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Open Keighronfinal.Pdf The Pennsylvania State University The Graduate School Department of Chemistry NANOPARTICLE BIOCONJUGATES AS “BOTTOM-UP” ASSEMBLIES OF ARTIFICAL MULTIENZYME COMPLEXES A Dissertation in Chemistry by Jacqueline D. Keighron 2010 Jacqueline D. Keighron Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2010 The dissertation of Jacqueline D. Keighron was reviewed and approved* by the following: Christine D. Keating Associate Professor of Chemistry Dissertation Advisor Chair of Committee Philip C. Bevilaqua Professor of Chemistry Scott Showalter Assistant Professor of Chemistry Peter J. Butler Associate Professor of Bioengineering Barbara Garrison Shapiro Professor of Chemistry Head of the Department of Chemistry *Signatures are on file in the Graduate School iii ABSTRACT The sequential enzymes of several metabolic pathways have been shown to exist in close proximity with each other in the living cell. Although not proven in all cases, colocalization may have several implications for the rate of metabolite formation. Proximity between the sequential enzymes of a metabolic pathway has been proposed to have several benefits for the overall rate of metabolite formation. These include reduced diffusion distance for intermediates, sequestering of intermediates from competing pathways and the cytoplasm. Restricted diffusion in the vicinity of an enzyme can also cause the pooling of metabolites, which can alter reaction equilibria to control the rate of reaction through inhibition. Associations of metabolic enzymes are difficult to isolate ex vivo due to the weak interactions believed to colocalize sequential enzymes within the cell. Therefore model systems in which the proximity and diffusion of intermediates within the experiment system are controlled are attractive alternatives to explore the effects of colocalization of sequential enzymes. To this end three model systems for multienzyme complexes have been constructed. Direct adsorption enzyme:gold nanoparticle bioconjugates functionalized with malate dehydrogenase (MDH) and citrate synthase (CS) allow for proximity between to the enzymes to be controlled from the nanometer to micron range. Results show that while the enzymes present in the colocalized and non-colocalized systems compared here behaved differently overall the sequential activity of the pathway was improved by (1) decreasing the diffusion distance between active sites, (2) decreasing the diffusion coefficient of the reaction intermediate to prevent escape into the bulk solution, and (3) decreasing the overall amount of bioconjugate in the solution to prevent the pathway from being inhibited by the buildup of metabolite over time. Layer-by-layer (LBL) assemblies of MDH and CS were used to examine the layering effect of sequential enzymes found in multienzyme complexes such as the pyruvate iv dehydrogenase complex (PDC). By controlling the orientation of enzymes in the complex (i.e. how deeply embedded each enzyme is) it was hypothesized that differences in sequential activity would determine an optimal orientation for a multienzyme complex. It was determined during the course of these experiments that the polyelectrolyte (PE) assembly itself served to slow diffusion of intermediates, leading to a buildup of oxaloacetate within the PE layers to form a pool of metabolite that equalized the rate of sequential reaction between the different orientations tested. Hexahistidine tag – Ni(II) nitriliotriacetic acid (NTA) chemistry is an attractive method to control the proximity between sequential enzymes because each enzyme can be bound in a specific orientation, with minimal loss of activity, and the interaction is reversible. Modifying gold nanoparticles or large unilamellar vesicles with this functionality allows for another class of model to be constructed in which proximity between enzymes is dynamic. Some metabolic pathways (such as the de novo purine biosynthetic pathway), have demonstrated dynamic proximity of sequential enzymes in response to specific cellular stimuli. Results indicate that Ni(II)NTA scaffolds immobilize histidine-tagged enzymes non-destructively, with a near 100% reversibility. This model can be used to demonstrate the possible implications of dynamic proximity such as pathway regulation. Insight into the benefits and mechanisms of sequential enzyme colocalization can enhance the general understanding of cellular processes, as well as allow for the development of new and innovative ways to modulate pathway activity. This may provide new designs for treatments of metabolic diseases and cancer, where metabolic pathways are altered. v TABLE OF CONTENTS LIST OF FIGURES ................................................................................................................. viii LIST OF TABLES ................................................................................................................... xiii LIST OF ABBREVIATIONS .................................................................................................. xiv ACKNOWLEDGEMENTS ..................................................................................................... xvi Chapter 1 Introduction ............................................................................................................. 1 Advantages of Colocalization .......................................................................................... 2 Proximity as a Mechanism for Metabolic Control ........................................................... 3 In vitro Enzyme Assemblies ............................................................................................ 4 Fusion Proteins ......................................................................................................... 4 Enzymes Attached to Artifical Scaffolds ................................................................. 5 MDH and CS as a model for Sequential Activity ............................................................ 8 Scaffolds for Artificial Multienzyme Complex Formation .............................................. 9 AuNP Bioconjugates ................................................................................................ 9 LBL Assemblies ........................................................................................................ 10 Ni(II)NTA Scaffolds ................................................................................................ 11 Summary and Objectives ................................................................................................. 11 References ........................................................................................................................ 13 Chapter 2 Enzyme: nanoparticle bioconjugates with two sequential enzymes: Stoichiometry and activity of malate dehydrogenase and citrate synthase on Au nanoparticles .................................................................................................................... 25 Experimental .................................................................................................................... 28 Materials ................................................................................................................... 28 Enzyme Labeling...................................................................................................... 28 Flocculation Assays.................................................................................................. 29 Enzyme Conjugation and Bioconjugate Purification ............................................... 29 Enzyme Activity Assays .......................................................................................... 30 Determination of Enzyme: Nanoparticle Stoichiometry .......................................... 32 Results and Discussion ..................................................................................................... 32 MDH:Au and CS:Au bioconjugates ......................................................................... 33 Dual Activity Bioconjugates .................................................................................... 38 Conclusions ...................................................................................................................... 45 References ........................................................................................................................ 46 Chapter 3 Kinetic Consequences of Restricted Diffusion and Proximity on Sequential Enzyme-Au Bioconjugates............................................................................................... 64 Experimental .................................................................................................................... 66 Materials ................................................................................................................... 66 vi Enzyme Labeling...................................................................................................... 67 Enzyme Conjugation and Bioconjugate Purification ............................................... 67 Viscosity Measurements .......................................................................................... 68 Activity Assays ........................................................................................................ 68 Mathematical Modeling ........................................................................................... 69 Results and Discussion ....................................................................................................
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