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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Vitamin B6 metabolism and regulation of pyridoxal kinase

Gandhi, Amit K., January 1900 (has links)
Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Medicinal Chemistry. Title from title-page of electronic thesis. Bibliography: leaves 77-92.
2

A preformulation study of pyridoxal hydrochloride for solid dosage form desigh and development

Durig, Thomas. 08 1900 (has links)
A Dissertation Submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg for the Degree of Master of Pharmacy. Johannesburg, August 1991 / In this dissertation physicochemical properties of the Bs vitamer, pyridoxal hydrochloride (PL HC1), are investigated with the aim of generating the necessary profile for the rational development of a stable, safe and effective formulation containing this drug. Recent research suggests that administration of PL HC1 may be particularly effective in raising the depleted intracellular pyridoxal phosphate levels found in many asthmatics treated with theophylline. The solubility characteristics of PL HC1 suggest that its absorption and bioavailability should not be problematic / IT2018
3

Kinetic studies of the reaction of pyridoxal and alanine

Fleck, George M. January 1961 (has links)
Thesis (Ph. D.)--University of Wisconsin--Madison, 1961. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographies.
4

Structural and Inhibitory Studies of LL-Diaminopimelate Aminotransferase and Investigation of Methods for Small Peptide Crystallization

Fan, Chenguang Unknown Date
No description available.
5

Importancia do grupo alfa-amino terminal da bradicinina e cininas relacionadas sobre o aumento da permeabilidade capilar

SUGAVARA, SUEMI 09 October 2014 (has links)
Made available in DSpace on 2014-10-09T12:24:58Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:02:22Z (GMT). No. of bitstreams: 1 00049.pdf: 1153051 bytes, checksum: aae78f211763e10ec7bfcd3b38f09df1 (MD5) / Tese (Doutoramento) / IEA/T / Instituto de Quimica, Universidade de Sao Paulo - IQ/USP
6

Importancia do grupo alfa-amino terminal da bradicinina e cininas relacionadas sobre o aumento da permeabilidade capilar

SUGAVARA, SUEMI 09 October 2014 (has links)
Made available in DSpace on 2014-10-09T12:24:58Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:02:22Z (GMT). No. of bitstreams: 1 00049.pdf: 1153051 bytes, checksum: aae78f211763e10ec7bfcd3b38f09df1 (MD5) / Tese (Doutoramento) / IEA/T / Instituto de Quimica, Universidade de Sao Paulo - IQ/USP
7

VITAMIN B6 METABOLISM AND REGULATION OF PYRIDOXAL KINASE

Gandhi, Amit 07 December 2009 (has links)
Pyridoxal 5'-phosphate (PLP) is the cofactor for over 140 vitamin B6 (PLP)-dependent enzymes that are involved in various metabolic and biosynthetic pathways. Pyridoxal kinase (PL kinase) and pyridoxine 5’-phosphate oxidase (PNP oxidase) are the two key enzymes that metabolize nutritional forms of vitamin B6, including pyridoxal (PL), pyridoxine (PN), and pyridoxamine (PM) to the active cofactor form, PLP. Disruption of the PLP metabolic pathway due to mutations in PNP oxidase or PL kinase result in PLP deficiency, which is implicated in several neurological pathologies. Several ingested compounds are also known to result in PLP deficiency with concomitant neurotoxic effects. How these mutations and compounds affect B6 metabolism is not clearly understood. On the other hand, an emerging health problem is the intake of too much vitamin B6 as high doses of the reactive PLP in the cell exhibits toxic effects, including sensory and motor neuropathies. The overall aim of this research is to understand the catalytic function of PL kinase and the regulatory pathway of PLP metabolism. Using site-directed mutagenesis (Asp235Asn, Asp235Ala), kinetic and structural studies, we have shown that Asp235 may play a catalytic role in PL kinase phosphorylation activity. We also show that human PL kinase binds its substrates, PL and MgATP synergistically, and that the enzyme requires Na+ (or K+) and Mg2+ for its activity. Using kinetic study, we show severe induced MgATP substrate inhibition of PL kinase in the presence of its product, PLP, and we postulate this to be due to the formation of a non-productive ternary complex (Enzyme•PLP•MgATP). Consistently, our crystal structure of human PL kinase (2.1 Å) co-crystallized with MgATP and PLP showed both MgATP and PLP trapped at the active site. Our hypothesis is that this abortive ternary complex might be a physiological process, and that PL kinase uses this mechanism to self-regulate its activity. Our inhibition studies show theophylline, a bronchodilator as a mixed competitive inhibitor of human PL kinase with Ki of 71 μM. Our structural study (2.1 Å) shows theophylline bound at the substrate, PL binding site of human PL kinase. We also identified several potential PL kinase inhibitors from the DrugBank Chemical Compound database. Some of these compounds, including enprofylline, theobromine, caffeine, and lamotrigine, which incidentally exhibit similar neurotoxic effects as theophylline, show significant inhibitory effect on human PL kinase. Further studies are also planned to investigate the effect of these drugs on vitamin B6 metabolism in vivo.
8

