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Mechanistic Studies of Some Chemical and Biochemical Reactions University of Huddersfield Repository Mistry, Dharmit Mechanistic studies of some chemical and biochemical reactions Original Citation Mistry, Dharmit (2014) Mechanistic studies of some chemical and biochemical reactions. Doctoral thesis, University of Huddersfield. This version is available at http://eprints.hud.ac.uk/id/eprint/23444/ The University Repository is a digital collection of the research output of the University, available on Open Access. Copyright and Moral Rights for the items on this site are retained by the individual author and/or other copyright owners. Users may access full items free of charge; copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational or not-for-profit purposes without prior permission or charge, provided: • The authors, title and full bibliographic details is credited in any copy; • A hyperlink and/or URL is included for the original metadata page; and • The content is not changed in any way. For more information, including our policy and submission procedure, please contact the Repository Team at: [email protected]. http://eprints.hud.ac.uk/ MECHANISTIC STUDIES OF SOME CHEMICAL AND BIOCHEMICAL REACTIONS DHARMIT MISTRY A thesis submitted to the University of Huddersfield in partial fulfilment of the requirements for the degree of Doctor of Philosophy The University of Huddersfield Submission date: February 2014 Abstract Three aspects of chemical and biochemical reactions were investigated. 1. The relative reactivities of pyrophosphate (phosphorus(V)) and pyro-di-H- phosphonate (phosphorus(III)) and its derivatives have been analysed at various pHs. The hydrolysis rate of pyro-di-H-phosphonate (PP(III)) was found to be higher than pyrophosphate at all pHs. Using ITC and NMR, pyrophosphate showed metal-ion complexing abilities whereas pyro-di-H-phosphonate showed weak or no complexing to metal-ions, although the rate of hydrolysis at pH 7 slightly increased compared to the spontaneous hydrolysis of PP(III). The enzymatic hydrolysis of pyrophosphate, which is thought to occur via MgPP(V)2-, occurs efficiently and is close to being diffusion controlled. Pyro-di-H-phosphonate on the other hand does not act as a substrate or as an inhibitor of pyrophosphatase. 2. Dichloromethane (DCM) is an alkylating agent for pyridine, producing methylene bis-pyridinium dication (MDP) upon refluxing the solution. The kinetics and mechanism of hydrolysis of methylene bis-pyridinium dication have been studied. Below pH 7 MDP is extremely stable and hydrolysis is first-order in hydroxide-ion. Above pH 9 an unusual intermediate is formed on hydrolysis which has a chromophore at 366 nm in water and its formation is second-order in hydroxide-ion. The carbon acidity of the central methylene group was also investigated kinetically using H/D exchange and the pKa was surprisingly high at 21.2 at 25oC (I = 1.0 M). 3. Isothermal titration calorimetry (ITC) is a technique mainly used by biochemists to obtain a range of physical and thermodynamic properties of a reaction. Analysing the data can become difficult when investigating complex reactions involving more than one step, for instance metal-ions binding to an enzyme. In this work models have been developed to simulate sequential reactions. These were used to simulate experimental ITC data for metal- ions: Zn2+, Co2+ and Cd2+ complexing to the active sites of BcII, a metallo β-lactamase responsible for antibiotic resistance, providing additional information on the mechanism by which this enzyme acts to deactivate β-lactam antibiotics. The simulations suggest that BcII has two very similar binding affinities to metal-ions which are filled sequentially. i Acknowledgements First and foremost I would like to thank my supervisors, Professor Michael I Page and Professor David R Brown. It has been an honour to be your student and I appreciate the time and effort you have taken to supervise and encourage me through this research, it has been of enormous value. I thank Innovative Physical Organic Solutions (IPOS), for providing the funding for this research and having available top of the range analytical equipment. All the members of IPOS have contributed to my personal and professional time as part of the group. I am especially grateful for the experimental and theoretical help given by Dr Nicholas T Powles and Dr Matthew J Stirling. I also thank the members of the research group especially Professor John H Atherton, Dr Haifeng Sun, Victoria L Sutcliffe and Joseph M Griffin for their useful conversations. To the members of my research office, past and present, they know who they are. Thank you for always being there, you have made this truly unforgettable. I thank Professor Robert A Cryan (VC) for taking the time and effort out of his busy schedule to help with the mathematics and solutions to the isothermal titration calorimetry modelling equations. I would also like to thank Professor Christian Damblon (university of Liege, Belgium) for providing the plasmid containing the gene for the β-lactamase strain we used in this work. I also thank Dr Neil McLay for his work and help with the NMR. ii Table of contents Abstract ...................................................................................................................................... i Acknowledgements ...................................................................................................................ii Table of contents .................................................................................................................... iii Abbreviations ........................................................................................................................ viii Chapter 1 – PHOSPHATES AND H-PHOSPHONATES .................... 1 1 Introduction ...................................................................................................... 1 1.1 Background .................................................................................................... 2 1.1.1 Phosphate esters within DNA ........................................................................ 2 1.1.2 Phosphorylating agents .................................................................................. 3 1.1.3 H-phosphonates.............................................................................................. 6 1.1.4 P-H Exchange ................................................................................................ 7 1.1.5 pKa of phosphorus acids ............................................................................... 10 1.1.6 Mechanism of hydrolysis of phosphate esters ............................................. 12 1.1.6.1 Associative mechanism ................................................................................ 12 1.1.6.2 Dissociative mechanism ............................................................................... 13 1.1.6.3 Concerted mechanism .................................................................................. 13 1.1.7 The mechanisms of hydrolysis and reactivity of phosphate esters .............. 14 1.1.7.1 Mono-ester Hydrolysis ................................................................................. 14 1.1.7.2 Di-ester hydrolysis ....................................................................................... 18 1.1.8 Hydrolysis of the P-O-P bond ...................................................................... 20 1.1.9 Metal coordinated hydrolysis ....................................................................... 22 1.1.10 Enzymatic Hydrolysis of phosphate esters .................................................. 25 1.1.10.1 Non-specific phosphatase – Alkaline phosphatase....................................... 26 1.1.10.2 Alkaline pyrophosphatase ............................................................................ 27 1.1.10.3 Acid phosphatases ........................................................................................ 29 1.1.10.4 Phosphoprotein phosphatases ....................................................................... 30 1.1.10.5 Substrate specific/similar phosphatases ....................................................... 31 iii 1.1.11 Heats of hydrolysis of phosphates ............................................................... 32 1.1.12 Aim .............................................................................................................. 34 1.2 Experimental ................................................................................................ 35 1.2.1 Materials ...................................................................................................... 35 1.2.2 Kinetics/pKa ................................................................................................. 35 1.2.2.1 Enzyme kinetics ........................................................................................... 37 1.2.3 Metal-ion complexing .................................................................................. 37 1.2.4 Heats of hydrolysis ...................................................................................... 38 1.3 Results and discussion ................................................................................. 40 1.3.1 Pyro-di-H-phosphonate identification.......................................................... 40 1.3.2 pKa of pyro-di-H-phosphonate (III) and ethyl-H-phosphonate .................... 42 1.3.3 pH-rate
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