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Eira Kelo | Kelo | 156 | Eira View metadata, citation and similar papers at core.ac.uk brought to you by CORE dissertations provided by UEF Electronic Publications | 156 | Eira| 156 Kelo | Eira Kelo Catalytic and Therapeutic Characteristics of Human Aspartylglycosaminuria (AGU), Recombinant Glycosylasparaginase an inherited lysosomal storage Catalytic and Therapeutic Characteristics Human of Recombinant Glycosylasparaginase and Bacterial L-asparaginases Eira Kelo disease, is caused by the deficient and Bacterial L-asparaginases activity of a lysosomal enzyme glycosylasparaginase (GA). Catalytic and Therapeutic Loss of GA activity results in the Characteristics of Human accumulation of glycoasparagines in tissues leading to progressive Recombinant Glycosylasparaginase psychomotor retardation and a shortened life span. Currently there is no cure for and Bacterial L-asparaginases AGU. In this study, the effectiveness of enzyme replacement therapy (ERT) with human recombinant GA was evaluated in the mouse model of AGU. Furthermore, the enzymatic properties of GA and bacterial asparaginases were compared. This study reveals new therapeutic and catalytic properties of human GA and bacterial asparaginases. Publications of the University of Eastern Finland Dissertations in Health Sciences Publications of the University of Eastern Finland Dissertations in Health Sciences isbn 978-952-61-1045-5 EIRA KELO EIRA KELO Catalytic and therapeutic characteristics of Catalytic and therapeutic characteristics of human recombinant glycosylasparaginase human recombinant glycosylasparaginase and bacterial L-asparaginases and bacterial L-asparaginases To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in the Auditorium 2, Kuopio University Hospital, Kuopio, public examination in the Auditorium 2, Kuopio University Hospital, Kuopio, on Friday, April 19th 2013, at 12 noon on Friday, April 19th 2013, at 12 noon Publications of the University of Eastern Finland Publications of the University of Eastern Finland Dissertations in Health Sciences Dissertations in Health Sciences Number 156 Number 156 Department of Clinical Chemistry, Institute of Clinical Medicine, School of Medicine, Department of Clinical Chemistry, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland Faculty of Health Sciences, University of Eastern Finland Kuopio Kuopio 2013 2013 Kopijyvä Oy Kopijyvä Oy Kuopio, 2013 Kuopio, 2013 Series Editors: Series Editors: Professor Veli-Matti Kosma, M.D., Ph.D. Professor Veli-Matti Kosma, M.D., Ph.D. Institute of Clinical Medicine, Pathology Institute of Clinical Medicine, Pathology Faculty of Health Sciences Faculty of Health Sciences Professor Hannele Turunen, Ph.D. Professor Hannele Turunen, Ph.D. Department of Nursing Science Department of Nursing Science Faculty of Health Sciences Faculty of Health Sciences Professor Olli Gröhn, Ph.D. Professor Olli Gröhn, Ph.D. A.I. Virtanen Institute for Molecular Sciences A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences Faculty of Health Sciences Distributor: Distributor: University of Eastern Finland University of Eastern Finland Kuopio Campus Library Kuopio Campus Library P.O.Box 1627 P.O.Box 1627 FI-70211 Kuopio, Finland FI-70211 Kuopio, Finland http://www.uef.fi/kirjasto http://www.uef.fi/kirjasto ISBN (print): 978-952-61-1045-5 ISBN (print): 978-952-61-1045-5 ISBN (pdf): 978-952-61-1046-2 ISBN (pdf): 978-952-61-1046-2 ISSN (print): 1798-5706 ISSN (print): 1798-5706 ISSN (pdf): 1798-5714 ISSN (pdf): 1798-5714 ISSN-L: 1798-5706 ISSN-L: 1798-5706 III III Author’s address: Department of Clinical Chemistry Author’s address: Department of Clinical Chemistry Faculty of Health Sciences Faculty of Health Sciences University of Eastern Finland University of Eastern Finland KUOPIO KUOPIO FINLAND FINLAND Supervisors: Professor Ilkka Mononen, M.D., Ph.D. Supervisors: Professor Ilkka Mononen, M.D., Ph.D. Department of Clinical Chemistry and Joint Laboratory Department of Clinical Chemistry and Joint Laboratory University of Turku University of Turku TURKU TURKU FINLAND FINLAND Reviewers: Professor Kimmo Porkka, M.D., Ph.D Reviewers: Professor Kimmo Porkka, M.D., Ph.D Hematology Research Unit Hematology Research Unit University of Helsinki University of Helsinki HELSINKI HELSINKI FINLAND FINLAND Professor Risto Renkonen, M.D., Ph.D Professor Risto Renkonen, M.D., Ph.D Faculty of Medicine Faculty of Medicine University of Helsinki University of Helsinki HELSINKI HELSINKI FINLAND FINLAND Opponent: Emeritus Professor Aimo Ruokonen, M.D. Opponent: Emeritus Professor Aimo Ruokonen, M.D. Institute of Diagnostics Institute of Diagnostics Department of Clinical Chemistry Department of Clinical Chemistry University of Oulu University of Oulu OULU OULU FINLAND FINLAND IV IV V V Kelo, Eira Kelo, Eira Catalytic and therapeutic characteristics of human recombinant glycosylasparaginase and bacterial L- Catalytic and therapeutic characteristics of human recombinant glycosylasparaginase and bacterial L- asparaginases asparaginases University of Eastern Finland, Faculty of Health Sciences University of Eastern Finland, Faculty of Health Sciences Publications of the University of Eastern Finland. Dissertations in Health Sciences 156. 