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