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Dissertations / Theses on the topic 'Pyruvate'

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Published: 4 June 2021

Last updated: 14 March 2023

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1

Debebe, Tewodros, Monika Krüger, Klaus Huse, Johannes Kacza, Katja Mühlberg, Brigitte König, and Gerd Birkenmeier. "Ethyl pyruvate." Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-212525.

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The microbiota has a strong influence on health and disease in humans. A causative shift favoring pathobionts is strongly linked to diseases. Therefore, anti-microbial agents selectively targeting potential pathogens as well as their biofilms are urgently demanded. Here we demonstrate the impact of ethyl pyruvate, so far known as ROS scavenger and antiinflammatory agent, on planktonic microbes and biofilms. Ethyl pyruvate combats preferably the growth of pathobionts belonging to bacteria and fungi independent of the genera and prevailing drug resistance. Surprisingly, this anti-microbial agent preserves symbionts like Lactobacillus species. Moreover, ethyl pyruvate prevents the formation of biofilms and promotes matured biofilms dissolution. This potentially new anti-microbial and anti-biofilm agent could have a tremendous positive impact on human, veterinary medicine and technical industry as well.

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2

Blalock, LeeAnn Talarico. "Expression of pyruvate decarboxylase in a Gram positive host Sarcina ventriculi pyruvate decarboxylase versus other known pyruvate decarboxylases /." [Gainesville, Fla.] : University of Florida, 2003. http://purl.fcla.edu/fcla/etd/UFE0002366.

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3

Walker, Dianne. "Bacillus stearothermophilus pyruvate kinase." Thesis, University of Bristol, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335572.

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4

Wexler, Isaiah David. "Disorders of pyruvate metabolism." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1057937741.

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5

Peng, YI. "Pyruvate formate lyase and pyruvate formate lyase activating enzyme spectroscopic characteristics, interaction and mechanism /." Diss., Connect to online resource - MSU authorized users, 2008.

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6

Johnson, Sam. "Insulin regulation of pyruvate dehydrogenase." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390644.

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7

Burthier, Jean Michel. "Les déficits en pyruvate déshydrogénase." Paris 5, 1990. http://www.theses.fr/1990PA05P176.

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8

Cassady, Alan Ian. "Pyruvate carboxylase : a molecular biological study /." Title page, contents and summary only, 1987. http://web4.library.adelaide.edu.au/theses/09PH/09phc343.pdf.

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9

Chen, Yiyuan. "Regulation studies on human pyruvate kinases." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33175.

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Human pyruvate kinase performs the last step in glucose glycolysis in all cells and organisms and can be a key regulator of glycolytic flux. Pyruvate produced by PYK is transported into the mitochondria to fuel the TCA cycle, which enables the production of ATP; the main energy source of the cell. Human PYK contains four isoforms: M1 (found in muscle, heart and brain), M2 (in foetal cells and tumours), L (liver), and R (red blood cells) PYK. M2PYK plays a crucial role in tumour cell proliferation; by down-regulating metabolic flux, upstream metabolites can be used for protein and DNA synthesis. Reprogramming the metabolism of fast proliferating cells is called the 'Warburg effect'. The biological relevance of the different isoform activities is also discussed. For example RPYK in red blood cells is exposed to slowly altering metabolite concentrations, especially after intestinal absorption in plasma and RBCs uptake some of the metabolites. This thesis describes biochemical and biophysical studies of human M1PYK, M2PYK, LPYK, and RPYK. PYK is allosterically regulated by a range of metabolites. A comparative enzyme kinetics study of the four isoforms was performed to examine the mechanisms of activation and inhibition of these small molecule regulators, including all 20 amino acids and the thyroid hormone T3. The redox state of the environment was also found to be an important regulator of PYK activity. All four PYK isoforms were successfully expressed and purified. Interestingly, only M2PYK and RPYK were strongly regulated by amino acids and metabolites. We also found that the redox state regulates the activity of all four PYK isoforms as well as the sensitivity of M2PYK in response to natural regulators. These studies also confirmed the dissociation of tetrameric PYK into inactive monomers as an important mechanism of regulation, particularly for M2PYK activity. Nuclear magnetic resonance (NMR) and Small-angle X-ray scattering (SAXS) studies were performed to investigate the conformational behaviour of PYK isoforms in solution and to compare the effects of ligand binding. NMR data of all four isoforms reveal a conserved binding mechanism between isoforms and specific amino acids. SAXS data of all four isoforms demonstrate that ligands affect tetramerisation of PYK isoforms.

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10

Robinson, Andrew James Cave. "Pyruvate kinase & glycolysis in potato." Thesis, University of Cambridge, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335799.

