Manganese in Health and Disease: Volume 22 - Rilegato

Rilegato

ISBN 10: 1849739439 ISBN 13: 9781849739436

Casa editrice: Royal Society of Chemistry, 2014

Riassunto

Manganese in the diet is nutritionally essential for normal physiologic functioning. However, excessive exposure to manganese has been associated with developmental, neurodegenerative and other disorders.

The book comprehensively covers the toxicology of manganese. Leading investigators provide perspectives from toxicology, neuroscience, nutrition, molecular biology and risk assessment disciplines and chapters cover the toxicokinetics, toxicodynamic interactions and health effects of manganese, as well as its potential role in neurodegenerative diseases. A large section devoted to health effects presents the latest research that associates manganese exposure to potential human diseases.

Any scientists, health professional or regulator involved with metal exposure and toxicology should find this volume essential reading. Students and researchers in neurotoxicology will also find this book a useful reference.

Su questo libro

Informazioni sull?autore

Dr Michael Aschner is currently a Professor of Toxicology, Pharmacology and Pediatrics at Vanderbilt University Medical School. He is a world-known authority on the toxicology of manganese and of other metals. Also world-renowned for his contributions to the field, Dr Lucio Costa is a Professor of Toxicology at the University of Washington with over thirty years of experience in the area of neurotoxicology.

Dalla quarta di copertina

Manganese in the diet is nutritionally essential for normal physiologic functioning. However, excessive exposure to manganese has been associated with developmental, neurodegenerative and other disorders.

This book comprehensively covers the toxicology of manganese. Leading investigators provide perspectives from toxicology, neuroscience, nutrition, molecular biology and risk assessment disciplines and chapters cover the toxicokinetics, toxicodynamic interactions and health effects of manganese, as well as its potential role in neurodegenerative diseases. A large section devoted to health effects presents the latest research that associates manganese exposure to potential human diseases.

Any scientists, health professional or regulator involved with metal exposure and toxicology should find this volume essential reading. Students and researchers in neurotoxicology will also find this book a useful reference.

Dal risvolto di copertina interno

Manganese in the diet is nutritionally essential for normal physiologic functioning. However, excessive exposure to manganese has been associated with developmental, neurodegenerative and other disorders.

This book comprehensively covers the toxicology of manganese. Leading investigators provide perspectives from toxicology, neuroscience, nutrition, molecular biology and risk assessment disciplines and chapters cover the toxicokinetics, toxicodynamic interactions and health effects of manganese, as well as its potential role in neurodegenerative diseases. A large section devoted to health effects presents the latest research that associates manganese exposure to potential human diseases.

Any scientists, health professional or regulator involved with metal exposure and toxicology should find this volume essential reading. Students and researchers in neurotoxicology will also find this book a useful reference.

Estratto. © Ristampato con autorizzazione. Tutti i diritti riservati.

