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New Insight Into Vitamin B6 Metabolism and Related Diseases

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New insight into vitamin B6 metabolism and related diseases Rúben José Jesus Faustino Ramos New insight into vitamin B6 metabolism and related diseases Nieuw inzicht in het metabolisme van vitamine B6 en aanverwante ziekten (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. H.R.B.M. Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 10 oktober 2019 des ochtends te 10.30 uur Cover design: Gianluca Di Vincenzo Thesis layout: Guus Gijben door Printed by: Proefschrift AIO ISBN: 978-94-92801-99-9 Rúben José Jesus Faustino Ramos © Rúben José Jesus Faustino Ramos, 2019 geboren op 18 april 1984 te Évora, Portugal All rights are reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without the prior written permission of the author. Promotor: TABLE OF CONTENTS Prof. dr. N.M. Verhoeven-Duif Copromotor: Chapter 1 General introduction and outline of the thesis 7 Dr. J.J.M. Jans Chapter 2 Vitamin B6 is essential for serine de novo biosynthesis 29 Chapter 3 Biallelic GOT2 mutations cause a treatable malate- 51 aspartate shuttle related encephalopathy Chapter 4 Metabolic consequences of GOT2 deficiency 91 Chapter 5 Serine biosynthesis flux as diagnostic tool for serine 115 biosynthesis defects Chapter 6 Discovery of pyridoxal reductase activity as part of 129 human vitamin B6 metabolism Chapter 7 General Discussion 153 Appendix Nederlandse samenvatting 164 Summary 168 Acknowledgements 172 List of publications 176 Curriculum Vitae 178 Dit proefschrift werd (mede) mogelijk gemaakt met financiële steun van Metakids Foundation. 1 Chapter 1 General introduction General introduction Vitamin B6 Vitamin B6 refers to six structurally related compounds that have a 2-methyl- 1 3-hydroxypyridine structure in common but have different C4 and C5 chemical moieties: pyridoxal (PL; aldehyde group at C4; -CHO), pyridoxine (PN; alcohol group at C4; -CH2OH), pyridoxamine (PM; amine group at C4; -CH2NH2), and their respective 5’-phosphate esters pyridoxal 5’-phosphate (PLP), pyridoxine 5’-phosphate (PNP) and pyridoxamine 5’-phosphate (PMP) (Snell, 1953). 4-Pyridoxic acid (PA) is the main catabolism product of vitamin B6 (Hufft and Perlzweig, 1944) (Figure 1). Figure 1 Pyridoxal Pyridoxine Pyridoxamine Catabolism Product H O HO H2 H2N H2 C C C HO HO HO OH OH OH Pyridoxic acid H C N 3 H3C N H C N 3 HO O C HO Pyridoxal 5’-phosphate Pyridoxine 5’-phosphate Pyridoxamine 5’-phosphate OH H C N H N H 3 H O HO H2 2 2 C O OH C O OH C O OH HO P HO P HO P O OH O OH O OH H C N H C N 3 3 H3C N Figure 1. Chemical structures of vitamin B6 vitamers. Pyridoxal: aldehyde group at C4; pyridoxine: alcohol group at C4; pyridoxamine: amine group at C4 and the respective 5’-phosphate esters: pyridoxal 5’-phosphate; pyridoxine 5’-phosphate and pyridoxamine 5’-phosphate. Pyridoxic acid (vitamin B6 catabolism product): carboxylic group at C4. All organisms depend on vitamin B6 for survival, but only microorganisms and plants can synthesize it de novo (Di Salvo, et al., 2011). Humans rely on vitamin B6 uptake from the diet to fulfil their needs. A minor part of the vitamin B6 pool is derived from the intestinal bacterial flora (Surtees, et al., 2006). Vitamin B6 is widely distributed in animal- and plant-derived foods. In animal-derived foods (such as beef, pork, poultry, fish, milk and eggs) it is mainly present as PLP and PMP and in smaller amounts as PL, PM and PN (McCormick, 1989). In plant-derived foods (such as cereals, vegetables and some fruits) vitamin B6 is mainly present as PN, PNP and pyridoxine-5’-β-D- glucoside (PN-glucoside) (McCormick, 1989; Clayton, 2006; Surtees et al., 2006). Pyridoxine (hydrochloride) is the most commonly used vitamer to fortify foods (Bender, 2005). Although humans cannot synthesize vitamin B6 de novo, all vitamers can be interconverted through the vitamin B6 salvage pathway. 