UvA-DARE (Digital Academic Repository) Isoprenoid biosynthesis and mevalonate kinase deficiency Henneman, L. Publication date 2011 Document Version Final published version Link to publication Citation for published version (APA): Henneman, L. (2011). Isoprenoid biosynthesis and mevalonate kinase deficiency. 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. 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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:28 Sep 2021 Isoprenoid Biosynthesis and Mevalonate Kinase Deficiency Isoprenoid O Uitnodiging - O P O - P O O - O O Isoprenoid Biosynthesis voor het bijwonen van de openbare verdediging and van het proefschrift van HO Mevalonate Kinase Deficiency Linda Henneman N N FeII HN N N O HN N N O - N N O N P N O HO - O O P O - N H H O N O O HO H H OH O OH H OH O O H H O O H H OH H O O - H O P O O - H H P O O HO O P O - O O O O - O P O O P op woensdag 5 oktober 2011 - O - O - O Linda Henneman om 14.00 uur in de Agnietenkapel HN O P O - O Oudezijds Voorburgwal 231 N - N HO Amsterdam N N HO O H H Receptie ter plaatse N N H H OH H FeII na afloop van de promotie N N H O H H Paranimfen: HO Merel Ebberink 06-18411478 O H OH OH O Judith Henneman 06-55118408 H O 2011 H H HO Linda Henneman Isoprenoid Biosynthesis and Mevalonate Kinase Deficiency Author Linda Henneman Cover Image End products of isoprenoid biosynthesis with GGPP in red GGPP becomes limiting in MKD Printed by Gildeprint drukkerijen, Enschede, The Netherlands ISBN 978-94-6108-209-1 Isoprenoid Biosynthesis and Mevalonate Kinase Deficiency Academisch proefschrift ter verkrijging van de graad van doctor aan d­­e Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op woensdag 5 oktober 2011, te 14:00 uur door Linda Henneman geboren te Alkmaar Promotiecommissie Promotor: Prof. dr. R.J.A. Wanders Co-promotor: Dr. H.R. Waterham Overige leden: Prof. dr. R.A.W. van Lier Prof. dr. C.J.F. van Noorden Prof. dr. A.J. Verhoeven Prof. dr. F.A. Wijburg Dr. F.M. Vaz Dr. J. Frenkel Faculteit der Geneeskunde The work described in this thesis was carried out at the laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands. The Research was financially supported by a grant of ZonMW, grant number 912-03-024. TABLe oF CoNTeNTS Abbreviations 6 Chapter 1 General introduction 9 Chapter 2 Detection of nonsterol isoprenoids by HPLC–MS/MS 31 Analytical Biochemistry (2008) 383: 18-24 Chapter 3 Inhibition of the isoprenoid biosynthesis pathway; 47 detection of intermediates by UPLC–MS/MS Biochimica et Biophysica Acta (2011) 1811: 227-233 Chapter 4 Compromised geranylgeranylation of RhoA and Rac1 in 61 mevalonate kinase deficiency Journal of Inherited Metabolic Disease (2010) 33: 625-632 Chapter 5 Fever induces ectopic activation of small GTPases in the 75 autoinflammatory disorder mevalonate kinase deficiency In preparation for submission Chapter 6 Generation and characterization of two mouse models for 89 mevalonate kinase deficiency General discussion and summary 107 Samenvatting voor iedereen 113 Dankwoord 119 ABBreviatioNS AGP a1-glycoprotein DMAPP dimethylallyl pyrophosphate DMEM Dulbecco’s Modified Eagles medium DMSO dimethylsulfoxide ER endoplasmic reticulum ES embryonic stem FCS fetal calf serum FMF familial Mediterranean fever FMVA 6-fluoromevalonate FPP farnesyl pyrophosphate FPPS farnesyl pyrophosphate synthase FTase farnesyltransferase FTI farnesyltransferase inhibitor GAP GTPase activating protein GDI guanine nucleotide dissociation inhibitor GEF guanine nucleotide exchange factor GGOH geranylgeraniol GGPP geranylgeranyl pyrophosphate GGTase geranylgeranyltransferase GGTI geranylgeranyltransferase inhibitor GPP geranyl pyrophosphate GST-PAK glutathione S-transferase p21-activated Ser/Thr kinase GST-RBD glutathione S-transferase Ras-binding domain HEPES 4-2-hydroxyethyl-1-piperazineethanesulfonic acid HIDS hyper-IgD and periodic fever syndrome HMG-CoA 3-hydroxy-3-methylglutaryl-CoA HPLC-MS/MS high performance liquid chromatography-tandem mass spectrometry IFN interferon IgD immunoglobulin D IL interleukin IPP isopentenyl pyrophosphate IPPI isopentenyl pyrophosphate isomerase IS internal standard LDL low density lipoprotein LOD limit of detection LOQ limit of quantification LPS lipopolysaccharide MA mevalonic aciduria MBP