Download or read book Modulation of Functional Properties of Bifunctional S adenosylmethionine Decarboxylase ornithine Decarboxylase of Plamodium Falciparum by Structural Motifs in Parasite specific Inserts written by Suretha Roux and published by . This book was released on 2006 with total page 178 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Modulation of Functional Properties of Bi functional S Adenosylmethionine Decarboxylase written by Suretha Roux and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is a global health threat that causes 300 500 million clinical cases annually, resulting in approximately 2 million deaths. Chemotherapy and prophylaxis are becoming less effective because of increasing drug resistance by the parasite. Resurgence of malaria calls for the development of mechanistically novel drugs. The bifunctional organization of the two rate-limiting enzymes, AdoMetDC and ODC, in the P. Falciparum polyamine pathway and the presence of six parasite-specific inserts, present potential target sites for novel Plasmodia-specific drugs. The inserts are species-specific, hydrophilic, low complexity segments and form non-globular domains. The inserts are involved in intra- and interdomain interactions, which are important for stability and activity of the bifunctional construct. This study investigated properties of the parasite-specific inserts, one being the mobility of the O1 insert and the other the secondary structures present in the parasitespecific inserts. It is postulated that the mobility of the O1 insert plays a role in either heterotetrameric complex formation of the bifunctional construct or that the O1 insert acts as a lid to the ODC active site, which is necessary for catalytic function. Successful mutagenesis of the O1 flanking Gly residues to Ala, rendered the O1 insert immobile. The probable immobility of the O1 insert had a detrimental effect on the activity of both the AdoMetDC and ODC domains of the bifunctional protein. Molecular dynamics studies showed that movement restriction of the insert caused a conformational change in the ODC monomers. The decrease of both domain activities upon movement restriction of the O1 insert suggests that the insert is involved in protein-protein interactions, which is communicated throughout the protein. In addition, the roles of selected, predicted secondary structures in the Hinge, O1 and O2 parasite-specific inserts were investigated.? -Helices were disrupted by the introduction of a Pro residue,? -plates were removed with deletion mutagenesis. The effects of the secondary structure alterations on protein activity were monitored in the bifunctional PfAdoMetDC/ODC protein. Both domain activities were affected by the disruptions, although the ODC domain was more sensitive to the small changes. The results obtained in this study showed that the secondary structures in the parasite-specific insert are important for activity of both the AdoMetDC and ODC domains of the bifunctional protein, possibly via interdomain protein-protein interactions. The delineation of essential intra- and interdomain protein-protein interactions presents possible interaction sites for disruptive molecules in the combat against malaria. Copyright.