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11

Hildyard, John Carl Westgarth. "Identification of the mitochondrial pyruvate carrier." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410146.

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12

Burnett, Paul. "Intramitochondrial Ca'2'+ and pyruvate dehydrogenase." Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389169.

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13

Cheung, Wing Yee. "A yeast pyruvate decarboxylase regulatory gene." Thesis, Imperial College London, 1985. http://hdl.handle.net/10044/1/37659.

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14

Naik, Sharon S. "Regulation of the pyruvate dehydrogenase complex." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062509957.

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15

Jitrapakdee, Sarawut. "Characterisation of the pyruvate carboxylase gene and studies on the regulation of its expression in rat /." Title page, contents and summaryn only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phj6117.pdf.

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16

Worku, Netsanet, August Stich, Arwid Daugschies, Iris Wenzel, Randy Kurz, Rene Thieme, Susanne Kurz, and Gerd Birkenmeier. "Ethyl pyruvate emerges as a safe and fast acting agent against Trypanosoma brucei by targeting pyruvate kinase activity." Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-179599.

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Background: Human African Trypanosomiasis (HAT) also called sleeping sickness is an infectious disease in humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100% mortality. Currently available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to similarities in cell metabolism between cancerous tumors and trypanosoma cells, some of the current registered drugs against HAT have also been tested in cancer chemotherapy. Here we demonstrate for the first time that the simple ester, ethyl pyruvate, comprises such properties. Results: The current study covers the efficacy and corresponding target evaluation of ethyl pyruvate on T. brucei cell lines using a combination of biochemical techniques including cell proliferation assays, enzyme kinetics, phasecontrast microscopic video imaging and ex vivo toxicity tests. We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase (Ki = 3.0±0.29 mM). The potential of ethyl pyruvate as a trypanocidal compound is also strengthened by its fast acting property, killing cells within three hours post exposure. This has been demonstrated using video imaging of live cells as well as concentration and time dependency experiments. Most importantly, ethyl pyruvate produces minimal side effects in human red cells and is known to easily cross the blood-brain-barrier. This makes it a promising candidate for effective treatment of the two clinical stages of sleeping sickness. Trypanosome drug-resistance tests indicate irreversible cell death and a low incidence of resistance development under experimental conditions. Conclusion: Our results present ethyl pyruvate as a safe and fast acting trypanocidal compound and show that it inhibits the enzyme pyruvate kinase. Competitive inhibition of this enzyme was found to cause ATP depletion and cell death. Due to its ability to easily cross the bloodbrain- barrier, ethyl pyruvate could be considered as new candidate agent to treat the hemolymphatic as well as neurological stages of sleeping sickness.

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17

Khew-Goodall, Yee Sim. "Pyruvate carboxylase: its interactions with acetyl CoA /." Title page, table of contents and summary only, 1985. http://web4.library.adelaide.edu.au/theses/09PH/09phk454.pdf.

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18

Mistry, Sharad C. "Longer term regulation of pyruvate dehydrogenase kinase." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335116.

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19

Ridout, Cheryl Kathleen. "Splicing mutations in pyruvate dehydrogenase subunit genes." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526109.

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20

Lovell, Simon Christopher. "Structural studies of Bacillus stearothermophilus pyruvate kinase." Thesis, University of Bristol, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337172.

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21

Dunford, Robin. "Pyruvate kinase and glycolytic control in potatoes." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259704.

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22

Mitchell, Rosie. "The regulation of human M2 pyruvate kinase." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/21690.

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Pyruvate kinase catalyses the final step in glycolysis and is responsible for net ATP production. There are four pyruvate kinase isoforms expressed in humans; LPYK, RPYK, M1PYK and M2PYK. The allosteric enzyme M2PYK plays an important role in cancer cell metabolism and is subject to complex regulation by numerous naturally occurring small-molecule metabolites. Post-translational modifications have also been found to play a key role in the regulation of M2PYK, among these cysteine oxidation. This thesis describes the production and characterisation of M2PYK cysteine point mutants in order to investigate the mechanism of regulation by cysteine modification. From a total of ten cysteines present in M2PYK, five were chosen for mutation based on a combination of the results from the cysteine oxidation prediction program (COPP) web interface and published experimental evidence for cysteine modification of M2PYK. Eight point mutants of these five cysteines were produced and characterised. Low resolution gel filtration of all the mutants shows that mutation of these cysteines has an effect on tetramer:dimer:monomer equilibrium of M2PYK suggesting that cysteine modifications could regulate M2PYK activity by affecting oligomeric state. Activity assays show that none of the cysteine point mutations are sufficient to protect M2PYK from oxidation by H2O2 indicating that more than one cysteine is involved in the regulation of M2PYK by oxidation. Nitric oxide (NO) imbalance has recently emerged as playing a key role in numerous diseases including cancer. NO regulates the function of target proteins through the addition of a nitroso moiety from NO-derived metabolites to a reactive cysteine, a process known as protein S-nitrosylation. M2PYK has been found to be S-nitrosylated in vivo. Using the biotin-switch assay in vitro combined with mass spectrometry I have shown that a likely candidate for the target of S-nitrosylation of M2PYK is C326. This thesis also describes the structures of two cysteine point mutants; M2PYK C424A and M2PYK C358S. The structures show that these mutations have very little effect on the overall conformation of M2PYK with only very subtle localised changes. The structure of the mutant M2PYK C358S shows some interesting features including varying occupation of the active site resulting in differing conformations of the B domains within the same tetramer, and an unusual B factor distribution which could be indicative of a perturbation in cooperativity within the tetramer caused by the mutation.

