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Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways

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biology Review Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways Antonin Ginguay 1,2, Luc Cynober 1,2,*, Emmanuel Curis 3,4,5,6 and Ioannis Nicolis 3,7 1 Clinical Chemistry, Cochin Hospital, GH HUPC, AP-HP, 75014 Paris, France; [email protected] 2 Laboratory of Biological Nutrition, EA 4466 PRETRAM, Faculté de Pharmacie, Université Paris Descartes, 75006 Paris, France 3 Laboratoire de biomathématiques, plateau iB2, Faculté de Pharmacie, Université Paris Descartes, 75006 Paris, France; [email protected] (E.C.); [email protected] (I.N.) 4 UMR 1144, INSERM, Université Paris Descartes, 75006 Paris, France 5 UMR 1144, Université Paris Descartes, 75006 Paris, France 6 Service de biostatistiques et d’informatique médicales, hôpital Saint-Louis, Assistance publique-hôpitaux de Paris, 75010 Paris, France 7 EA 4064 “Épidémiologie environnementale: Impact sanitaire des pollutions”, Faculté de Pharmacie, Université Paris Descartes, 75006 Paris, France * Correspondence: [email protected]; Tel.: +33-158-411-599 Academic Editors: Arthur J.L. Cooper and Thomas M. Jeitner Received: 26 October 2016; Accepted: 24 February 2017; Published: 6 March 2017 Abstract: Ornithine δ-aminotransferase (OAT, E.C. 2.6.1.13) catalyzes the transfer of the δ-amino group from ornithine (Orn) to α-ketoglutarate (aKG), yielding glutamate-5-semialdehyde and glutamate (Glu), and vice versa. In mammals, OAT is a mitochondrial enzyme, mainly located in the liver, intestine, brain, and kidney. In general, OAT serves to form glutamate from ornithine, with the notable exception of the intestine, where citrulline (Cit) or arginine (Arg) are end products. Its main function is to control the production of signaling molecules and mediators, such as Glu itself, Cit, GABA, and aliphatic polyamines. It is also involved in proline (Pro) synthesis. Deficiency in OAT causes gyrate atrophy, a rare but serious inherited disease, a further measure of the importance of this enzyme. Keywords: ornithine aminotransferase; glutamate; ornithine; gyrate atrophy 1. Introduction Ornithine δ-aminotransferase (E.C. 2.6.1.13; OAT), or ornithine δ-transaminase, is an enzyme found in almost all eukaryotic organisms, from protozoans to humans, and from fungi to higher plants. It is strongly conserved among these organisms. In humans, OAT deficiency causes gyrate atrophy, a serious inherited disease. This suggests that OAT plays an important role in metabolism. In most situations, it uses L-ornithine (Orn) as a substrate, with L-glutamate (Glu) as an end product; OAT therefore belongs to what is termed the “glutamate crossway” [1]. At first sight, the importance of OAT may appear to be related to the roles of Glu in metabolism (bioenergetics, nitrogen flux, acid-base homeostasis), like the major enzymes involved in Glu metabolism (e.g., aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and glutamate dehydrogenase (GDH)). This paper summarizes current knowledge on OAT, in particular in the light of recent advances in large scale analysis, and of clinical experience, and argues that viewing the role of OAT as limited to glutamate-related energy metabolism, especially in mammals, probably misses other important functions of OAT. This is evident from an examination of the pathways relating glutamate and ornithine Biology 2017, 6, 18; doi:10.3390/biology6010018 www.mdpi.com/journal/biology Biology 2017, 6, 1 2 of 40 BiologyornithineBiology 20172017 , 6,to,6 1, 18several key molecules in cell metabolism and “fate” regulation (Figure 1); 2these 2of of 40 38 functions are briefly summarized here—a detailed description lies outside the scope of this paper, ornithinebut interested to several readers key can molecules find information in cell metabolism in recent andreviews “fate” [2 –regulation5]. To present (Figure the 1)state; these of to several key molecules in cell metabolism and “fate” regulation (Figure1); these functions are briefly functionsknowledge are on briefly OAT, summarizedwe will first describe here—a thedetail physiced descriptional, chemical lies and outside biological the characteristicsscope of this paper, of the summarized here—a detailed description lies outside the scope of this paper, but interested readers butOAT interested reaction, andreaders then gocan on find to consider information the involvement in recent reviewsof OAT in[2 pathological–5]. To present states the or diseases.state of can find information in recent reviews [2–5]. To present the state of knowledge on OAT, we will first knowledgeThis systematic on OAT overview, we will will first alsodescribe highlight the physic needals, chemicalfor further and studies biological of thischaracteristics enzyme and of theits describe the physical, chemical and biological characteristics of the OAT reaction, and then go on to OATregulation. reaction , and then go on to consider the involvement of OAT in pathological states or diseases. Thisconsider systematic the involvement overview ofwill OAT also in pathologicalhighlight need statess for or diseases.further studies This systematic of this overviewenzyme and will alsoits regulation.highlight needs for further studies of this enzyme and its regulation. Figure 1. End products of the reaction mediated by ornithine (Orn) aminotransferase (OAT) and theirFigure functions 1. End (in products italics) ofGABA: the reaction γ-aminobutyric mediated acid, byornithine Glu: glutamate, (Orn)aminotransferase Pro: proline, Arg: (OAT) arginine, and FigureCit:their citrulline, functions1. End Put:products (in putrescine, italics) of GABA:the NO: reaction γnitric-aminobutyric mediated oxide. by acid, ornithine Glu: glutamate, (Orn) aminotransferase Pro: proline, Arg: (OAT) arginine, and theirCit: functions citrulline, Put:(in italic putrescine,s) GABA: NO: γ-aminobutyric nitric oxide. acid, Glu: glutamate, Pro: proline, Arg: arginine, 1.1. PhysicCit: citrulline,al And Chemical Put: putrescine, Aspects NO: of the nitric Oat oxide-Mediated. Reaction 1.1. Physical And Chemical Aspects of the Oat-Mediated Reaction 1.11.1.1. Physic. Reactional And Chemical Aspects of the Oat-Mediated Reaction 1.1.1. Reaction 1.1.1. OATReaction catalyzes the conversion of Orn into glutamyl-5-semi-aldehyde (GSA) and vice versa, using OATaKG and catalyzes Glu as the cosubstrates conversion (Figure of Orn 2). into This glutamyl-5-semi-aldehyde reaction has an apparent equilibrium (GSA) and constant, vice versa, K [Glu][GSA] =using OAT aKG ,catalyzes that and favor Glu the ass the cosubstratesconversion degradation of (Figure ofOrn Orn: into2). experimentally, This glutamyl reaction-5-semi has K lies an-aldehydeapparent between (GSA) equilibrium50 and and 70 viceat constant,25 versa°C [6], using[Orn[ ]Glua[aKGKG][GSA] and] Glu as cosubstrates (Figure 2). This reaction has an apparent equilibrium constant,◦ K K = [Orn][aKG] , that favors the degradation of Orn: experimentally, K lies between 50 and 70 at 25 C[6] and[Glu pH][GSA 7.] 1. Even so, when Orn is at a very low concentration, or GSA in large excess, the reaction =and pH 7.1., that Even favor so,s the when degradation Orn is ata of very Orn: low experimentally, concentration, K orlies GSA between in large 50 and excess, 70 at the 25 reaction °C [6] can[Orn proceed][aKG] towards Orn synthesis, which has indeed been demonstrated in vitro by Strecker et al. can proceed towards Orn synthesis, which has indeed been demonstrated in vitro by Strecker et al. [6]. and[6]. OATpH 7. can1. Even thus so,catalyze when the Orn reaction is at a invery either low direction, concentration, dependi or ngGSA on inthe large relative excess, amounts the reaction of each OAT can thus catalyze the reaction in either direction, depending on the relative amounts of each cansubstrate proceed present, towards and Orn their synthesis use by ,subsequent which has indeedenzymes. been This demonstrated observation isin thevitro first by indication Strecker et that al. substrate present, and their use by subsequent enzymes. This observation is the first indication that [6]OAT. OAT stands can atthus the catalyze crossroad thes ofreaction several in metabolic either direction, pathways. dependi ng on the relative amounts of each substrateOAT stands present, at the and crossroads their use of by several subsequent metabolic enzymes. pathways. This observation is the first indication that OAT stands at the crossroads of several metabolic pathways. Figure 2. Overview of the reaction catalyzed by OAT. Figure 2. Overview of the reaction catalyzed by OAT. 1.1.2. A Key Feature: Spontaneous Cyclization of GSA 1.1.2. A Key Feature: SpontaneousFigure 2. Overview Cyclization of the of GSAreaction catalyzed by OAT. Since GSA contains both an aldehyde and an amine function, internal imination can occur (Figure3), leading to a chemical equilibrium with the cyclic form ( S)-D1-pyrroline-5-carboxylate 1.1.2. A Key Feature: Spontaneous Cyclization of GSA Biology 2017, 6, 1 3 of 40 Since GSA contains both an aldehyde and an amine function, internal imination can occur (Figure 3), leading to a chemical equilibrium with the cyclic form (S)-Δ1-pyrroline-5-carboxylate (P5C). In addition, the aldehyde can react with water to give a GSA hydrated form, as shown in Figure 3. It has been suggested since the 1930s that the cyclic forms of these types of compounds are Biologyfavored2017 for, 6, 18entropic reasons, as is often the case for similar reactions (almost all oses), at least3 of 38at physiological
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    Fungal Pathogenesis in Humans The Growing Threat Edited by Fernando Leal Printed Edition of the Special Issue Published in Genes www.mdpi.com/journal/genes Fungal Pathogenesis in Humans Fungal Pathogenesis in Humans The Growing Threat Special Issue Editor Fernando Leal MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editor Fernando Leal Instituto de Biolog´ıa Funcional y Genomica/Universidad´ de Salamanca Spain Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Genes (ISSN 2073-4425) from 2018 to 2019 (available at: https://www.mdpi.com/journal/genes/special issues/Fungal Pathogenesis Humans Growing Threat). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03897-900-5 (Pbk) ISBN 978-3-03897-901-2 (PDF) Cover image courtesy of Fernando Leal. c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editor ...................................... vii Fernando Leal Special Issue: Fungal Pathogenesis in Humans: The Growing Threat Reprinted from: Genes 2019, 10, 136, doi:10.3390/genes10020136 ..................
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    Supplementary Table 2

    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942