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BBA - Molecular Cell Research (v.1763, #7)
Between a rock and a hard place: Trace element nutrition in Chlamydomonas by Sabeeha S. Merchant; Michael D. Allen; Janette Kropat; Jeffrey L. Moseley; Joanne C. Long; Stephen Tottey; Aimee M. Terauchi (pp. 578-594).
Photosynthetic organisms are among the earliest life forms on earth and their biochemistry is strictly dependent on a wide range of inorganic nutrients owing to the use of metal cofactor-dependent enzymes in photosynthesis, respiration, inorganic nitrogen and sulfur assimilation. Chlamydomonas reinhardtii is a photosynthetic eukaryotic model organism for the study of trace metal homeostasis. Chlamydomonas spp. are widely distributed and can be found in soil, glaciers, acid mines and sewage ponds, suggesting that the genus has significant capacity for acclimation to micronutrient availability. Analysis of the draft genome indicates that metal homeostasis mechanisms in Chlamydomonas represent a blend of mechanisms operating in animals, plants and microbes. A combination of classical genetics, differential expression and genomic analysis has led to the identification of homologues of components known to operate in fungi and animals (e.g., Fox1, Ftr1, Fre1, Fer1, Ctr1/2) as well as novel molecules involved in copper and iron nutrition (Crr1, Fea1/2). Besides activating iron assimilation pathways, iron-deficient Chlamydomonas cells re-adjust metabolism by reducing light delivery to photosystem I (to avoid photo-oxidative damage resulting from compromised FeS clusters) and by modifying the ferredoxin profile (perhaps to accommodate preferential allocation of reducing equivalents). Up-regulation of a MnSOD isoform may compensate for loss of FeSOD. Ferritin could function to buffer the iron released from programmed degradation of iron-containing enzymes in the chloroplast. Some metabolic adjustments are made in anticipation of deficiency while others occur only with sustained or severe deficiency. Copper-deficient Chlamydomonas cells induce a copper assimilation pathway consisting of a cell surface reductase and a Cu+ transporter (presumed CTR homologue). There are metabolic adaptations in addition: the synthesis of “back-up� enzymes for plastocyanin in photosynthesis and the ferroxidase in iron assimilation plus activation of alternative oxidase to handle the electron “overflow� resulting from reduced cytochrome oxidase function. Oxygen-dependent enzymes in the tetrapyrrole pathway (coproporphyrinogen oxidase and aerobic oxidative cyclase) are also increased in expression and activity by as much as 10-fold but the connection between copper nutrition and tetrapyrroles is not understood. The copper-deficiency responses are mediated by copper response elements that are defined by a GTAC core sequence and a novel metalloregulator, Crr1, which uses a zinc-dependent SBP domain to bind to the CuRE. The Chlamydomonas model is ideal for future investigation of nutritional manganese deficiency and selenoenzyme function. It is also suited for studies of trace nutrient interactions, nutrition-dependent metabolic changes, the relationship between photo-oxidative stress and metal homeostasis, and the important questions of differential allocation of limiting metal nutrients (e.g., to respiration vs. photosynthesis).
Keywords: Copper; Iron; Chloroplast; Algae; Oxidative stress
Molecular aspects of Cu, Fe and Zn homeostasis in plants by Natasha Grotz; Mary Lou Guerinot (pp. 595-608).
Proper metal transport and homeostasis are critical for the growth and development of plants. In order to potentially fortify plants pre-harvest with essential metals in aid of human nutrition, we must understand not only how metals enter the plant but also how metals are then delivered to the edible portions of the plant such as the seed. In this review, we focus on three metals required by both plants and humans: Cu, Fe and Zn. In particular, we present the current understanding of the molecular mechanisms of Cu, Fe and Zn transport, including aspects of uptake, distribution, chelation and/or sequestration.
Keywords: Iron; Zinc; Copper; Transport; Regulation; Chelation
The NRAMP family of metal-ion transporters by Yaniv Nevo; Nathan Nelson (pp. 609-620).