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23

Potter, Simon. "Evaluation of pyruvate kinase as a potential phylogenetic marker : studies on the pyruvate kinase of the archaebacterium Thermoplasma acidophilum." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/20117.

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In this study the glycolytic enzyme pyruvate kinase was chosen as a potential phylogenetic marker. It was considered to be particularly appropriate for two reasons; first, it fulfils the criteria outlined above and secondly, there is a wealth of structural information for the enzyme from various sources available in the sequence databases. The pyruvate kinase chosen for study was that of the the thermoacidophilic archaebacterium, Thermoplasma acidophilum, because whilst there is a great deal of information in the databases on pyruvate kinases isolated from organisms within the eucaryal and bacterial domains, no sequence information previously existed for an archaebacterial equivalent. The aim of this study, therefore, was first to characterise the enzyme to ensure that the constancy of function requirement was fulfilled, and secondly to obtain sufficient primary structure information to facilitate a realistic evaluation of the potential of pyruvate kinase as a phylogenetic marker. The pyruvate kinase was purified to homogeneity using a series of chromatographic steps, and then characterised with respect to its physical and kinetic properties. The enzyme has a native Mr of 250 K, and a subunit Mr of 60 K. It exhibits typical Km values towards its substrates PEP and ADP, and is allosterically regulated by AMP. It is one of the most thermostable pyruvate kinases yet isolated, being active at up to 90^oC. Initial sequencing attempts were frustrated by the chemical blockage of the N-terminus of the enzyme, and hence it was cleaved both chemically and proteolytically into peptide fragments, which were then sequenced by automated Edman degradation. The sequences of these internal peptides were then used in conjunction with a codon usage table derived from the citrate synthase gene of T. acidophilum to design a number of oligonucleotide probes. These probes were then a) fluorescently labelled and hybridised to Southern blots of restriction digests of T. acidophilum genomic DNA, and b) used as primers for the polymerase chain reaction.

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24

Seyda, Agnieszka. "Pyruvate dehydrogenase complex, correlation between structure and function." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ58921.pdf.

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25

Zhong, Wenhe. "Biochemical and structural studies on trypanosomatid pyruvate kinases." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/7725.