PLP-Dependent α-Oxoamine Synthases: Phylogenetic Analysis, Structural Plasticity, and Structure-Function Studies on 5-Aminolevulinate Synthase

Turbeville, Tracy D 29 June 2009 (has links)
5-Aminolevulinate synthase (ALAS) and 8-amino-7-oxononanoate synthase (AONS) are two of four homodimeric members of the alpha-oxoamine synthase family of pyridoxal 5'-phosphate (PLP)-dependent enzymes. The evolutionary relationships among α-oxoamine synthases representing a broad taxonomic and phylogenetic spectrum have been examined to help identify residues that may regulate substrate specificity. The structural plasticity of ALAS has been documented in studies of functional circularly permuted ALAS variants and the single polypeptide chain ALAS dimer (ALAS/ALAS) exhibiting a greater turnover number than wild-type ALAS. An examination of the contribution of each ALAS/ALAS active site to the enzymatic activity shows that each active site makes distinct contributions to the steady-state activity of the enzyme. Chimeric ALAS/AONS proteins exhibited an oligomeric structure with two sites having ALAS activity and two sites having AONS activity. Remarkably, the steady-state rates for both the ALAS and AONS activities were lower than that observed in the parent enzymes, while the reactivity of the ALAS sites in ALAS/AONS was similar to that of wild-type ALAS. We propose that the different contribution of each active site to the steady-state activity of ALAS/ALAS and the reduced steady-state activities of the ALAS/AONS chimera, compared to the parent enzymes, relate to different extents of conformational changes associated with product release due to the strain caused with the linking the two ALAS (or ALAS and AONS) subunits. Thus, the extensive plasticity seen in ALAS extends to another member of the α-oxoamine family, AONS. In the α-oxoamine synthase family a conserved histidine hydrogen bonds with the phenolic oxygen of PLP and may be significant for substrate-binding, PLP-positioning, and maintaining the pKa of the imine nitrogen. The replacement of this conserved histidine, H282, with alanine in murine erythroid ALAS has multiple effects on the spectral, binding, and kinetic properties of the enzyme and supports the conclusion that H282 plays multiple roles in the enzymology of ALAS. Altogether, these results imply that amino acid H282 coordinates the movement of the pyridine ring with the reorganization of the active-site hydrogen bond network and acts as a hydrogen bond donor to the phenolic oxygen to maintain the protonated Schiff base and enhance the electron sink function of the PLP cofactor.
9

