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Relevance to Disorders of Propionyl-Coa Metabolism

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Relevance to Disorders of Propionyl-Coa Metabolism INTERRELATIONS BETWEEN PROPIONATE, 3-HYDROXYPROPIONATE, AND β-ALANINE METABOLISM: RELEVANCE TO DISORDERS OF PROPIONYL-COA METABOLISM By KIRKLAND A. WILSON Submitted in fulfillment of the requirements for the Degree of Doctor of Philosophy Thesis Advisor: Henri Brunengraber, M.D., Ph.D. Department of Nutrition School of Medicine CASE WESTERN RESERVE UNIVERSITY January, 2018 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Kirkland A Wilson candidate for the degree of Doctor of Philosophy. Committee Chair Danny Manor Committee Member Michelle Puchowicz Committee Member George Dubyak Committee Member Gregory Tochtrop Committee Member Shawn McCandless Committee Member Douglas Kerr Date of Defense 06/21/17 *We also certify that written approval has been obtained for any proprietary material contained therein. ii Dedication I dedicate this work to my parents, family, and loved ones, all of whom have provided continued love and support throughout my life. They have encouraged me to set lofty goals and have given me the strength to reach for them. Their love has helped me succeed in my work. iii Table of Contents List of Tables ................................................................................................................... viii List of Schemes and Figures .............................................................................................. ix Acknowledgements ........................................................................................................... xii List of Abbreviations .........................................................................................................xv Abstract ............................................................................................................................ xvi Chapter 1: Disorders of Propionyl-CoA Metabolism 1.1 Introduction ....................................................................................................................1 1.2 Propionic Acidemia ......................................................................................................2 1.2.1 Overview .........................................................................................................2 1.2.1.1 Propionyl-Coenzyme A Carboxylase .............................................4 1.2.2 Signs and Symptoms .......................................................................................5 1.2.2.1 Neurological Complications ...........................................................6 1.2.2.2 Cardiac Abnormalites .....................................................................8 1.2.2.3 Additional Complications .............................................................11 1.2.3 Biochemical Parameters ...............................................................................12 1.2.4 Diagnosis and Treatment .............................................................................14 1.2.5 Patient Outcomes Post Newborn Screening ................................................19 1.3 Methylmalonic Acidemia ............................................................................................21 1.3.1 Overview ......................................................................................................21 1.3.1.1 Methylmalonyl-CoA Epimerase and Methylmalonyl-CoA Mutase ............................................................................................22 1.3.1.1.1 Methylmalonyl-CoA Epimerase ....................................23 1.3.1.1.2 Methylmalonyl-CoA Mutase .........................................24 1.3.2 Signs and Symptoms ....................................................................................24 1.3.2.1 Renal Complications .....................................................................25 1.3.2.2 Neurological Complications .........................................................26 1.3.2.3 Additional Complications .............................................................27 1.3.3 Biochemical Parameters ...............................................................................28 1.3.4 Diagnosis and Treatment .............................................................................29 iv 1.3.5 Patient Outcomes Post Newborn Screening ................................................31 Chapter 2: Metabolism of Propionate 2.1 Normal Metabolism of Propionate ...............................................................................33 2.2 Metabolism of Propionate and Metabolic Toxicity in Disorders of Propionyl-CoA Metabolism .................................................................................................................34 Chapter 3: Metabolism of Methylmalonate 3.1 Normal Metabolism of Methylmalonate ......................................................................41 3.2 Metabolism of Methylmalonate and Metabolic Toxicity in Disorders of Propionyl- CoA Metabolism .........................................................................................................42 Chapter 4: Metabolism of 3-Hydroxypropionate 4.1 Normal Metabolism of 3-Hydroxypropionate .............................................................44 4.2 Metabolism of 3-Hydroxypropionate and Metabolic Toxicity in Disorders of Propionyl-CoA Metabolism ........................................................................................46 Chapter 5: Hyperammonemia in Disorders of Propionyl-CoA Metabolism 5.1 Ammonia Homeostasis ................................................................................................49 5.2 ATP Utilization in Ureagenesis ..................................................................................51 5.3 Dyregulation of the Urea Cycle in Disorders of Propionyl-CoA Metabolism ...........51 Chapter 6: Metabolism of β-alanine 6.1 Normal Metabolism of β-alanine ................................................................................55 5.2 Metabolism of β-alanine and Metabolic Toxicity in Disorders of Propionyl-CoA Metabolism ........................................................................................57 Chapter 7: Research Plan v 7.1 Overview .....................................................................................................................59 7.2 Metabolism of 3HP and Propionate in Perfused Rat Livers: Summary of Strategy and Methods .......................................................................................................................60 7.2.1 Characterizing the Metabolism of 3HP ........................................................60 7.2.2 Investigating the Metabolism of 3HP and/or Propionate .............................62 7.2.3 Health Relevance .........................................................................................64 7.2.4 Strategy ........................................................................................................64 7.2.4.1 Perfused Liver Experiments ..........................................................65 7.2.4.2 Analytical Procedures ...................................................................65 7.2.4.2.1 Ultraviolet-Visible Absorption Spectroscopy ................66 7.2.4.2.2 Nuclear Magnetic Resonance Spectroscopy ..................66 7.3 Metabolism of β-alanine: Summary of Strategy and Methods ...................................66 7.3.1 Characterizing and Investigating the Metabolism of β-alanine ...................66 7.3.2 Public Health Relevance ..............................................................................67 7.3.3 Strategy ........................................................................................................68 7.3.3.1 Perfused Liver Experiments ..........................................................68 7.3.3.2 In vivo Experiments ......................................................................69 7.3.3.3 Analytical Procedures ...................................................................69 Chapter 8: Publications 8.1 Overview .....................................................................................................................70 8.1.1 Wilson, K.A., Han, Y., Zhang, M., Hess, J., Chapman, K.A., Cline, G.W., Tochtrop, G.P., Brunengraber, H., Zhang, G-F. Interrelations between 3- hydroxypropionate and propionate metabolism in rat liver: Relevance to disorders of propionyl-CoA metabolism. Am. J. Physiol. Endocrinol. Metab. (In Press): 2017. ...........................................................................................71 8.1.2 Wilson, K.A., Bedoyan, J., Zhang, G-F., Venditti, C.P., Brunengraber, H. Maleate, a nephrotoxic plasma biomarker of propionic and methylmalonic acidemias in humans and mice. (To be submitted to Mol Genet Metab.): 2017.............................................................................................................125 8.1.3 Wilson, K.A., Hess, J., Zhang, M., Chapman, K.A., Derave W., Zhang, G-F, vi Brunengraber, H., Tochtrop, G.P. Metabolism of β-alanine in the perfused rat liver and live rats: Stimulation of CoA synthesis and carboxylation to 2- (aminomethyl)-malonate. (To be submitted to Am. J. Physiol. Endocrinol. Metab.): 2017 . ............................................................................................143 Chapter 9: Discussion, Implications, and Future Directions 9.1 CoA Trapping in Disorders of Propionyl-CoA Metabolism .....................................179 9.1.1 Discussion and Conclusions ......................................................................179
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