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Glycolytic enzymes have been indicated as potential drug targets in trypanosomatid parasites such as Trypanosoma brucei (T. brucei), Trypanosoma cruzi (T. cruzi) and Leishmania spp. Pyruvate kinase (PYK) catalyses the final reaction in the glycolytic pathway to produce ATP and pyruvate from ADP and phosphoenolpyruvate (PEP), and has been validated by RNAi experiments as a suitable drug target in T. brucei. This thesis describes biochemical and structural studies of PYKs from T. cruzi (TcPYK) and T. brucei (TbPYK), providing not only a foundation but also new clues for PYK-specific inhibitor screening and structure-based drug design. Soluble TcPYK and TbPYK (81% sequence identity) have been expressed and purified from E. coli, and their kinetics have been fully characterised. X-ray crystal structures of apoenzyme TcPYK (apo TcPYK), and of TbPYK in complex with fructose 2,6-bisphosphate (F26BP) (TbPYK/F26BP/Mg) have been determined, and each possesses a tetrameric architecture composed of four identical protein chains. Each chain contains four domains which are A-domain, B-domain, C-domain and N-terminal domain. The active site is located in the cleft between the A- and B-domains, while the F26BP-bound effector site is within the C-domain. The conformational transition between inactive T-state and active R-state for both enzymes requires a concerted 8o rigid-body rotation of each of the four AC-cores (Aand C-domains) in the tetramer. During the T- to R-state transition induced by F26BP binding, the side chain of Arg311 is re-orientated to stabilise the short Aα6′ helix at the active site, and the flexible loop at the effector site is stabilised by F26BP. In this active conformation additional salt bridges form across the C-C interface to lock the enzyme in a more stable R-state. TbPYK/F26BP/Mg is the first ‘effector only’ PYK structure and identifies a third Mg2+ binding site (Mg-3) which is distinct from the two canonical Mg2+ binding sites. The substrate PEP was soaked into crystals of TbPYK/F26BP/Mg resulting in an ‘in crystallo’ 23° B-domain rotation forming a partially closed active site. This is accompanied by active site side-chain reorientations, and the movement of Mg2+ from its ‘priming’ position Mg-3 to its canonical position Mg-1. It is plausible that Mg2+ is retained in its ‘priming’ position after product release to act as a co-activator with F26BP to maintain the enzyme in its R-state conformation, as long as F26BP is present. The inherent oxaloacetate decarboxylase activity of PYK was reported over 30 years ago and has been further characterised by 1H NMR studies in this thesis. In addition, a series of TbPYK structures in complex with product (pyruvate), with analogues of the decarboxylase substrate oxaloacetate (D-malate and α-ketoglutarate), or with the competitive inhibitor oxalate have been determined by crystal soaking, and indicate that both decarboxylase activity and kinase activity share a common active site. A proposed mechanism explains the conserved decarboxylase activity of PYK where the active-site Mg2+ and Lys239 in TbPYK (which is conserved between species) play essential roles in the decarboxylation reaction. Three strategies for designing novel inhibitors against trypanosomatid PYKs have been proposed in this thesis. (1) Develop selective modulators to increase the binding affinity of inhibitors. As an example, F16BP has been shown to regulate the inhibitory effect of PEP analogues (oxalate, D-malate, α-ketoglutarate, malonate and L-tartrate) on TbPYK activity. (2) Develop allosteric inhibitors in order to lock trypanosomatid PYKs in an inactive state where the enzyme has low affinity for substrate binding. (3) A third strategy is to combine multiple modulators and inhibitors to increase the inhibition efficiency and selectivity.

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26

Smolle, Michaela. "Molecular architecture of the human pyruvate dehydrogenase complex." Thesis, University of Glasgow, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439249.

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27

Jones, Bethan Sian. "Regulation of pyruvate dehydrogenase complex by reversible phosphorylation." Thesis, University of Newcastle Upon Tyne, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315644.

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28

Mullick, Abdul. "Engineering the cooperativity of Bacillus stearothermophilus pyruvate kinase." Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388329.

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29

Scotney, Pierre David. "The catalytic mechanism of Bacillus stearothermophilus pyruvate kinase." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266959.

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30

Williams, K. P. "Studies on pyruvate : ferredoxin oxidoreductase from Trichomonas vaginalis." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234978.

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In the anaerobic protozoon Trichomonas vaginalis, the oxidative decarboxylation of pyruvate is catalysed in a CoA-dependent reaction by pyruvate: ferredoxin oxidoreductase (PFOR). This enzyme has been identified as a potential target for the development of a relatively non-toxic anti-trichomonal agent. 1. T. vaginalis PFOR was localised in the hydrogenosomal membrane fraction, and could be solubilised by buffer of high ionic strength. A high salt concentration was required to prevent aggregation of PFOR. These results suggested that PFOR was either an extrinsic protein bound to the hydrogenosomal membrane or that the enzyme exists in vivo in the hydrogenosomal matrix in an aggregated state. PFOR was solubilised and purified to homogeneity, the most _ffective step being salting-out chromatography on Sepharose 4B. Low recoveries of active enzyme were caused by inactivation by oxygen and the irreversible loss of thiamin pyrophosphate (TPP). 2. PFOR is a dimeric enzyme of overall M_r240000. The enzyme contains 0.5 mol of TPP per mol of dimer, and equivalent amounts of non-haem iron and acid-labile sulphur, consistent with the presence of two [4Fe-4S] centres per enzyme molecule. Flavin nucleotides and lipoic acid are absent. PFOR from T. vaginalis is therefore broadly similar to the 2-oxo acid:ferredoxin (flavodoxin) oxidoreductases purified from bacterial sources, and clearly different from the 2-oxo acid dehydrogenase multienzyme complexes which occur in aerobic organisms. 3. A steady-state kinetic analysis of purified PFOR demonstrated that the enzyme obeyed Bi Bi Ping Pong kinetics except at very high CoA concentrations, where substrate inhibition occurred. The inhibition produced by the product of acetyl-CoA, in the presence of saturating CoA, was competitive with respect to pyruvate. In the absence of CoA, stoichiometric amounts of pyruvate were decarboxylated by PFOR. These results suggest that decarboxylation, formation of the stable imtermediate and its reaction with CoA to form acetyl-CoA all take place at one active site. 4. Spectroscopic investigations using electron paramagnetic resonance indicated that the stable intermediate formed after pyruvate decarboxylation was a free-radical species. This substrate-based radical is proposed to arise by the transfer of a single electron from the initial decarboxylation product to a [4Fe-4S] centre. The free-radical signal was greatly diminished if the enzyme was subsequently incubated with CoA, suggesting that it represents a real catalytic intermediate. 5. T. vaginalis PFOR was inactivated by incubation with pyruvate alone, a reaction the enzyme has in common with the E. coli pyruvate dehydrogenase (PDH) complex and yeast pyruvate decarboxylase, suggesting similarities between these enzymes at least in the initial formation of the decarboxylated intermediate, presumed to be the enamine of hydroxyethyl-TPP. The conjugated 2-oxo acid, (E)-4-(-chorophenyl)-2-oxo-3-butenoic acid, was an irreversible inhibitor of T. vaginalis PFOR and yeast pyruvate decarboxylase, a result taken to reflect the initial formation of an enamine intermediate in each case. 6. 3-hydroxypyruvate was a potent irreversible inhibitor of T. vaginalis PFOR. The observation that 3-hydroxypyruvate was also an alternative substrate for pyruvate in the overall reaction suggested that it might be acting as a mechanism-based inactivator. 3-hydroxypyruvate was ineffective against E. coli PDH complex suggesting an interesting difference in active site geometry that might be exploited for potential drug design.