The family of NRAMP metal ion transporters functions in diverse organisms from bacteria to human. NRAMP1 functions in metal transport across the phagosomal membrane of macrophages, and defective NRAMP1 causes sensitivity to several intracellular pathogens. DCT1 (NRAMP2) transport metal ions at the plasma membrane of cells of both the duodenum and in peripheral tissues, and defective DCT1 cause anemia. The driving force for the metal-ion transport is proton gradient (protonmotive force). In DCT1 the stoichiometry between metal ion and proton varied at different conditions due to a mechanistic proton slip. Though the metal ion transport by Smf1p, the yeast homolog of DCT1, is also a protonmotive force, a slippage of sodium ions was observed. The mechanism of the above phenomena could be explained by a combination between transporter and channel mechanisms.
Keywords: NRAMP; Metal-ions; Transport; Transporters; Homeostasis
Cell biology of molybdenum by Ralf R. Mendel; Florian Bittner (pp. 621-635).
The transition element molybdenum (Mo) is of essential importance for (nearly) all biological systems as it is required by enzymes catalyzing diverse key reactions in the global carbon, sulfur and nitrogen metabolism. The metal itself is biologically inactive unless it is complexed by a special cofactor. With the exception of bacterial nitrogenase, where Mo is a constituent of the FeMo-cofactor, Mo is bound to a pterin, thus forming the molybdenum cofactor (Moco) which is the active compound at the catalytic site of all other Mo-enzymes. In eukaryotes, the most prominent Mo-enzymes are (1) sulfite oxidase, which catalyzes the final step in the degradation of sulfur-containing amino acids and is involved in detoxifying excess sulfite, (2) xanthine dehydrogenase, which is involved in purine catabolism and reactive oxygen production, (3) aldehyde oxidase, which oxidizes a variety of aldehydes and is essential for the biosynthesis of the phytohormone abscisic acid, and in autotrophic organisms also (4) nitrate reductase, which catalyzes the key step in inorganic nitrogen assimilation. All Mo-enzymes, except plant sulfite oxidase, need at least one more redox active center, many of them involving iron in electron transfer. The biosynthesis of Moco involves the complex interaction of six proteins and is a process of four steps, which also includes iron as well as copper in an indespensable way. Moco as released after synthesis is likely to be distributed to the apoproteins of Mo-enzymes by putative Moco-carrier proteins. Xanthine dehydrogenase and aldehyde oxidase, but not sulfite oxidase and nitrate reductase, require the postranslational sulfuration of their Mo-site for becoming active. This final maturation step is catalyzed by a Moco-sulfurase enzyme, which mobilizes sulfur froml-cysteine in a pyridoxal phosphate-dependent manner as typical for cysteine desulfurases.
Keywords: Abbreviations; AO; aldehyde oxidase; A. thaliana; Arabidopsis thaliana; Cnx1-E; N-terminal domain of Cnx1, homologous to; E. coli; MoeA; Cnx1-G; C-terminal domain of Cnx1, homologous to; E. coli; MogA; C. rheinhardtii; Chlamydomonas rheinhardtii; Cu; copper; Fe; iron; FAD; flavin adenine dinucleotide; MCP; molybdenum cofactor carrier protein; Mo; molybdenum; Moco; molybdenum cofactor; MPT; molybdopterin; NR; nitrate reductase; NO; nitric oxide; ROS; reactive oxygen species; SO; sulfite oxidase; XDH; xanthine dehydrogenase; XO; xanthine oxidaseMolybdenum cofactor; Sulfite oxidase; Nitrate reductase; Xanthine dehydrogenase; Aldehyde oxidase; Molybdenum cofactor deficiency
Iron uptake in fungi: A system for every source by Caroline C. Philpott (pp. 636-645).
Fungi have a remarkable capacity to take up iron when present in any of a wide variety of forms, which include free iron ions, low-affinity iron chelates, siderophore–iron chelates, transferrin, heme, and hemoglobin. Appropriately, these unicellular eukaryotes express a variety of iron uptake systems, some of which are unique to fungi and some of which are present in plants and animals, as well. The reductive system of uptake relies upon the external reduction of ferric salts, chelates, and proteins prior to uptake by a high-affinity, ferrous-specific, oxidase/permease complex. This system recognizes a broad range of substrates. The non-reductive system exhibits specificity for siderophore–iron chelates, and transporters of this system exhibit multiple substrate-dependent intracellular trafficking events.
