ascorbic acid (vitamin C) is a water-soluble micronutrient required for multiple biological functions. Ascorbic acid is a cofactor for several enzymes participating in the post-translational hydroxylation of collagen, in the biosynthesis of carnitine, in the conversion of the neurotransmitter dopamine to norepinephrine, in peptide amidation and in tyrosine metabolism. In addition, vitamin C is an important regulator of iron uptake, It reduces ferric Fe 3+ to ferrous Fe 2+ ions, thus promoting dietary non-haem iron absorption from the gastrointestinal tract, and stabilizes iron-binding proteins. Most animals are able to synthesise vitamin C from glucose, but humans, other primates, guinea pigs and fruit bats lack the last enzyme involved in the synthesis of vitamin C (gulonolactone oxidase) and so require the presence of the vitamin in their diet. Thus the prolonged deprivation of vitamin C generates defects in the post-translational modification of collagen that cause scurvy and eventually death. In addition to its antiscorbutic action, vitamin C is a potent reducing agent and scavenger of free radicals in biological systems. Key words: Ascorbic acid, Vitamin C, Antioxidant, Oxidative stress ÖZET Askorbik asit, suda çözünen çoklu biyolojik fonksiyonları olan bir mikrobesindir. Kollajen hidroksilasyonu, karnitin biyosentezi, dopaminin norepinefrine çevrimi, peptid amidasyonu ve tirozin metabolizmasına katılan çeşitli enzimler için bir kofaktördür. Ayrıca vitamin C demir alımında önemli bir regülatördür, ferrik demiri ferro formuna redükler ve böylece gastrointestinal sistemden diyet nonhem demir absorbsiyonunu sağlar ve demir bağlı proteinleri stabilize eder.
    [Show full text]
  • Analysis of Carnitine and Acylcarnitines in Biological Fluids and Application to a Clinical Study
    ANALYSIS OF CARNITINE AND ACYLCARNITINES IN BIOLOGICAL FLUIDS AND APPLICATION TO A CLINICAL STUDY Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Laurence Vernez aus Villars-Bramard, VD Genf, 2005 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von: Prof. Dr. Stephan Krähenbühl Prof. Dr. Gérard Hopfgartner Prof. Dr. Wolfgang Thormann Basel, den 6. April 2004 Prof. Dr. Marcel Tanner Dekan POUR TOI QUI M’ATTENDS ENCORE Un savant dans son laboratoire n’est pas seulement un technicien: c’est aussi un enfant placé en face de phénomènes naturels qui l’impressionnent comme un conte de fées Marie Curie-Sklodowska, 1933 Table of contents TABLE OF CONTENTS Résumé 13 Zusammenfassung 16 Summary 18 List of abbreviations 21 1. Introduction 23 1.1 General aspects 23 1.2 Carnitine functions 25 1.2.1. Mitochondrial long-chain fatty acid oxidation 25 1.2.2. Buffering of the mitochondrial acyl-CoA/CoA ratio 27 1.2.3. Removal of potentially toxic acyl-groups 27 1.2.4. Fatty acids oxidation in peroxisomes 28 1.3 Carnitine biosynthesis 28 1.4 Carnitine homeostasis 31 1.4.1. Absorption 31 1.4.2. Tissue distribution - carnitine transporters 32 i. Regulation of tissue distribution 33 ii. Kinetic of exogenous carnitine 33 1.4.3. Metabolism 34 1.4.4. Elimination - role of kidney 35 1.5 Carnitine deficiency 36 1.5.1. Primary carnitine deficiency 37 i. Systemic carnitine deficiency (SCD) 37 ii. Muscle carnitine deficiency (MCD) 38 1.5.2. Secondary carnitine deficiency 38 i.