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31

Al-Amodi, Hiba Saeed Ahmed Bagader. "Immunological and biosynthetic studies of the human pyruvate dehydrogenase complex." Connect to e-thesis, 2007. http://theses.gla.ac.uk/139/.

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Thesis (Ph.D.) - University of Glasgow, 2007.
Ph.D. thesis submitted to the Division of Biochemistry & Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, 2007. Includes bibliographical references. Print version also available.

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32

Brown, Audrey Elaine. "Constructing a recombinant model of the human pyruvate dehydrogenase complex." Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248119.

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33

Bowker-Kinley, Melissa M. "Pyruvate dehydrogenase kinase Kinetics, site-directed mutagenesis, and regulation /." [Bloomington, Ind.] : Indiana University, 2005. http://wwwlib.umi.com/dissertations/fullcit/3183930.

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Thesis (Ph.D.)--Indiana University, 2005.
Source: Dissertation Abstracts International, Volume: 66-07, Section: B, page: 3690. Chair: Robert A. Harris. Title from dissertation home page (viewed Oct. 5, 2006).

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34

Yazdanpanah, Mehrdad. "Pyruvate improves myocardial functional recovery after ischemia and reperfusion." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0028/MQ34078.pdf.

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35

Han, Hongmei. "Molecular characterization of pyruvate ferredoxin oxidoreductase from Helicobacter pylori." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ36459.pdf.

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36

Hu, Liangyan. "Characterization of human pyruvate dehydrogenase kinase isoform 2 (PDHK2." Diss., Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/856.

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37

Gao, Xueliang. "Nuclear Pyruvate Kinase M2 Functional Study in Cancer Cells." Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/biology_diss/89.

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Cancer cells take more glucose to provide energy and phosphoryl intermediates for cancer progression. Meanwhile, energy-provider function of mitochondria in cancer cells is disrupted. This phenomenon is so-called Warburg effect, which is discovered over eighty years ago. The detail mechanisms for Warburg effect are not well defined. How glycolytic enzymes contribute to cancer progression is not well known. PKM2 is a glycolytic enzyme dominantly localized in the cytosol, catalyzing the production of ATP from PEP. In this study, we discovered that there were more nuclear PKM2 expressed in highly proliferative cancer cells. The nuclear PKM2 levels are correlated with cell proliferation rates. According to our microarry analyses, MEK5 gene was upregulated in PKM2 overexpression cells. Our studies showed that PKM2 regulated MEK5 gene transcription to promote cell proliferation. Moreover, nuclear PKM2 phosphorylated Stat3 at Y705 site using PEP as a phosphoryl group donor to regulate MEK5 gene transcription. Our study also showed that double phosphorylated p68 RNA helicase at Y593/595 interacted with PKM2 at its FBP binding site. Under the stimulation of growth factors, p68 interacted with PKM2 to promote the conversion from tetrameraic to dimeric form so as to regulate its protein kinase activity. Overexpression PKM2 in less aggressive cancer cells induced the formation of multinuclei by regulating Cdc14A gene transcription. Overall, this study presents a step forward in understanding the Warburg effect.

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38

Pulido-Cejudo, Gabriel. "Chemical and biological properties of iron-pyruvate-transferrin complexes." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74529.