Download or read book Delineation of Functional Roles of Parasite specific Inserts in the Malarial S adenosylmethionine Decarboxylase written by Marni Williams and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The polyamines putrescine, spermidine and spermine play essential roles in the proliferation and differentiation of most eukaryotic cells. Inhibition of the polyamine pathway is known to have antitumour and antiparasitic effects and? -difluoromethylornithine (DFMO), a polyamine biosynthesis inhibitor, is clinically used in the treatment of African sleeping sickness caused by Trypanosoma brucei gambiense. Ornithine decarboxylase (ODC) and Sadenosylmethionine decarboxylase (AdoMetDC) are the rate-limiting enzymes in polyamine metabolism. Usually, these enzymes are individually regulated, however, in the malaria parasite, Plasmodium falciparum, these enzymes are part of a unique bifunctional PfAdoMetDC/ODC protein. In addition, compared to homologous proteins, this malarial protein contains six unique parasite-specific inserted regions, which can be targeted with novel drugs. A modified restriction enzyme-mediated inverse PCR method was developed to delete the largest parasite-specific insert (411 bp) from the large PfAdoMetDC/ODC gene (4257 bp). The method was compared to existing deletion mutagenesis PCR protocols and was shown to be the most effective method (80% mutagenesis efficiency) as opposed to the 40% positively mutated clones obtained with the overlapping primer method in deleting a>100 bp region. The independent removal of all three the PfAdoMetDC domain parasite-specific inserts and subsequent activity analysis thereof showed that these inserts are essential for the catalytic activities of both the decarboxylase domains. Plasmodia conserved secondary structures within these inserts were identified and were also shown to be very important for domain activities, possibly through protein-protein interactions across and within the domains of the bifunctional complex for the efficient regulation of intracellular polyamine levels. The N-terminally located O1 insert in the PfODC domain is a highly conserved and structurally distinct insert, which is essential for both domain activities. Previous studies showed that the deletion of this insert prevents dimerisation of the PfODC monomers and as a result influences association of PfODC with the PfAdoMetDC domain to form the bifunctional 3̃30 kDa complex. In addition, immobilisation of the insert via the mutagenesis of flanking Gly residues and the disruption of a single conserved ; -helix within the insert severely affected both PfODC and PfAdoMetDC activities. It was thus hypothesised that the helix is involved in protein-protein interactions and the dimerisation of the PfODC domain. Size-exclusion chromatography of the monofunctional PfODC and bifunctional PfAdoMetDC/ODC proteins with disrupted helices resulted in the elution of only the monomeric (8̃5 kDa) and heterodimeric PfAdoMetDC/ODC (1̃60 kDa) proteins, respectively. The mono- and bifunctional wild type and immobile proteins eluted as both dimeric PfODC (1̃70 kDa) and heterotetrameric (3̃30 kDa) fractions as a result of intact protein-protein interactions. These results were subsequently exploited in the design and application of a parasite-specific, mechanistically novel, inhibitory peptide specific for this non-homologous insert in the bifunctional protein. A 1000x molar excess of a synthetic peptide, complementary to the ; -helix within the O1 insert but opposite in charge, resulted in a 4̃0% inhibition of the PfODC enzyme. This study thus provides a proof-of-principle for the use of an inhibitory peptide targeting a parasite-specific insert in the dimerisation interface of a uniquely bifunctional malarial protein.

Download or read book Structural and Functional Validation of S adenosylmethionine Decarboxylase as a Novel Drug Target in the Malaria Parasite Plasmodium Falciparum written by Dina Coertzen and published by . This book was released on 2014 with total page 236 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is considered the most prevailing human parasitic disease. Despite various chemotherapeutic interventions being available, the parasite responsible for the most lethal form of malaria, Plasmodium falciparum, is continuously developing resistance towards drugs targeted against it. This, therefore, necessitates the need for validation of new antimalarial development. Polyamine biosynthetic enzymes, particularly S-adenosylmethionine-L-decarboxylase (PfAdoMetDC), has been identified as a suitable drug target for protozoan parasitic diseases due to its essential role in cell proliferation. Furthermore, in Plasmodium polyamine biosynthesis, PfAdoMetDC is organised into a unique bifunctional complex with ornithine decarboxylase (PfAdoMetDC/ODC) covalently linked by a hinge region, distinguishing this enzyme as unique a drug target. However, inhibitors targeting this pathway have not been successful in clinical assessment, creating the need for further research in identifying novel inhibitors. This study focused on the structural and functional characterisation of protein-specific properties of the AdoMetDC domain in P. falciparum parasites, as well as identifying novel inhibitors targeting this enzyme as a potential antimalarial therapeutic intervention. In order to develop novel inhibitors specifically targeting PfAdoMetDC through a structure-based drug discovery approach, the three-dimensional structure is required. However, due to a lack of structural and functional characterisation, determination of the crystal structure has been challenging. Heterologous expression of monofunctional PfAdoMetDC was achieved from a wild-type construct of the PfAdoMetDC domain including the covalently linked hinge region. In chapter 2, deletion of a large non-homologous, low-complexity parasite-specific insert (A3) in monofunctional PfAdoMetDC resulted in an increased yield, purity and sample homogeneity, whilst maintaining protein functionality and structural integrity. However, truncation of the proposed non-essential hinge region resulted in low-level expression of insoluble protein aggregates and a complete loss of protein activity, indicating that the hinge region is essential for monofunctional PfAdoMetDC. However, in the absence of the three-dimensional PfAdoMetDC crystal structure, novel derivatives of a well-known AdoMetDC inhibitor, MDL73811, were tested for their activity against heterologous PfAdoMetDC, as well as their potency against P. falciparum parasites, in chapter 3. The compound Genz-644131 was identified as a lead inhibitor of PfAdoMetDC, however, the poor membrane permeability of the compound resulted in low in vitro activity. Drug permeability of Genz-644131 into P. falciparum infected erythrocytes and its potency was significantly improved by its encapsulation into a novel immunoliposome based drug delivery system. The results presented here provide essential information for development of a unique strategy in obtaining suffiecient levels of fully active recombinant PfAdoMetDC of sufficient purity for crystallisation studies and subsequent structure-based drug design efforts. The combination of Genz-644131 with the novel drug delivery system, which markedly improved its potency against PfAdoMetDC may proof to be a viable antimalarial chemotherapeutic strategy for future investigations.