    [Show full text]
  • Ascorbic Acid, Carnitine and Fatigue R
    Med. Sci..Res., 1988; 15,'12l-,723 FOfUm 72r Ascorbic acid, carnitine and fatigue R. Elwyn Hughes Department of Applied Biologt, University of l4lales Institute of Science and TÞchnologt, CardifÍ, Wales This paper reviews the evidence that ascorbic acid (vitamin and the fatty acyl-carnitine esters are transported across the C) may have a contributory role in the prevention of fatigue inner mitochondrial membrane by a carnitine-acyl in humàns. translocase. Fatty acid-CoA esters are released by a carnitine The biochemical history of carnitine (B-hydroxy-7-N- acyl (palmitoyl)transferase II on the inner membrane and trimethylammonium butyrate) is characterised by alter- the cycle is repeated [3, 15]. A lack of carnitine, or a nating periods of activity and dormancy. The re-emergence diminished or defective activity of one or more of the ofinterest during the past 15 years has been characterised by transport system enzymes, will reduce the availability of fatty a source energy. This, apart from producing a three main areas of emphasis - the endogenous biosynthe- acids as of sis of carnitine from lysine, the involvement of carnitine as a generally reduced 'energy status', could be of critical co-factor in the metabolism of long-chain fatty acids, and the significance in situations where the bulk of the energy identifrcation of the comparatively rare, but metabolically metabolism is believed to be derived from fatty acid metabolism such as in the newly-born infant or in the interesting, camitine deficiency diseases [1 - 4]. - [16] metabolism of normal cardiac muscle U7l. It has been Biosynthesis of c¡rnitine suggested that endogenous production of carnitine is impaired in the newly-born infant and that consequently Two essential amino acids - methionine and lysine - are involved in the biosynthesis of carnitine.
    [Show full text]
  • Function, Detection and Alteration of Acylcarnitine Metabolism in Hepatocellular Carcinoma
    H OH metabolites OH Review Function, Detection and Alteration of Acylcarnitine Metabolism in Hepatocellular Carcinoma Shangfu Li 1,2, Dan Gao 1,2,3,* and Yuyang Jiang 1,4 1 State Key Laboratory of Chemical Oncogenomics, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; [email protected] (S.L.); [email protected] (Y.J.) 2 National & Local United Engineering Lab for Personalized Anti-tumour Drugs, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China 3 Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China 4 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China * Correspondence: [email protected]; Tel.: +86-755-26036035 Received: 11 January 2019; Accepted: 14 February 2019; Published: 21 February 2019 Abstract: Acylcarnitines play an essential role in regulating the balance of intracellular sugar and lipid metabolism. They serve as carriers to transport activated long-chain fatty acids into mitochondria for β-oxidation as a major source of energy for cell activities. The liver is the most important organ for endogenous carnitine synthesis and metabolism. Hepatocellular carcinoma (HCC), a primary malignancy of the live with poor prognosis, may strongly influence the level of acylcarnitines. In this paper, the function, detection and alteration of acylcarnitine metabolism in HCC were briefly reviewed. An overview was provided to introduce the metabolic roles of acylcarnitines involved in fatty acid β-oxidation. Then different analytical platforms and methodologies were also briefly summarised. The relationship between HCC and acylcarnitine metabolism was described. Many of the studies reported that short, medium and long-chain acylcarnitines were altered in HCC patients.
    [Show full text]
  • Carnitine Inborn Errors of Metabolism
    molecules Review Carnitine Inborn Errors of Metabolism Mohammed Almannai 1, Majid Alfadhel 2,3,4 and Ayman W. El-Hattab 5,* 1 Section of Medical Genetics, Children’s Hospital, King Fahad Medical City, Riyadh 11525, Saudi Arabia 2 Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia 3 King Abdullah International Medical Research Center (KAIMRC), Riyadh 11426, Saudi Arabia 4 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia 5 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE * Correspondence: [email protected]; Tel.: +971508875123 Academic Editors: Cesare Indiveri and Lara Console Received: 7 August 2019; Accepted: 4 September 2019; Published: 6 September 2019 Abstract: Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6-N-trimethyllysine dioxygenase (TMLD), 3-hydroxy-6-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation. This transport is achieved by mitochondrial carnitine–acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II).