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The preparation of a novel complex, ferric bromopyruvate, is described. In solutions from which most of the carbonate has been removed, ferric bromopyruvate can be used both as an iron and pyruvate source for the full iron saturation of apotransferrin. Using ferric bromopyruvate as an iron donor, iron incorporation into human apotransferrin is biphasic; the N-terminal domain is saturated three times faster than its homologous C-terminal iron binding site. Following the reaction of apotransferrin with ferric bromopyruvate, 4 moles of pyruvate per mole of transferrin are covalently bound. Based on the effect of acetylation on pyruvate and iron binding, it is suggested that lysyl residues could be the target of pyruvate bonding. However, the reaction of pyruvate with other positively charged amino acid residues cannot be excluded. The possible sites of pyruvate binding within the N-terminal domain of human serum transferrin are discussed. Covalent attachment of pyruvate to cationic amino acid residues decreased both in vitro and in vivo iron release, preferentially from the N-terminal domain of transferrin. The decreased rate of iron incorporation from iron-pyruvate-transferrin complexes by rabbit reticulocytes caused a lower iron incorporation into heme. It is suggested that an impairment of iron release from transferrin may decrease the rate of heme synthesis in reticulocytes. In vitro studies on the iron removal from iron-pyruvate-transferrin complexes showed that pyrophosphate can remove iron from this complex at an acid pH to a similar extent to the cellular mediated iron release from this complex. Based on this data, a model for the intravesicular iron release from transferrin is proposed.

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39

Denyer, G. "Regulation of hepatic pyruvate dehydrogenase complex by reversible phosphorylation." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233529.

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40

Day, S. E. "Detection of tumour treatment response using hyperpolarized 13C pyruvate." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598434.

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The exchange reaction between hyperpolarized 1-¹³C pyruvate and lactate, catalysed by the enzyme lactate dehydrogenase (LDH), can now be measured in real-time with ¹³C nuclear magnetic resonance spectroscopy and imaged in tissues using ¹³C MRI. EL-4 murine lymphoma cells catalyse this pyruvate-lactate exchange in a substrate-dependent fashion, and we demonstrate that the reaction is inhibited following treatment with chemotherapeutic drugs both in vitro and in vivo. The LDH reaction specifically labels the intratumoural lactate pool present within solid EL-4 murine lymphoma tumours, and this exchange was reduced following treatment with the chemotherapeutic drug etoposide. This novel metabolic imaging technique can be predictive of therapeutic success. The C6 intracranial rat glioma faithfully reproduces many morphological aspects of the human disease, and can be used as a model for the study of human brain tumours. When hyperpolarized pyruvate was administered to C6 glioma bearing rats, there was specific labelling of intratumoural lactate, and little to no polarized substrate in the normal brain. Following radiation therapy of these glioma bearing rats, the exchange of label between pyruvate and lactate was reduced as measured using chemical-shift imaging and was predictive of therapeutic success. Taken together, these results demonstrate the potential for hyperpolarized ¹³C pyruvate imaging to detect treatment response in vivo in different models of cancer. This work details initial studies into what might be a potentially valuable metabolic imaging tool. Hopefully this tool may one day be used by clinicians to improve the management of human cancer patients.

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41

Abayomi, Louise Anike. "Disposable pyruvate biosensors for routine assessment of onion flavour." Thesis, Cranfield University, 2007. http://dspace.lib.cranfield.ac.uk/handle/1826/5663.

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The UK-grown onion sector shows strong potential for growth through new product development as consumers become increasingly aware of the health and dietary benefits of fresh onion consumption. Prospects for the production of new, more palatable sweet onions will be boosted by the development of improved grower diagnostics for flavour standardisation. Growers require simple-to-use on-farm diagnostics to assure flavour quality. The introduction of pungency tests has led to increased mild onion sales, however currently tests are out-sourced and as a result costly. Through this Defra- (Department for Agriculture Food and Rural Affairs) sponsored research project (HL0164), hand-held biosensor technology, adapted from the medical sector, has been developed for improved and lower cost pungency and sweetness analysis in onions. Cont/d.

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Stewart, Melanie Ann. "Fatty acids and the regulation of pyruvate dehydrogenase interconversion." Thesis, University of Oxford, 1997. http://ora.ox.ac.uk/objects/uuid:d05910c0-f7a1-4363-ac2c-a9a1eb857964.