Keywords: Yeast; Siderophore; Transport; Iron; Fungi; Ferrichrome
Iron-dependent metabolic remodeling in S. cerevisiae by Jerry Kaplan; Diane McVey Ward; Robert J. Crisp; Caroline C. Philpott (pp. 646-651).
All eukaryotes require iron although iron is not readily bioavailable. Organisms expend much effort in acquiring iron and in response have evolved multiple mechanisms to acquire iron. Because iron is essential, organisms prioritize the iron use when iron is limiting; iron-sparing enzymes or metabolic pathways are utilized at the expense of iron-rich enzymes. A large percentage of cellular iron containing proteins is devoted to oxygen binding or metabolism, therefore, changes in oxygen availability affect iron usage. Transcriptional and post-transcriptional mechanisms have been shown to affect the concentration of iron-containing proteins under iron or oxygen limiting conditions. In this review, we describe how the budding yeast Saccharomyces cerevisiae utilizes multiple mechanisms to optimize iron usage under iron limiting conditions.
Keywords: Iron; Heme; Metabolism; Oxygen; Sterol; Yeast
Mechanisms of iron–sulfur protein maturation in mitochondria, cytosol and nucleus of eukaryotes by Roland Lill; Rafal Dutkiewicz; Hans-Peter Elsässer; Anja Hausmann; Daili J.A. Netz; Antonio J. Pierik; Oliver Stehling; Eugen Urzica; Ulrich Mühlenhoff (pp. 652-667).
Iron–sulfur (Fe/S) clusters are important cofactors of numerous proteins involved in electron transfer, metabolic and regulatory processes. In eukaryotic cells, known Fe/S proteins are located within mitochondria, the nucleus and the cytosol. Over the past years the molecular basis of Fe/S cluster synthesis and incorporation into apoproteins in a living cell has started to become elucidated. Biogenesis of these simple inorganic cofactors is surprisingly complex and, in eukaryotes such as Saccharomyces cerevisiae, is accomplished by three distinct proteinaceous machineries. The ‘iron–sulfur cluster (ISC) assembly machinery’ of mitochondria was inherited from the bacterial ancestor of mitochondria. ISC components are conserved in eukaryotes from yeast to man. The key principle of biosynthesis is the assembly of the Fe/S cluster on a scaffold protein before it is transferred to target apoproteins. Cytosolic and nuclear Fe/S protein maturation also requires the function of the mitochondrial ISC assembly system. It is believed that mitochondria contribute a still unknown compound to biogenesis outside the organelle. This compound is exported by the mitochondrial ‘ISC export machinery’ and utilised by the ‘cytosolic iron–sulfur protein assembly (CIA) machinery’. Components of these two latter systems are also highly conserved in eukaryotes. Defects in the mitochondrial ISC assembly and export systems, but not in the CIA machinery have a strong impact on cellular iron uptake and intracellular iron distribution showing that mitochondria are crucial for both cellular Fe/S protein assembly and iron homeostasis.
Keywords: Iron–sulfur cluster; Ferredoxin; ABC protein; Chaperone; P-loop ATPase; Glutathione
Molecular control of vertebrate iron homeostasis by iron regulatory proteins by Michelle L. Wallander; Elizabeth A. Leibold; Richard S. Eisenstein (pp. 668-689).
Both deficiencies and excesses of iron represent major public health problems throughout the world. Understanding the cellular and organismal processes controlling iron homeostasis is critical for identifying iron-related diseases and in advancing the clinical treatments for such disorders of iron metabolism. Iron regulatory proteins (IRPs) 1 and 2 are key regulators of vertebrate iron metabolism. These RNA binding proteins post-transcriptionally control the stability or translation of mRNAs encoding proteins involved in iron homeostasis thereby controlling the uptake, utilization, storage or export of iron. Recent evidence provides insight into how IRPs selectively control the translation or stability of target mRNAs, how IRP RNA binding activity is controlled by iron-dependent and iron-independent effectors, and the pathological consequences of dysregulation of the IRP system.