    [Show full text]
  • Redesign of Carnitine Acetyltransferase Specificity by Protein Engineering
    UNIVERSIDAD DE BARCELONA Facultad de Farmacia Departamento de Bioquímica y Biología Molecular REDESIGN OF CARNITINE ACETYLTRANSFERASE SPECIFICITY BY PROTEIN ENGINEERING ANTONIO FELIPE GARCIA CORDENTE 2006 INTRODUCTION Introduction 1. MODULATION OF COENZYME A POOLS IN THE CELL Cells contain limited pools of sequestered coenzyme A (CoA) that are essential for the activation of carboxylate metabolites. Esterification of carboxylic acids to CoA through the formation of a thioester bond is a common strategy used in metabolic processes to ‘activate’ the relevant metabolite. The process requires an input of energy in the form of the hydrolysis of nucleotide triphosphate. In general, it represents the first step through which the metabolite enters a particular pathway (e.g., Krebs cycle or synthesis of fatty acids and cholesterol). This activation has two universal consequences: 1) it renders the metabolite (in the form of the CoA ester) impermeant to cell membranes and 2) it sequesters CoA from the limited pools that exist in individual subcellular compartments. As a result, the pools of acyl-CoA esters remain separate in the different cellular compartments and may have specific properties and exert different effects in their respective locations. In the case of acyl-CoA esters, it is imperative that the concentration of individual esters is controlled, since many exhibit high biological activity, including the regulation of gene expression, membrane trafficking and modulation of ion-channel activities. Consequently, the cell has two requirements: 1) a mechanism for the control of CoA-ester concentrations that is rapid and does not involve the energetically expensive hydrolysis and resynthesis of the esters from the free acid, and 2) a system that, after the initial synthesis of the CoA ester, enables the acyl moiety to permeate membranes without the need to re-expend energy (Zammit, 1999; Ramsay, 2004).
    [Show full text]
  • The Role of Fasting Acylcarnitines in Metabolic Flexibility from Short
    The Role of Fasting Acylcarnitines in Metabolic Flexibility from Short Term High Fat Feeding Christopher Angiletta Submitted to the Graduate Faculty of Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Masters of Science in Human Nutrition, Foods and Exercise Matthew Hulver, PhD: Committee Chair Andrew Neilson, PhD Kevin Davy, PhD Madlyn Frisard, PhD 1 Abstract Metabolic flexibility plays a significant role in energy homeostasis by regulating fuel selection in correspondence to energy demand. Obese and type II diabetic populations have displayed a hindered ability to properly transition from fat oxidation while in a fasted state to carbohydrate oxidation once fed, leading to a buildup of mitochondrial metabolites such as acylcarnitines. Carnitine, essential for fatty acyl-CoA transport through the inner and outer mitochondrial membranes, can be an indicator of mitochondrial distress as elevated levels tend to spill over into plasma suggesting a disruption in oxidation. The current study was designed to examine the effect of short term, high fat feeding on plasma acylcarnitine species diversity and levels and if acylcarnitines are associated with metabolic flexibility. 13 healthy, non-obese, sedentary males, aged 18-40 years participated in this study. Following a 12-hour overnight fast a biopsy was taken from the quadricep before and 4 hours after a high fat meal. Blood draws were obtained pre-biopsy while fasted and every hour for 4 hours post high fat meal consumption. Acylcarnitines from plasma were converted to their butyl esters and analyzed by electrospray ionization tandem mass spectrometry (MS/MS). Changes were observed in acetylcarntine (P=0.0125), glucose oxidation (P=0.0295), C16:1/C16:0 desaturation index (P= 0.0397), and C18:1/C18:0 desaturation index (P=0.0012).
    [Show full text]
  • Intracellular Acetyl Unit Transport in Fungal Carbon Metabolism
    UvA-DARE (Digital Academic Repository) Intracellular Acetyl Unit Transport in Fungal Carbon Metabolism Strijbis, K.; Distel, B. DOI 10.1128/EC.00172-10 Publication date 2010 Document Version Accepted author manuscript Published in Eukaryotic Cell Link to publication Citation for published version (APA): Strijbis, K., & Distel, B. (2010). Intracellular Acetyl Unit Transport in Fungal Carbon Metabolism. Eukaryotic Cell, 9(12), 1809-1815. https://doi.org/10.1128/EC.00172-10 General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:25 Sep 2021 Intracellular acetyl unit transport in fungal carbon metabolism Karin Strijbis # and Ben Distel* Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam # Current address: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, 02142, USA * Correspondence to: Dr.