9 General introduction Animal-derived food Plant-derived food Vitamin B6 metabolism PMP PLP PNP PN-glucoside PM PL PM Vitamin B6 absorption in the intestine is rapid and occurs after hydrolysis of the 1 ALPL ALPL ALPL PN-B-D-Glucoside phosphorylated forms in the intestinal lumen by the membrane-bound intestinal Hydrolese PM PL PN PN alkaline phosphatases (ALPL; EC 3.1.3.1) (Waymire et al., 1995) (Figure 2). PN-glucoside Diet and absorption is hydrolyzed to PN by the cytosolic pyridoxine-β-D-glucoside hydrolase in the intestinal mucosa (Mcmahon et al., 1997). Uptake of the unphosphorylated vitamers PM PL PN was first believed to occur via simple diffusion (Hamm et al., 1979; Mehansho et al., PM PL PN PL 1979; Middleton III, 1977; Ink and Henderson, 1984), until studies performed on human- oxidase PA PDXK PDXP PDXK PDXP PDXK PDXP Liver derived intestinal epithelial Caco-2 cells and intestinal colonocytes of mice and men PNPO PNPO Metabolism PMP PLP PNP Excreted showed the existence of specific carrier-mediated mechanisms for PN uptake (Said et Transaminase Urine al., 2003; Said et al., 2008). In Caco-2 and young adult mouse colonic epithelial (YAMC) Albumine bound (Lys190) cells, the carrier-mediated mechanism is specific, Na+ independent, and temperature Hemoglobin bound + & RBC and pH dependent, suggesting a pyridoxine:H symport mechanism. In addition, PN Circulation TNSALP uptake seems to be regulated by an intracellular protein kinase A (PKA)-mediated memb. pathway in Caco-2 cells (Said et al., 2003), and by a Ca2+/CaM-mediated pathway in Plasma YAMC cells (Said et al., 2008). PN uptake in human colonic apical membrane vesicles PL (AMV) is, as described for the other two models, saturable (Said et al., 2008). Although PDXK Metabolism Intracellular the liver is the main organ responsible for vitamin B6 metabolism, intestinal Caco-2 cells PLP Intercellular enzymatic reactions possess all enzymes involved in B6 metabolism and convert small amounts of PN and PM into PL, secreting all three unphosphorylated B6 vitamers (Albersen et al., 2013). Figure 2. Vitamin B6 absorption and metabolism. The different vitamin B6 vitamers are present The portal circulation delivers PL, PN and PM to the liver and, once inside liver cells, in animal- and plant-derived food sources. Vitamin B6 absorption is rapid and occurs after hydrolysis of the phosphorylated forms (PLP, pyridoxal 5’-phosphate; PNP, pyridoxine 5’-phosphate and PMP, the B6 vitamers are converted to PLP through the salvage pathway (Figure 2). The pyridoxamine 5’-phosphate) in the intestinal lumen by the membrane-bound intestinal alkaline vitamin B6 salvage pathway recycles the different B6 vitamers through the action of phosphatases (ALPL). Inside the cells, PL kinase (PDXK) phosphorylates the hydroxymethyl group of the pyridoxal phosphatase (PDXP; EC 3.1.3.74), the ATP-dependent pyridoxal kinase PL, PN and PM to their respective 5’-phosphate forms. Dephosphorylation of PLP, PNP and PMP is catalysed by PL phosphatase (PDXP). Aminotransferases use PLP during the interchange of the amino (PDXK; EC 2.7.1.35) and the flavin mononucleotide (FMN)-dependent pyridox(am)ine group between one amino acid and an α-keto acid, producing PMP as an intermediary in the first 5′-phosphate oxidase (PNPO; EC 1.4.3.5). PL, PN and PM are phosphorylated to their part of the reaction. PL can be oxidized to pyridoxic acid (PA) by PL oxidase and excreted in the urine. respective 5’-phosphate esters by PDXK, entrapping the phosphorylated B6 vitamers intracellularly (Hanna et al., 1997). PNPO oxidizes PNP and PMP to PLP (Mills et al., 2005). Dephosphorylation of PLP (but also PNP and PMP) is catalysed by pyridoxal phosphatase (PDXP; EC 3.1.3.74) (Jang et al., 2003). These three enzymes provide a mean of converting dietary B6 to circulating PL(P). The main circulating B6 vitamer in blood is PLP bound to albumin (accounting for 60% of the total circulating vitamin B6). PL, PN and PM are present in lower concentrations (Lumeng et al., 1974; Lumeng et al., 1980; Ink and Henderson, 1984; Spinneker et al., 2007). 10 11 General introduction Vitamin B6 function The role of vitamin B6 in neurotransmitter metabolism PLP, the metabolically active form of vitamin B6, is an essential cofactor in more than γ-Aminobutyric acid (GABA), the key inhibitory neurotransmitter in the central 1 160 enzyme-catalysed reactions (Percudani and Peracchi, 2009), representing 4% nervous system, is synthesized from glutamate (the main excitatory neurotransmitter) of all known cellular catalytic activities (Percudani and Peracchi, 2003). Most of the via the PLP-dependent enzyme glutamic acid decarboxylase (GAD, EC 4.1.1.15). PLP-dependent reactions are involved in synthesis, degradation and interconversion For a long time, deficient GABA levels were appointed as the main reason for the of amino acids (Ebadi, 1981; Surtees et al., 2006; Clayton, 2006; Ueland et al., 