Manganese in Health and Disease

By Lucio G. Costa, Michael Aschner

The Royal Society of Chemistry

Copyright © 2015 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-943-6

Contents

Chapter 1 Manganese Transport, Trafficking and Function in Invertebrates, 1, 
Chapter 2 Nutritional Requirements for Manganese, 34, 
Chapter 3 Manganese Superoxide Dismutase, 79, 
Chapter 4 Olfactory Transport of Manganese: Implications for Neurotoxicity, 119, 
Chapter 5 Manganese Transport Across the Pulmonary Epithelium, 133, 
Chapter 6 Are There Distinguishable Roles for the Different Oxidation States of Manganese in Manganese Toxicity?, 158, 
Chapter 7 Effect of Manganese on Signaling Pathways, 182, 
Chapter 8 Manganese and Oxidative Stress, 199, 
Chapter 9 Mutual Neurotoxic Mechanisms Controlling Manganism and Parkisonism, 221, 
Chapter 10 Mechanism of Manganese-Induced Impairment of Astrocytic Glutamate Transporters, 258, 
Chapter 11 Impairment of Glutamine/Glutamate-γ-aminobutyric Acid Cycle in Manganese Toxicity in the Central Nervous System, 279, 
Chapter 12 Manganese and Neuroinflammation, 297, 
Chapter 13 Modeling Manganese Kinetics for Human Health Risk Assessment, 322, 
Chapter 14 Significance and Usefulness of Biomarkers of Exposure to Manganese, 355, 
Chapter 15 Manganese and Parenteral Nutrition, 405, 
Chapter 16 Developmental Effects of Manganese, 426, 
Chapter 17 The Effects of Manganese on Female Pubertal Development, 437, 
Chapter 18 A Decade of Studies on Manganese Neurotoxicity in Non-Human Primates: Novel Findings and Future Directions, 459, 
Chapter 19 Imaging Modalities for Manganese Toxicity, 477, 
Chapter 20 Epidemiological Studies of Parkinsonism in Welders, 513, 
Chapter 21 Cognitive Effects of Manganese in Children and Adults, 524, 
Chapter 22 Manganese and Huntington Disease, 540, 
Chapter 23 Manganese and Prion Disease, 574, 
Chapter 24 DNA Damage Induced by Manganese, 604, 
Post-face, 621, 
Subject Index, 624, 

CHAPTER 1

Manganese Transport, Trafficking and Function in Invertebrates

AMORNRAT NARANUNTARAT JENSEN AND LARAN T. JENSEN

1.1 Introduction

Manganese is a biologically important trace metal and is required for the growth and survival of most, if not all, living organisms. It is perhaps best known for its prominent role as a redox-active cofactor in free radical detoxifying enzymes. However, the utilization of manganese in biological systems is substantially more diverse. The uptake and distribution of manganese is critical for proper function of manganese-requiring enzymes; however, this same metal can have deleterious effects in biological systems if homeostasis is disrupted. In order to prevent toxicity, cells maintain manganese under tight homeostatic control. Adding complexity to the cellular control of manganese homeostasis is the presence of multiple types of manganese transporter that participate in the specific transport of manganese or in general divalent metal ion transport.

Cells appear to transport manganese solely as the divalent cation and several classes of manganese transporters have been characterized. These include Nramp H+-manganese transporters, ATP-binding cassette (ABC) manganese permeases, manganese transporting P-type ATPases, cation diffusion facilitators (CDFs), and inorganic phosphate transporters with high affinity for Mn-HPO4 complexes. Bacteria typically contain one or more of these types of transporter, and these classes of transporter are also present in eukaryotic cells. These transporters comprise both high and low affinity manganese uptake systems and the transporter utilized depends on the concentration of manganese in the environment. The homeostatic range for manganese is quite wide, with cellular levels of manganese between 0.04 and 2.0 mM under optimal growth conditions. Cells rarely experience optimal environmental levels of manganese and often face extreme conditions of either manganese deficiency or excess. Cells activate stress response mechanisms in an attempt to return manganese levels to the homeostatic range. The response typically results in the upregulation or downregulation of cell surface and intracellular transport systems. The regulation of manganese uptake, distribution, and efflux can occur at both the transcriptional and post-translational levels, although the specific route of regulation varies in different organisms.

1.2 Function of Manganese in Biological Systems

1.2.1 Manganese Metalloenzymes

Manganese metalloenzymes are involved in a wide range of cellular functions, including detoxification of reactive oxygen species, protein glycosylation, polyamine biosynthesis, DNA biosynthesis, nucleic acid degradation, phospholipid biosynthesis and processing, polysaccharide biosynthesis, protein catabolism, the urea cycle, photosynthesis, and sugar catabolism. Manganese-dependent enzymes that participate in these processes typically utilize manganese in Lewis acid-base reactions or as a reduction/oxidation center to facilitate catalysis. These types of reaction are exemplified by arginase (Lewis acid) and Mn superoxide dismutase (reduction/oxidation), and the role of manganese in these reactions is shown in Figure 1.1.