2013. 54 p. Publications of the University of Eastern Finland. Dissertations in Health Sciences 156. 2013. 54 p. ISBN (print): 978-952-61-1045-5 ISBN (print): 978-952-61-1045-5 ISBN (pdf): 978-952-61-1046-2 ISBN (pdf): 978-952-61-1046-2 ISSN (print): 1798-5706 ISSN (print): 1798-5706 ISSN (pdf): 1798-5714 ISSN (pdf): 1798-5714 ISSN-L: 1798-5706 ISSN-L: 1798-5706 ABSTRACT ABSTRACT Glycosylasparaginase (GA) is a lysosomal enzyme which cleaves the linkage between N- Glycosylasparaginase (GA) is a lysosomal enzyme which cleaves the linkage between N- acetylglucosamine and L-asparagine in asparagine-linked glycoproteins. The deficiency of GA in acetylglucosamine and L-asparagine in asparagine-linked glycoproteins. The deficiency of GA in aspartylglucosaminuria (AGU) patients leads to progressive psychomotor retardation and a aspartylglucosaminuria (AGU) patients leads to progressive psychomotor retardation and a shortened life span due to the massive accumulation of aspartylglucosamine (GlcNAc-Asn) and shortened life span due to the massive accumulation of aspartylglucosamine (GlcNAc-Asn) and other glycoasparagines into tissues and body fluids. Currently there is no curative therapy available other glycoasparagines into tissues and body fluids. Currently there is no curative therapy available for AGU. Development of treatment strategies is challenging due to the fact that AGU also affects for AGU. Development of treatment strategies is challenging due to the fact that AGU also affects the central nervous system (CNS). the central nervous system (CNS). In the first part of the present study, the effectiveness of enzyme replacement therapy (ERT) with In the first part of the present study, the effectiveness of enzyme replacement therapy (ERT) with human recombinant GA was evaluated in the mouse model of AGU by using biochemical methods. human recombinant GA was evaluated in the mouse model of AGU by using biochemical methods. It was found that intravenously administered GA effectively cleared GlcNAc-Asn from the non- It was found that intravenously administered GA effectively cleared GlcNAc-Asn from the non- neuronal tissues of the treated adult AGU mice, and surprisingly, to some extent also from brains. neuronal tissues of the treated adult AGU mice, and surprisingly, to some extent also from brains. Moreover, a glycoasparagine Man2GlcNAc2-Asn was present as high concentrations in the non- Moreover, a glycoasparagine Man2GlcNAc2-Asn was present as high concentrations in the non- neuronal tissues of the untreated AGU mice, whereas its accumulation in brain was negligible. The neuronal tissues of the untreated AGU mice, whereas its accumulation in brain was negligible. The level of Man2GlcNAc2-Asn in liver and spleen increased with age of the mice, but no such similar level of Man2GlcNAc2-Asn in liver and spleen increased with age of the mice, but no such similar trend was found in other tissues. ERT with intraperitoneal injections of GA effectively removed trend was found in other tissues. ERT with intraperitoneal injections of GA effectively removed both GlcNAc-Asn and Man2GlcNAc2-Asn from non-neuronal tissues of adult AGU mice. both GlcNAc-Asn and Man2GlcNAc2-Asn from non-neuronal tissues of adult AGU mice. In the second part of the study, the enzymatic properties of GA and asparaginase were In the second part of the study, the enzymatic properties of GA and asparaginase were compared. In addition to GlcNAc-Asn, GA is known to hydrolyze β-aspartylpeptides. Encouraged compared. In addition to GlcNAc-Asn, GA is known to hydrolyze β-aspartylpeptides. Encouraged by the structural similarity of GA and bacterial asparaginases, it was possible to demonstrate that by the structural similarity of GA and bacterial asparaginases, it was possible to demonstrate that bacterial L-asparaginases, which are used in the treatment of acute lymphoblastic leukemia (ALL), bacterial L-asparaginases, which are used in the treatment of acute lymphoblastic leukemia (ALL), are also able to catalyze the hydrolysis of certain β-aspartylpeptides, especially small size β-aspartyl are also able to catalyze the hydrolysis
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