2015). clinical phenotype observed in vitamin B6 dependent epilepsy (Gospe et al., 1994). In addition, PLP is essential for biosynthesis of neurotransmitters (γ-aminobutyric In line with these observations, studies performed in zebrafish embryos showed that acid, dopamine and serotonin), sphingolipids, heme, histamine, carbohydrates and exposure to ginkgotoxin (4’-O-methylpyridoxine, a PLP antimetabolite) leads to a nucleotides. The special electrophilic characteristics of the aldehyde group of PLP seizure-like behavior. In addition, the ginkgotoxin-induced seizures were reversed at C4 derives from the existence of a protonated pyridinium hydrogen (N1) and a by GABA and/or PLP, supporting the hypothesis that the seizures were caused by phenoxide anion at C3. These stabilize the protonated state of the imine nitrogen reduced PLP, leading to imbalance between GABA and glutamate (Lee et al., 2012).
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    471 Review Article on Inborn Errors of Metabolism Page 1 of 10 Amino acid disorders Ermal Aliu1, Shibani Kanungo2, Georgianne L. Arnold1 1Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 2Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA Contributions: (I) Conception and design: S Kanungo, GL Arnold; (II) Administrative support: S Kanungo; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: E Aliu, GL Arnold; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Georgianne L. Arnold, MD. UPMC Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Suite 1200, Pittsburgh, PA 15224, USA. Email: [email protected]. Abstract: Amino acids serve as key building blocks and as an energy source for cell repair, survival, regeneration and growth. Each amino acid has an amino group, a carboxylic acid, and a unique carbon structure. Human utilize 21 different amino acids; most of these can be synthesized endogenously, but 9 are “essential” in that they must be ingested in the diet. In addition to their role as building blocks of protein, amino acids are key energy source (ketogenic, glucogenic or both), are building blocks of Kreb’s (aka TCA) cycle intermediates and other metabolites, and recycled as needed. A metabolic defect in the metabolism of tyrosine (homogentisic acid oxidase deficiency) historically defined Archibald Garrod as key architect in linking biochemistry, genetics and medicine and creation of the term ‘Inborn Error of Metabolism’ (IEM). The key concept of a single gene defect leading to a single enzyme dysfunction, leading to “intoxication” with a precursor in the metabolic pathway was vital to linking genetics and metabolic disorders and developing screening and treatment approaches as described in other chapters in this issue.
  • Supplementary Materials

    Supplementary Materials

    Supplementary Materials COMPARATIVE ANALYSIS OF THE TRANSCRIPTOME, PROTEOME AND miRNA PROFILE OF KUPFFER CELLS AND MONOCYTES Andrey Elchaninov1,3*, Anastasiya Lokhonina1,3, Maria Nikitina2, Polina Vishnyakova1,3, Andrey Makarov1, Irina Arutyunyan1, Anastasiya Poltavets1, Evgeniya Kananykhina2, Sergey Kovalchuk4, Evgeny Karpulevich5,6, Galina Bolshakova2, Gennady Sukhikh1, Timur Fatkhudinov2,3 1 Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia 2 Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, Moscow, Russia 3 Histology Department, Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia 4 Laboratory of Bioinformatic methods for Combinatorial Chemistry and Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia 5 Information Systems Department, Ivannikov Institute for System Programming of the Russian Academy of Sciences, Moscow, Russia 6 Genome Engineering Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia Figure S1. Flow cytometry analysis of unsorted blood sample. Representative forward, side scattering and histogram are shown. The proportions of negative cells were determined in relation to the isotype controls. The percentages of positive cells are indicated. The blue curve corresponds to the isotype control. Figure S2. Flow cytometry analysis of unsorted liver stromal cells. Representative forward, side scattering and histogram are shown. The proportions of negative cells were determined in relation to the isotype controls. The percentages of positive cells are indicated. The blue curve corresponds to the isotype control. Figure S3. MiRNAs expression analysis in monocytes and Kupffer cells. Full-length of heatmaps are presented.