maltose-binding protein MDP muramyldipeptide MK mevalonate kinase MKD mevalonate kinase deficiency MPD mevalonate pyrophosphate decarboxylase MRM multiple reaction monitoring MVA mevalonate MVAL mevalonolactone MVAP 5-phosphomevalonate MVAPP 5-pyrophosphomevalonate MVK gene encoding MK PAGE polyacrylamide gel electrophoresis PAM pamidronate PBMC peripheral blood mononuclear cell PBS phosphate buffered saline PMK phosphomevalonate kinase SAA serum amyloid A SCAP SREBP cleavage-activating protein SDS sodium dodecyl sulfate SRE sterol regulatory element SREBP sterol regulatory element binding protein TNF tumor necrosis factor TRAPS TNF-receptor associated periodic syndrome UPLC-MS/MS ultra performance liquid chromatography-tandem mass spectrometry ZAA zaragozic acid A ZOL zoledronate Chapter 1 O O P P O O O- O- O- General introduction Chapter 1 ISoPreNoID BIoSyNTHeSIS pathwAy Introduction The isoprenoid biosynthesis pathway plays an important role in cellular metabolism. 1 It provides the cell with sterol and nonsterol isoprenoids which are incorporated into diverse classes of end products that participate in processes relating to cell growth, differentiation, glycosylation, isoprenylation and various signal transduction pathways [1;2]. Cholesterol is the major sterol end product of the pathway and is not only an important structural component of cellular membranes and myelin, but is also the precursor of oxysterols, steroid hormones and bile acids. Furthermore, cholesterol plays a crucial role in human embryogenesis and development [3]. In addition to the synthesis of sterol compounds, the isoprenoid biosynthesis pathway produces a variety of nonsterol isoprenoids. These include, among others: 1) ubiquinone-10 and the side chains of heme A, which are both involved in electron transport in the mitochondrial respiratory chain; 2) dolichol, a mediator of N-linked protein glycosylation; 3) isopentenyl tRNAs, involved in protein translation; 4) farnesyl and geranylgeranyl moieties, used for the prenylation of cellular proteins, which in most cases makes them membrane associated. Many isoprenylated proteins participate in important cellular functions, such as signal transduction, cell cycle control, cytoskeletal organization, intracellular vesicle traffic and inflammation [1;2]. Pathway intermediates and enzymes The first part of the isoprenoid biosynthesis pathway is also known as the mevalonate pathway and consists of a series of reactions in which acetyl-CoA is converted into farnesyl pyrophosphate (FPP) (Figure 1). The pathway starts with two acetyl-CoAs, which are converted into acetoacetyl-CoA by the enzyme acetoacetyl-CoA thiolase. 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is then formed through the addition of a third acetyl-CoA by HMG-CoA synthase. The reduction of HMG-CoA is catalyzed by the rate-limiting enzyme of the pathway, HMG-CoA reductase, and yields mevalonate. Subsequently, mevalonate is phosphorylated twice, first by mevalonate kinase (MK) followed by phosphomevalonate kinase, which produces 5-phosphomevalonate and 5-pyrophosphomevalonate, respectively. Decarboxylation of this latter compound by mevalonate pyrophosphate decarboxylase yields isopentenyl pyrophosphate (IPP). This basic C5 isoprene unit is used for the synthesis of all isoprenoid end products including some tRNAs in which IPP is added to adenosine. After isomerization of IPP to dimethylallyl pyrophosphate (DMAPP) by the enzyme isopentenyl pyrophosphate isomerase, a head- to-tail condensation of IPP to DMAPP by farnesyl pyrophosphate synthase results in the formation of geranyl pyrophosphate (GPP). The same enzyme then adds another IPP to GPP, which forms FPP [1;4]. At the level of FPP, the pathway branches off into a sterol and nonsterol part of the isoprenoid biosynthesis pathway. The conversion of two FPP molecules into squalene is the first reaction exclusively committed to the synthesis of sterol end products. This reaction is catalyzed by squalene synthase and is followed by the condensation of squalene into lanosterol. To eventually generate C27 cholesterol from lanosterol, a series of at least 8 different enzyme reactions is required (Figure 2). This complex set of enzyme reactions include one methylation at C14 and two demethylations