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This thesis presents evidence for a novel mechanism of regulation of pyruvate dehydrogenase (PDH) kinase by fatty acids and also results of a study of muscle triacylglycerol concentration. In animals regulation of PDH complex activity is central to the selection of respiratory fuels and to the conservation of glucose during carbohydrate deprivation. The principal means of regulation of PDH complex is interconversion of phosphorylated (inactive) and dephosphorylated (active) forms effected by PDH kinase and PDH phosphatase. Earlier in vitro studies by others had identified both shorter term (min) and longer term (hours) mechanisms of activation of PDH kinase by fatty acid. In the present study PDH kinase activity (as measured by rates of ATP-dependent inactivation of PDH complex in extracts) was shown to be increased when rat heart mitochondria were incubated with palmitoyl-L-carnitine [PC] (and other CoA utilising respiratory substrates). The activation of PDH kinase persisted through removal of respiratory substrate following incubation with CCCP. A comparable effect of PC was also demonstrable in heart mitochondria from 48h-starved rats (i.e. the mechanism may be distinct from that which increases PDH kinase activity in starvation). Rates of ATP-dependent inactivation of PDH complex were also increased when extracts of rat heart mitochondria were incubated with palmitoyl-CoA (PCoA); the increase was comparable with that seen on incubation of intact mitochondria with PC. The PC effect in intact mitochondria and the PCoA effect in mitochondrial extracts may not be identical as PCoA further increased PDH kinase activity in extracts from mitochondria incubated with PC. Rates of incorporation of ³²P from [γ-³²

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Ward, Jason David. "Targeting, assembly and regulation of the pyruvate dehydrogenase complex." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264108.

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Dave, Emma. "The physiology of the Escherichia coli pyruvate dehydrogenase complex." Thesis, University of Sheffield, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364242.

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Canas, Ana. "Acetoin production from pyruvate in Leuconostoc mesenteroides NCDO 518." Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319244.

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Poole, Robert C. "Transport of lactate and pyruvate across mammalian plasma membranes." Thesis, University of Bristol, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.330043.

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47

Allen, Mark Devin. "Interaction of protein domains in pyruvate dehdrogenase multienzyme complex." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242899.

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48

Tulloch, Lindsay B. "Pyruvate kinase from Leishmania mexicana as a chemotherapeutic target." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/14592.

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The neglected diseases of African sleeping sickness, Chagas’ disease, and leishmaniasis are caused by the protozoan trypanosomatid parasites Trypanosoma and Leishmania, and are major world-wide causes of disease and death. There is a compelling need for the development of new drug treatments because existing treatments are inadequate due to high levels of toxicity and growing drug resistance within the parasites. Glycolysis is an attractive target because many of the trypanosomatid glycolytic enzymes are sequestered within the glycosome, giving them unique regulatory properties. Trypanosomatid pyruvate kinase (PYK) is particularly attractive because, although a cytosolic enzyme, is allosterically regulated by fructose-2,6-bisphosphate whilst the allosteric PYK in mammalians is regulated by fructose-1,6-bisphosophate. X-ray crystallography has been used in this study to solve three structures of pyruvate kinase from Leishmania mexicana in order to determine the mechanism of allosteric activation of PYK. Knowledge of the conformational changes that PYK undergoes during enzyme activation showed that the best place for the design of inhibitors of PYK from L. mexicana is the effector site and the surrounding area. This study has used a structure-based approach to drug design, encompassing virtual screening and combinatorial chemistry to identify novel inhibitors of PYK from L. mexicana. The most potent inhibitor of PYK from L. mexicana was MN92, synthesised through combinatorial chemistry, which had an IC₅₀ of 71μM and a K_iPEP of 45μM. This compound is believed to bind to the PYK effector site and is suitable for further studies of ligand optimisation.

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McNally, Teresa. "Studies on the allosteric control of yeast pyruvate kinase." Thesis, University of Edinburgh, 1991. http://hdl.handle.net/1842/19133.

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Pyruvate kinase [EC.2.7.1.40.] is ubiquitous and catalyses the second of the ATP forming reactions of glycolysis, namely the interconversion of phosphoenolpyruvate to pyruvate with concomitant phosphotransfer to ADP to form ATP. The enzyme requires one monovalent and two divalent cations for full activity, one of which is enzyme bound and the others being abstracted to the nucleotide. The enzyme is considered to be the control point for the lower part of the glycolytic pathway. Pyruvate kinases can be allosterically regulated by a number of effectors which bind to the enzyme at sites distinct from the substrate binding site and modify the enzyme activity. It was the purpose of this project to attempt to determine the nature of this form of regulation using site directed mutagenesis to alter residues to be involved in mediating the allosteric effect. In this project the pyruvate kinase from the yeast Saccharomyces cerevisiae is used as the model for an allosterically regulated pyruvate kinase. This yeast has only one gene encoding a pyruvate kinase (pyk1) which is subject to allosteric control. This gene had been cloned and sequenced prior to the outset of this project, however the sequence was seen to contain a number of errors which led me to repeat this process. The approach adopted in this project was to overexpress pyruvate kinase on a multicopy yeast shuttle vector, this facilitated its subsequent purification. It is hoped that this approach will facilitate the production of very large amounts of protein which can be used for x-ray crystallography and other physico-chemical techniques which require large amounts of protein.