1.2.2 Non-Protein Manganese Antioxidants

The importance of manganese in biological systems is not limited to enzyme-mediated catalysis. Non-enzymatic manganese is involved in the formation of bacterial products, including secreted antibiotics, and contributes to the stabilization of bacterial cell walls. In addition, the accumulation of non-protein complexes of manganese can function in the removal of reactive oxygen species (ROS), especially superoxide. These Mn-antioxidants are divalent manganese complexes of small metabolites, and while the nature of the intracellular Mn-complexes has not been clearly defined, phosphate and lactate Mn-complexes have been shown to display the capacity to react efficiently with superoxide in vitro. Complexes of both iron and copper exhibit superoxide scavenging activity, however these metal ions also exhibit pro-oxidant activity. In contrast, manganese ions react poorly with hydrogen peroxide and do not generate the highly toxic hydroxyl radical, providing a beneficial antioxidant activity without the pro-oxidant side effects of other redox active metals.

It appears that Mn-antioxidants can serve to enhance oxidative stress protection when enzymatic antioxidants are insufficient in various organisms. A critical role for Mn-antioxidants has been demonstrated in Deinococcus radiodurans, a bacterium that is extremely resistant to radiation and desiccation. In this organism, survival under extreme exposure to radiation and other oxidative stress conditions is not dependent on antioxidant enzymes but instead relies on the accumulation of millimolar concentrations of manganese and the subsequent formation of Mn-antioxidants. Interestingly, Lactobacillus plantarum, while resistant to oxidative stress, does not express the antioxidant enzyme superoxide dismutase. Indeed, L. plantarum appears to rely exclusively on Mn-antioxidants for protection against oxidative stress, highlighting the power of this alternative ROS detoxification pathway.

The majority of the information on manganese antioxidants has come from investigation of bacterial and yeast systems; however, it is also likely that these complexes are present in multicellular organisms. Elevated manganese accumulation in the nematode Caenorhabditis elegans enhances thermotolerance and oxidative stress resistance, and extends life span. The mechanism of the enhanced stress resistance due to manganese supplementation in C. elegans has not been fully elucidated but is suspected to involve elevated antioxidant activity.

1.2.3 Manganese and Bacterial Virulence

Manganese is either known or proposed to be important for virulence in bacterial species such as Salmonella enterica, Mycobacterium tuberculosis, Staphylococcus aureus, Yersinia pestis, and Streptococcus pneumoniae. Invasion and initial survival within host cells is not dependent on manganese; however, extended survival appears to require the element. The expression of manganese transporters is required to enhance bacterial survival when challenged by host defenses. Whether different classes of manganese transporter are redundant or involved at different stages of infection is not known. Models have been proposed in which manganese transporters, as well as iron transporters, are essential for virulence because of competition between the infecting bacterium and host cells for metal ions. The need for manganese in bacterial virulence appears to go beyond its role as a cofactor in ROS detoxifying enzymes such as Mn-superoxide dismutase and catalase. Enterobacteria are capable of rapidly increasing uptake of manganese in response to stress, and can accumulate millimolar levels of manganese. This concentration of manganese far exceeds the level needed to supply Mn-superoxide dismutase with its cofactor. It appears that the formation of non-protein Mn-antioxidant complexes may also be an important virulence factor in some bacterial species. The additional protection against reactive oxygen species generated by the host cells may allow invading bacteria to survive the initial stages of infection, and thus promote colonization.

1.3 Manganese Transport in Bacteria

1.3.1 Bacterial Manganese Uptake Systems

In prokaryotic cells, which lack internal compartmentalization, metal ion homeostasis is maintained primarily by tight regulation of metal cation flux across the cytoplasmic membrane. Manganese uptake in bacteria predominantly involves members of two transporter families, Nramp (MntH) and cation-transporting ABC permeases (MntABCD and related), with many species containing both types of transport system. In addition, utilization of other transport systems for manganese, such as a P-type adenosine triphosphatase (ATPase) by Lactobacillus species (MntP) and Mycobacterium tuberculosis (CtpC), has also been observed. Exposure to excess manganese leads to repression of these dedicated manganese transport systems. However, the tight control of manganese influx can be bypassed via other transporters that are capable of facilitating the uptake of manganese but escape regulation by this metal. An example of this is PitA, an inorganic phosphate transporter with high affinity for Mn-HPO4 complexes that appears to be a major source of manganese uptake during conditions of excess.