Structural and functional studies of pyridoxine 5'-phostate synthase from e.coli

Garrido Franco, Marta 28 May 2002 (has links)
El piridoxal 5'-fosfato es la forma biocatalíticamente activa de la vitamina B6, siendo uno de los cofactores más versátiles de la naturaleza, el cuál tiene un papel central en el metabolismo de aminoácidos. Mientras que la mayoria de microorganismos y plantas pueden sintetizar la vitamina B6 de novo, los mamíferos se ven obligados a obtener uno de sus vitámeros a través de la dieta. La maquinaria biosintética de Escherichia coli es, de lejos, la mejor caracterizada y consiste en cuatro proteínas pdx. PdxJ, también conocida como piridoxina 5'-fosfato sintasa, es la enzima clave en esta via. Cataliza el último paso, la complicada reacción de cierre del anillo entre 1-deoxi-D-xilulosa-5-fosfato y aminoacetona-3-fosfato para formar piridoxina 5'-fosfato. La comparación de secuencias de PdxJ entre espécies revela que existe un alto grado de conservación indicando así la enorme importancia fisiológica de esta enzima.Con el uso de un derivado de mercurio fue posible el resolver la estructura cristalina de la enzima de E. coli por el método del "single isomorphous replacement with anomalous scattering" y el refinar la estructura a 2.0 Å de resolución. El monómero corresponde al plegamiento TIM o barril (_/_)8, con la incorporación de tres hélices extra que median los contactos entre intersubunidades en el octámero. El octámero representa el estado fisiológicamente relevante, que fué observado tanto en el cristal como en solución, y que esta organizado como un tetrámero de dímeros activos. La caracterización de la estructura cristalográfica de la enzima con sustratos, análogos de sustrato y productos unidos permitió la identificación del centro activo y la propuesta de un mecanismo detallado. Los rasgos catalíticos más remarcables son: (1) el cierre del centro activo una vez se han unido los sustratos, de manera que el bolsillo de unión queda aislado del solvente y los intermediarios de la reacción quedan así estabilizados; (2) la existencia de dos sitios de unión de fosfato bien definidos; (3) y un canal de agua que penetra el núcleo del barril _ y permite liberar las moléculas de agua formadas durante la reacción.La cantidad de información presentada debería permitir el diseño de inhibidores de la piridoxina 5'-fosfato sintasa basados en su estructura. Es interesante el destacar que entre las bacterias que contienen el gen pdxJ se encuentran unos cuantos patógenos bien conocidos. La resistencia de bacterias contra antibióticos está aumentando cada vez más, hecho que se está convirtiendo en un auténtico problema. Por este motivo, es necesario el desarrollar medicamentos antibacterianos con un alto grado de especificidad y la piridoxina 5'-fosfato sintasa parece ser una diana muy prometedora. / Pyridoxal 5'-phosphate is the biocatalytically active form of vitamin B6, being one of nature's most versatile cofactors that plays a central role in the metabolism of amino acids. Whereas microorganisms and plants can synthetise vitamin B6 de novo, mammals have to obtain one of the B6 vitamers with their diet. The Escherichia coli biosynthetic machinery is the, by far, best characterised and it consists in four pdx proteins. PdxJ, also referred to as pyridoxine 5'-phosphate synthase, is the key enzyme in this pathway. It catalyses the last step, the complicated ring-closure reaction between 1-deoxy-D-xylulose-5-phosphate and aminoacetone-3-phosphate yielding pyridoxine 5'-phosphate. Sequence comparison of PdxJ from different species revealed a remarkable high degree of conservation indicating the paramount physiological importance of this enzyme.With the use of one mercury heavy-atom derivative, it was possible to solve the crystal structure of the E. coli enzyme by the single isomorphous replacement method with anomalous scattering and to refine the structure at 2.0 Å resolution. The monomer folds as a TIM or (_/_)8 barrel, with the incorporation of three extra helices that mediate intersubunits contacts within the octamer. The octamer represents the physiological relevant state that was observed in the crystal and in solution, and that is organised as a tetramer of active dimers. Characterisation of the enzyme crystal structure with bound substrates, substrate analogues, and products allowed the identification of the active site and the proposal of a detailed reaction mechanism. The most important catalytic features are: (1) active site closure upon substrate binding, in order to isolate the specificity pocket from the solvent und thus stabilise the reaction intermediates; (2) the existence of two well-defined phosphate binding sites; (3) and a water channel that penetrates the _ barrel core and allows the release of waters in the closed state.The amount of information here presented should permit the structure-based design of pyridoxine 5'-phosphate synthase inhibitors. Interestingly, among bacteria that contain the pdxJ gene there are several well-known pathogens. More and more, the bacterial resistance against antibiotics is increasing and therefore becoming a real problem. Thus, it is necessary the development of highly specific antibacterial drugs and pyridoxine 5'-phosphate synthase seems to be a promising novel target.
10

Pyridoxal Phosphate as a Tag to Identify Enzymes Within the “PLP-ome”

Messer, Kayla J. 2011 May 1900 (has links)
The main objective of this research was to develop a protocol in which pyridoxal phosphate (PLP) would act as a tag to identify PLP-dependent enzymes from complex mixtures or cell lysates. Following the purification of a PLP-dependent enzyme (CysM), a method was developed to reduce the PLP-lysine Schiff base to form a chemically stable bond between the PLP and the protein. The reduced protein was enzymatically digested resulting in multiple peptide fragments with one or more containing PLP (bound to the active site lysine). These fragments were analyzed by monitoring the absorbance or fluorescence using High Performance Liquid Chromatography. Immobilized Metal Ion Affinity Chromatography (IMAC) was then used to enrich the PLP-peptide(s) from the peptide mixture. The PLP-bound peptide(s) was then analyzed using Liquid Chromatography-Mass Spectrometry (LC-MS). More specifically, sodium borohydride (NaBH4) was used to reduce the Lysine-PLP bond in CysM. This reaction was monitored by either UV-vis spectroscopy or mass spectrometry. Trypsin was used to enzymatically digest the reduced CysM before it was enriched with IMAC and analyzed with LC-MS. Since the objective of this project was to develop a method which could be applied to a cell lysate, IMAC was used as an enrichment method to separate the PLP-peptide(s) from other peptides within the mixture. The PLP-peptide(s) was then located in the peptide mixture by monitoring the absorbance at 325 nm. The LC-MS results of the full reaction before IMAC treatment versus the final column, when monitoring the mass spectrum, showed that the treatment using the IMAC column separated the PLP-peptides from all other peptides within the sample. Using IMAC to enrich specifically the PLP-peptides, followed by analysis with LC-MS, may be a useful method for studying PLP-dependent enzymes within the proteome or the "PLP-ome."

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