Download or read book Structural Model and Properties of AdoMetDc Domain of the Bifunctional Plasmodium Falciparum S adenosylmethionine Decarboxylase Ornithine Decarboxylase written by Gordon Andreas Wells and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Structural Model and Properties of the AdoMetDC Domain of the Bifunctional Plasmodium Falciparum S adenisykmethionine Decarboxylase Ornithine Decarboxylase written by Gordon Andreas Wells and published by . This book was released on 2004 with total page 186 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Mitochondria and Anaerobic Energy Metabolism in Eukaryotes written by William F. Martin and published by Walter de Gruyter GmbH & Co KG. This book was released on 2020-12-07 with total page 269 pages. Available in PDF, EPUB and Kindle. Book excerpt: Mitochondria are sometimes called the powerhouses of eukaryotic cells, because mitochondria are the site of ATP synthesis in the cell. ATP is the universal energy currency, it provides the power that runs all other life processes. Humans need oxygen to survive because of ATP synthesis in mitochondria. The sugars from our diet are converted to carbon dioxide in mitochondria in a process that requires oxygen. Just like a fire needs oxygen to burn, our mitochondria need oxygen to make ATP. From textbooks and popular literature one can easily get the impression that all mitochondria require oxygen. But that is not the case. There are many groups of organismsm known that make ATP in mitochondria without the help of oxygen. They have preserved biochemical relicts from the early evolution of eukaryotic cells, which took place during times in Earth history when there was hardly any oxygen avaiable, certainly not enough to breathe. How the anaerobic forms of mitochondria work, in which organisms they occur, and how the eukaryotic anaerobes that possess them fit into the larger picture of rising atmospheric oxygen during Earth history are the topic of this book.

Download or read book Protein Evolution written by Laszlo Patthy and published by John Wiley & Sons. This book was released on 2009-03-12 with total page 392 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides an up-to-date summary of the principles of protein evolution and discusses both the methods available to analyze the evolutionary history of proteins as well as those for predicting their structure-function relationships. Includes a significantly expanded chapter on genome evolution to cover genomes of model organisms sequenced since the completion of the first edition, and organelle genome evolution Retains its reader-friendly, accessible style and organization Contains an updated glossary and new references, including a list of online reference sites

Download or read book Medicinal Natural Products written by Paul M. Dewick and published by John Wiley & Sons. This book was released on 2002-01-03 with total page 524 pages. Available in PDF, EPUB and Kindle. Book excerpt: This guide covers classes of natural products in medicine, whether derived from plants, micro-organisms or animals. Structured according to biosynthetic pathway, it is written from a chemistry-based approach.

Download or read book Opportunistic Infections written by David S. Lindsay and published by Springer Science & Business Media. This book was released on 2008-04-16 with total page 249 pages. Available in PDF, EPUB and Kindle. Book excerpt: Opportunistic Infections: Toxoplasma, Sarcocystis, and Microsporidia will focus on two important Genera of Apicomplexan parasites, Toxoplasma gondii and Sarcocystis species, and the medically important members of the Phylum Microsporida. We have been fortunate in obtaining excellent contributions from many experts in the field. Volumes in the "World Class Parasites" book series are written for researchers, students and scholars who enjoy reading about excellent research on problems of global significance. Each volume focuses on a parasite, or group of parasites, that has a major impact on human health, or agricultural productivity, and against which we have no satisfactory defense. The volumes are intended to supplement more formal texts that cover taxonomy, life cycles, morphology, vector distribution, symptoms and treatment. They integrate vector, pathogen and host biology and celebrate the diversity of approach that comprises modern parasitological research.