1.3.1.1 Bacterial Nramp Manganese Transporter, MntH

Members of the Nramp (natural resistance-associated macrophage protein) transporter family were first identified in yeast and mammalian cells and subsequently found to play a major role in metal ion homeostasis. Nramp proteins function in general metal ion transport, and members of this transporter family have been shown to facilitate the movement of divalent metal ions including manganese, zinc, copper, iron, cadmium, nickel, cobalt, and lead. Transport of metal ions through Nramp is energized by the symport of protons (Figure 1.2).

The majority of bacterial Nramp1 homologues, typically designated as MntH, appear to function in manganese homeostasis. The MntH transporters are commonly found in bacterial species, although examples of bacteria lacking Nramp transporters have been described. Metal accumulation studies revealed that overexpression of Staphylococcus aureus MntH resulted in increased cell-associated manganese but not calcium, copper, iron, magnesium or zinc, indicating that this Nramp1 transporter was selective for the uptake of manganese. Consistent with these observations, mutants of mntH in Bacillus subtilis exhibited impaired growth in metal-depleted media that could be rescued by the addition of manganese. Direct transport assays also indicated a preference for manganese in MntH from Salmonella enterica serovar Typhimurium and Escherichia coli. The affinity for manganese far exceeds that for iron in these MntH proteins, demonstrating the role of Nramp transporters in bacterial manganese uptake.

Species differences in MntH metal ion specificity have been observed, with some MntH homologues appearing to function in the transport of other metals in addition to manganese. While S. enterica, E. coli, and B. subtilis MntH exhibit a strong preference for manganese, the M. tuberculosis MntH homologue, Mramp, appears to transport not only manganese but also significant amounts of iron and zinc. Roles for Nramp transporters in the uptake of other metal ions, especially iron, have been documented in both prokaryotic and eukaryotic organisms. Multiple Nramp isoforms can be present in a single species, and these Nramp transporters, although highly similar, may have divergent metal ion preferences. Pseudo-monas aeruginosa expresses two distinct Nramp transporters capable of transporting manganese, and multiple Nramp isoforms are present in Burkholderia species, although the metal ion preferences of these transporters have not been determined. While the most physiologically relevant substrate for the majority of bacterial MntH transporters appear to be manganese, it is clear that these transporters have the capacity to facilitate the uptake of other metals when they are present in excess. This broad metal ion selectivity in Nramp transporters also appears to enhance the uptake of toxic metal ions, such as cadmium and lead.

1.3.1.2 Bacterial ABC-Type Manganese Permeases

The ATP-binding cassette (ABC) transporter superfamily is one of the largest classes of transporter, and this transporter family utilizes hydrolysis of ATP to facilitate the import or export of diverse substrates, ranging from ions to macromolecules. These transporters are present in the plasma membrane or inner membrane of Gram-negative bacteria, and are well known for their involvement in multi-drug resistance in both prokaryotic and eukaryotic cells by enhancing the export of toxins and drugs. However, ABC transporters functioning as importers have only been described in prokaryotic systems. Metal ion transporting ABC permeases have been identified with important roles in manganese acquisition. The cation selectivity of manganese ABC-type permeases extends to other divalent metal ions including iron, zinc, cobalt, nickel, molybdenum, and cadmium; however, the typical affinities for these metal ions are 10- to 100-fold lower than for manganese.