    [Show full text]
  • Carnitine Ester Excretion in Pediatric Patients Receiving Parenteral Nutrition
    003 I -3998/90/2802-0 158$02.00/0 PEDIATRIC RESEARCH Copyright O 1990 International Pediatric Research Foundation. Inc. Carnitine Ester Excretion in Pediatric Patients Receiving Parenteral Nutrition EBERHARD SCHMIDT-SOMMERFELD, DUNA PENN. LORAN L. BIEBER. JANOS KERNER. THOMAS M. ROSSI. AND EMANUEL LEBENTHAL D[purttnc*ntc?/'P~.dirrtric:~, Section of Gastroc~nterolo~~v,Hepatolo~p and Nlrtririon, Universitjr c?fCliica~o. Chic.cr,qo. 1llitioi.s 60637 [E.S.S.. D.P.]; Department of Biochemistrj*. Michigan State Univc~rsir~l.East Lansing. .Zli(,l~igati488-74 1L.L.B.. J.K.]: and Dc>partment r?fPediatrics, Division qf Ga.strocnrerologj~and Nutrition. Stare Univ~r.sit,rc?f'Nc\c. York at B~!ffalo,Bl!ffalo. New York 14222/T.M.R.. E.L.] ABSTRAm. Carnitine plasma concentrations and the ex- (I) and regenerating intramitochondrial coenzyme A through cretion of carnitine and individual carnitine esters were transport of acyl-groups out of the mitochondria, thereby main- determined in 25 children and adolescents with gastroin- taining conditions required for oxidative processes (2). testinal diseases receiving carnitine-free parenteral nutri- Although carnitine is synthesized de novo in mammalian tion for at least 1 mo using radiochemical and radioisotopic tissues (3). nutritional carnitine deficiency may occur under exchange HPLC methods. Children ~12-y-oldusually had certain circumstances if carnitine is not provided with the diet. carnitine plasma concentrations C-2 SD from the normal Infants receiving carnitine-free TPN are particularly prone to mean for age, whereas patients >12-y-old had carnitine develop carnitine deficiency, probably due to impaired carnitine plasma concentrations within the normal range.
    [Show full text]
  • Trimethyllysine: from Carnitine Biosynthesis to Epigenetics
    International Journal of Molecular Sciences Review Trimethyllysine: From Carnitine Biosynthesis to Epigenetics Marijn N. Maas y , Jordi C. J. Hintzen y , Miriam R. B. Porzberg y and Jasmin Mecinovi´c* Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark; [email protected] (M.N.M.); [email protected] (J.C.J.H.); [email protected] (M.R.B.P.) * Correspondence: [email protected]; Tel.: +45-6550-3603 These authors contributed equally to this work. y Received: 19 November 2020; Accepted: 9 December 2020; Published: 11 December 2020 Abstract: Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly. Keywords: trimethyllysine; epigenetics; post-translational modifications; protein lysine methyltransferases; protein lysine demethylases; carnitine; methylation; writers; readers; erasers 1. Introduction In nature, over 300 amino acids exist, of which 22 function as building blocks for the formation of polypeptide chains called proteins [1].
    [Show full text]
  • Vitamin C—Sources, Physiological Role, Kinetics, Deficiency, Use
    nutrients Review Vitamin C—Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination Martin Dosedˇel 1 , Eduard Jirkovský 2, KateˇrinaMacáková 3, Lenka Kujovská Krˇcmová 4,5 , Lenka Javorská 5 , Jana Pourová 2 , Laura Mercolini 6 , Fernando Remião 7 , Lucie Nováková 4 , PˇremyslMladˇenka 2,* and on behalf of The OEMONOM † 1 Department of Social and Clinical Pharmacy, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic; [email protected] 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic; [email protected] (E.J.); [email protected] (J.P.) 3 Department of Pharmacognosy, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic; [email protected] 4 Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic; [email protected] (L.K.K.); [email protected] (L.N.) 5 Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic; [email protected] 6 Research group of Pharmaco-Toxicological Analysis (PTA Lab), Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum—University of Bologna, 40126 Bologna, Italy; [email protected] 7 UCIBIO-REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; [email protected] * Correspondence: [email protected]; Tel.: +420-495067295 Citation: Dosedˇel,M.; Jirkovský, E.; † Listed at the end of Acknowledgments. Macáková, K.; Krˇcmová,L.K.; Javorská, L.; Pourová, J.; Mercolini, L.; Abstract: Vitamin C (L-ascorbic acid) has been known as an antioxidant for most people.
    [Show full text]