Download or read book Chemistry of Antibiotics and Related Drugs written by Mrinal K. Bhattacharjee and published by Springer Nature. This book was released on 2022-08-23 with total page 276 pages. Available in PDF, EPUB and Kindle. Book excerpt: This textbook builds on the success of the earlier edition, offering alternative strategies for discovering new antibiotics. It discusses how the various types of antibiotics and related drugs work to cure infections. Then it delves into the very serious matter of how bacteria are becoming resistant to these antibiotics. It also covers the global action plan on antimicrobial resistance from the World Health Organization and discusses several Antibiotic Stewardship Programs adopted by agencies at local levels. Appropriate for a one-semester course at either the graduate or advanced undergraduate level, the book is self-contained and written in accessible language. It includes all necessary background biochemistry material and a discussion of the latest developments in the field of antibiotics. Original research works are frequently cited and experimental procedures and interpretation of results are emphasized.

Download or read book Toxoplasma Gondii written by Louis M. Weiss and published by Academic Press. This book was released on 2013-08-10 with total page 1109 pages. Available in PDF, EPUB and Kindle. Book excerpt: This 2e of Toxoplasma gondii reflects the significant advances in the field in the last 5 years, including new information on the genomics, epigenomics and proteomics of T. gondii as well as a new understanding of the population biology and genetic diversity of this organism. T. gondii remains the best model system for studying the entire Apicomplexa group of protozoans, which includes Malaria, making this new edition essential for a broad group of researchers and scientists. Toxoplasmosis is caused by a one-celled protozoan parasite known as T. gondii. The infection produces a wide range of clinical syndromes in humans, land and sea mammals, and various bird species. Most humans contract toxoplasmosis by eating contaminated, raw or undercooked meat (particularly pork), vegetables, or milk products; by coming into contact with the T. gondii eggs from cat feces; or by drinking contaminated water. The parasite damages the ocular and central nervous systems, causing behavioral and personality alterations as well as fatal necrotizing encephalitis. It is especially dangerous for the fetus of an infected pregnant woman and for individuals with compromised immune systems, such as HIV-infected patients. Completely updated, the 2e presents recent advances driven by new information on the genetics and genomics of the pathogen Provides the latest information concerning the epidemiology, diagnosis, treatment and prevention of toxoplasmosis Offers a single-source reference for a wide range of scientists and physicians working with this pathogen, including parasitologists, cell and molecular biologists, veterinarians, neuroscientists, physicians, and food scientists

Download or read book Polyamines written by Anthony E. Pegg and published by Humana Press. This book was released on 2011-04-06 with total page 524 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recently, important new findings in the polyamine field and a variety of new experimental systems have revolutionized the study of these ubiquitous cellular components, essential for normal growth and development. In Polyamines: Methods and Protocols, leading researchers contribute an extensive collection of up-to-date laboratory techniques for the further pursuit of polyamine study. The volume delves into vital subjects such as neoplasia studies with animal models and human patients, therapeutic roles for polyamine inhibitors and analogs, polyamine metabolism and oxidative damage, polyamines as regulators of critical ion channels, as well as polyamine transport systems and polyamine-responsive genes. Written in the highly successful Methods in Molecular BiologyTM series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and expert notes on troubleshooting and avoiding known pitfalls. Comprehensive and cutting-edge, Polyamines: Methods and Protocols provides a key resource for all scientists pursuing the study of this dynamic and significant aspect of cellular biology.