Examples of bacterial ABC transporters involved in manganese import include, but are not limited to, MntABCD (Bacillus subtilis, Staphylococcus aureus), SitABCD (Shigella flexneri), PsaABCD (Streptococcus pneumoniae), and YfeABCD (Yersinia pestis), and these transporters exhibit similar subunit organization and function. The manganese transporter complex MntABCD (see Figure 1.2) consists of three subunits: MntC and MntD are integral membrane proteins that form the permease subunit and mediate cation import; MntB is the ATPase subunit; and MntA functions as a cation binding protein that delivers manganese to the permease complex. MntA is present as a soluble periplasmic protein in Gram-negative bacteria. In Gram-positive bacteria MntA is a lipoprotein anchored to the extracellular side of the plasma membrane, because these bacteria do not possess an outer membrane. Similar organization is also present in the operons of other manganese ABC transporters such as sitABCD, yfeABCD, and psaABCD.

1.3.1.3 Bacterial P-Type Manganese Transporting ATPases

P-type ATPases form a large superfamily of cation and lipid pumps and are distinct from the ABC class of ATPases in that ATP hydrolysis is coupled to transport within a single protein chain. A manganese/cadmium transporting P-type ATPase, MntP (also known as MntA, although distinct from MntABCD) from Lactobacillus plantarum, was identified and proposed to be the major source of manganese for this organism. Subsequent analysis of the L. plantarum genome revealed the presence of three Nramp transporters as well as a manganese ABC transporter. Mutations of L. plantarum mntP or the Nramp and ABC transporters did not alter intracellular manganese concentrations under either manganese deficiency or excess. A primary role for MntP in manganese acquisition in L. plantarum is not certain; however, Nramp and manganese ABC transporters were also not essential for manganese uptake. It appears that L. plantarum is highly adaptive in maintaining manganese uptake even in the absence of known transporters and additional, yet uncharacterized, transporters may participate in manganese accumulation. Three additional putative P-type calcium/manganese ATPases are present in L. plantarum and have been proposed as possible sources of manganese uptake in this bacterium.

1.3.1.4 Bacterial Transport of Manganese-Phosphate Complexes

In Salmonella lacking both the Nramp and manganese ABC transporters, manganese uptake activity has been observed, although at low levels. The proposed source of this residual manganese uptake is PitA, a low affinity phosphate transporter. The substrate for PitA is a neutral metal phosphate (metal-HPO4) complex, and this transporter has a preference for phosphate complexes of magnesium, calcium, cobalt, and manganese. In environments rich in metals and phosphate, PitA and related transporters have been proposed to be major suppliers of divalent metal cations and may contribute to metal ion toxicity. Experimental evidence for manganese uptake in intact cells through PitA or other phosphate transporters is limited. However, stimulation of manganese uptake was produced in L. plantarum and B. subtilis by the addition of phosphate.

1.3.2 Bacterial Manganese Efflux

A manganese efflux transporter, MntE, showing homology with the cation diffusion facilitator family (CDF) has been identified in several bacterial species. Members of the CDF family are found in most prokaryotic and eukaryotic cells and typically function in metal tolerance by exporting cations from the cytoplasm to the cell exterior. The most likely transport mechanism for MntE is an antiport cycle consisting of the efflux of manganese with the uptake of hydrogen and potassium ions.

Cells lacking functional MntE exhibit sensitivity to manganese but not other metal ions (cadmium, cobalt, copper, iron, nickel, and zinc) and accumulate three times the intracellular manganese seen in the wild-type strain. The high levels of intracellular manganese in mntE mutants increased resistance to oxidative stress but did not lead to enhanced virulence. Bacteria lacking MntE were actually less pathogenic than wild-type cells, indicating that control of manganese homeostasis is critical for both survival and virulence.

(Continues...)

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Dettagli dell?edizione

• Editore: Royal Society of Chemistry
• Data di pubblicazione: 2014
• Lingua: Inglese
• ISBN 10: 1849739439
• ISBN 13: 9781849739436
• Rilegatura: Copertina rigida
• Numero edizione: 1
• Numero di pagine: 632
• Redattore: Costa Lucio G, Aschner Michael
• Contatto del produttore: non disponibile
• Persona responsabile: non disponibile