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Seyran, Sevde Berfin. "Metabolic functions of the multifunctional protein E4F1 in skin homeostasis." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT024/document.

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L’étude des réseaux protéiques perturbés au cours de l’infection par les petits virus oncogéniques amena, vers la fin des années 80, à la découverte de nombreux régulateurs clés de la division et de la survie cellulaire. Parmi ceux-ci, la protéine E4F1 fût initialement identifiée comme une cible de l’oncoprotéine virale E1A. Originellement identifié comme un facteur de transcription, E4F1 est également une ubiquitine-E3 ligase atypique pour d'autres facteurs de transcription tel que le suppresseur de tumeurs p53. Au travers de ses multiples activités, E4F1 est nécessaire à la prolifération des cellules somatiques et souches, et à la survie des cellules cancéreuses. De plus, les travaux de différents laboratoires dont le mien suggèrent qu’E4F1 se situe au carrefour de plusieurs voies de signalisation qui sont fréquemment altérées au cours de l’oncogenèse, et notamment la voie impliquant le suppresseur de tumeurs p53. Afin d’étudier les fonctions physiologiques in vivo d’E4f1, mon laboratoire d’accueil a développé plusieurs modèles de souris génétiquement modifiées. La caractérisation de ces modèles a permis de mettre en évidence un rôle majeur d'E4F1 dans l'homéostasie de la peau. Plus précisément, E4F1 régule le pool de cellules souches de l'épiderme au travers de son rôle dans une voie de signalisation qui implique la protéine p53 et deux de ces régulateurs en amont: Arf et Bmi1. Cependant, il semble que les effets d'E4F1 dans le contrôle du maintien des cellules souches s'étendent au delà de son rôle sur cette voie de signalisation. En effet, j'ai récemment pu démontrer qu'E4F1, au travers de ces fonctions transcriptionnelles, régule directement l'expression d'un sous-groupe de gènes impliqués dans la régulation de l'activité de la pyruvate déshydrogénase (PDH). La PDH est un complexe multimérique situé dans la mitochondrie qui catalyse la décarboxylation du pyruvate (le produit final de la glycolyse) en acétyl coenzyme A (AcCoA), liant ainsi le métabolisme du pyruvate au cycle de Krebs. J’ai pu montrer que l’inactivation d’E4f1 spécifiquement dans l'épiderme conduisait à une diminution importante de l’activité de PDH et à une reprogrammation métabolique de ces cellules. Cette reprogrammation a pour conséquence d'altérer le micro-environnement des cellules souches qui conduit à leur détachement de leur niche et aboutit in fine à une absence du renouvellement de l'épiderme. Cette partie de mes travaux a donc permis d'illustrer pour la première fois l'importance du métabolisme du pyruvate dans l'homéostasie des cellules souches de la peau. Sur la base de ces résultats, je poursuis l'analyse des fonctions d’E4f1 dans l'homéostasie de la peau en étudiant son rôle dans d'autres types cellulaires tels que les mélanocytes
The multifunctional protein E4F1 is an essential regulator of normal skin homeostasis. During my Phd, I demonstrated that E4f1 inactivation in adult skin results in stem cell autonomous defects causing exhaustion of the epidermal stem cell (ESC) pool. At the molecular level, I identified E4F1 as a new regulator of the pyruvate dehydrogenase complex (PDC) in keratinocytes, an essential mitochondrial complex that converts pyruvate into Acetyl-CoEnzyme A. Using genetically engineered mouse models, I showed that E4F1-mediated control of PDH activity is required to maintain normal skin homeostasis. Consistently, E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetlytransferase (Dlat), a gene encoding the E2 subunit of the PDC, and impaired PDH activity. The metabolic reprogramming of E4f1 KO keratinocytes associated with the redirection of the glycolytic flux towards lactate production and increased lactate secretion in their microenvironment, leading to enhanced activity of extra-cellular-matrix remodelling proteases Finally, these defects ended in alterations of the basement membrane, ESC mislocalization and the exhaustion of the ESC pool. In the second part of my thesis, I have evaluated the role of E4F1-mediated control of the PDC in melanocytes and showed that the metabolic activities of E4F1 are important for melanocyte function. Consistently, mice with E4f1-deficient melanocytes exhibited hair graying and skin pigmentation defects. Altogether, my data demonstrate the importance of E4f1-mediated control of pyruvate metabolism for normal skin homeostasis

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