Download or read book Genome Mapping and Genomics in Animal Associated Microbes written by Vishvanath Nene and published by Springer Science & Business Media. This book was released on 2008-11-24 with total page 253 pages. Available in PDF, EPUB and Kindle. Book excerpt: Achievements and progress in genome mapping and the genomics of microbes supersede by far those for higher plants and animals, in part due to their enormous economic implication but also smaller genome size. In the post-genomic era, whole genome sequences of animal-associated microbes are providing clues to depicting the genetic basis of the complex host-pathogen relationships and the evolution of parasitism; and to improving methods of controlling pathogens. This volume focuses on a globally important group of intracellular prokaryotic pathogens which affect livestock animals. These include Brucella, Mycobacterium, Anaplasma and Ehrlichia, as well as the protozoan pathogens Cryptosporidium and Theileria, for which genome sequence data is available. Insights from comparative genomics of the microbes described provide clues to the adaptation involved in host-microbe interactions, as well as resources potentially useful for application in future research and product development.

Download or read book Drug Resistance in Leishmania Parasites written by Alicia Ponte-Sucre and published by Springer Science & Business Media. This book was released on 2012-09-04 with total page 458 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of the main problems concerning therapeutic tools for the treatment of parasitic diseases, including leishmaniasis, is that some field parasites are naturally resistant to the classical drugs; additionally, current therapies may select parasites prone to be resistant to the applied drugs. These features are (at least partially) responsible for the disappointing persistence of the disease and resultant deaths worldwide. This book provides a comprehensive view of the pathology of the disease itself, and of parasitic drug resistance, its molecular basis, consequences and possible treatments. Scientists both from academic fields and from the industry involved in biomedical research and drug design, will find in this book a valuable and fundamental guide that conveys the knowledge needed to understand and to improve the success in combating this disease worldwide.

Download or read book Epigenetics in Psychiatry written by Jacob Peedicayil and published by Academic Press. This book was released on 2021-08-21 with total page 848 pages. Available in PDF, EPUB and Kindle. Book excerpt: Epigenetics in Psychiatry, Second Edition covers all major areas of psychiatry in which extensive epigenetic research has been performed, fully encompassing a diverse and maturing field, including drug addiction, bipolar disorder, epidemiology, cognitive disorders, and the uses of putative epigenetic-based psychotropic drugs. Uniquely, each chapter correlates epigenetics with relevant advances across genomics, transcriptomics, and proteomics. The book acts as a catalyst for further research in this growing area of psychiatry. This new edition has been fully revised to address recent advances in epigenetic understanding of psychiatric disorders, evoking data consortia (e.g., CommonMind, ATAC-seq), single cell analysis, and epigenome-wide association studies to empower new research. The book also examines epigenetic effects of the microbiome on psychiatric disorders, and the use of neuroimaging in studying the role of epigenetic mechanisms of gene expression. Ongoing advances in epigenetic therapy are explored in-depth. Fully revised to discuss new areas of research across neuronal stem cells, cognitive disorders, and transgenerational epigenetics in psychiatric disease Relates broad advances in psychiatric epigenetics to a modern understanding of the genome, transcriptome, and proteins Catalyzes knowledge discovery in both basic epigenetic biology and epigenetic targets for drug discovery Provides guidance in research methods and protocols, as well how to employ data from consortia, single cell analysis, and epigenome-wide association studies (EWAS) Features chapter contributions from international leaders in the field

Download or read book Dorland s Dictionary of Medical Acronyms and Abbreviations E Book written by Dorland and published by Elsevier Health Sciences. This book was released on 2015-07-24 with total page 488 pages. Available in PDF, EPUB and Kindle. Book excerpt: Medical acronyms and abbreviations offer convenience, but those countless shortcuts can often be confusing. Now a part of the popular Dorland’s suite of products, this reference features thousands of terms from across various medical specialties. Its alphabetical arrangement makes for quick reference, and expanded coverage of symbols ensures they are easier to find. Effective communication plays an important role in all medical settings, so turn to this trusted volume for nearly any medical abbreviation you might encounter. Symbols section makes it easier to locate unusual or seldom-used symbols. Convenient alphabetical format allows you to find the entry you need more intuitively. More than 90,000 entries and definitions. Many new and updated entries including terminology in expanding specialties, such as Nursing; Physical, Occupational, and Speech Therapies; Transcription and Coding; Computer and Technical Fields. New section on abbreviations to avoid, including Joint Commission abbreviations that are not to be used. Incorporates updates suggested by the Institute for Safe Medication Practices (ISMP).