Keywords: Iron; Iron regulatory protein; Iron responsive element; Translational control; RNA stability; Protein degradation; Iron–sulfur protein; Phosphorylation; Protein kinase C
Regulation of iron acquisition and iron distribution in mammals by Tomas Ganz; Elizabeta Nemeth (pp. 690-699).
Both cellular iron deficiency and excess have adverse consequences. To maintain iron homeostasis, complex mechanisms have evolved to regulate cellular and extracellular iron concentrations. Extracellular iron concentrations are controlled by a peptide hormone hepcidin, which inhibits the supply of iron into plasma. Hepcidin acts by binding to and inducing the degradation of the cellular iron exporter, ferroportin, found in sites of major iron flows: duodenal enterocytes involved in iron absorption, macrophages that recycle iron from senescent erythrocytes, and hepatocytes that store iron. Hepcidin synthesis is in turn controlled by iron concentrations, hypoxia, anemia and inflammatory cytokines. The molecular mechanisms that regulate hepcidin production are only beginning to be understood, but its dysregulation is involved in the pathogenesis of a spectrum of iron disorders. Deficiency of hepcidin is the unifying cause of hereditary hemochromatoses, and excessive cytokine-stimulated hepcidin production causes hypoferremia and contributes to anemia of inflammation.
Keywords: Hepcidin; Iron; Hemochromatosis; Anemia of inflammamtion; Iron transport
Hereditary hemochromatosis by Antonello Pietrangelo (pp. 700-710).
The advent of the genetics era has profoundly changed the way we look at iron related diseases, particularly hemochromatosis. New discoveries have challenged historical concepts about the disease, such as its monogenic nature, intestinal origin or complete phenotypic penetrance. This review presents a new concept of hemochromatosis which stems from the idea that, beyond their genetic diversities, all known hemochromatoses have in common the same metabolic abnormality: the genetically determined failure to prevent unneeded iron from entering the circulatory pool. Inappropriate levels of hepcidin, the iron hormone, appear now as the central pathogenic event in all forms of hemochromatosis: depending on the protein involved, and its effect on hepatic production of hepcidin, the phenotype varies, ranging from massive early-onset iron loading with severe organ disease (e.g., associated with homozygous mutations of hemojuvelin or hepcidin itself) to the milder late-onset phenotype characterizing the classic and highly prevalent HFE-related form or the rare transferrin receptor 2-related form. In vitro and in vivo studies will be needed to dissect the consequences of each hereditary hemochromatosis allele and increase our understanding of the precise contribution of each gene to the hereditary hemochromatosis phenotype.
Keywords: Iron overload; HFE; Hepcidin; Ferroportin; Hemojuvelin; Transferrin receptor 2
Zinc transporters and the cellular trafficking of zinc by David J. Eide (pp. 711-722).
Zinc is an essential nutrient for all organisms because this metal serves as a catalytic or structural cofactor for many different proteins. Zinc-dependent proteins are found in the cytoplasm and within many organelles of the eukaryotic cell including the nucleus, the endoplasmic reticulum, Golgi, secretory vesicles, and mitochondria. Thus, cells require zinc transport mechanisms to allow cells to efficiently accumulate the metal ion and distribute it within the cell. Our current knowledge of these transport systems in eukaryotes is the focus of this review.
Keywords: Zinc; Cell biology; Transporters; ZIP; CDF
Biosynthesis of heme in mammals by Richard S. Ajioka; John D. Phillips; James P. Kushner (pp. 723-736).
Most iron in mammalian systems is routed to mitochondria to serve as a substrate for ferrochelatase. Ferrochelatase inserts iron into protoporphyrin IX to form heme which is incorporated into hemoglobin and cytochromes, the dominant hemoproteins in mammals. Tissue-specific regulatory features characterize the heme biosynthetic pathway. In erythroid cells, regulation is mediated by erythroid-specific transcription factors and the availability of iron as Fe/S clusters. In non-erythroid cells the pathway is regulated by heme-mediated feedback inhibition. All of the enzymes in the heme biosynthetic pathway have been crystallized and the crystal structures have permitted detailed analyses of enzyme mechanisms. All of the genes encoding the heme biosynthetic enzymes have been cloned and mutations of these genes are responsible for a group of human disorders designated the porphyrias and for X-linked sideroblastic anemia. The biochemistry, structural biology and the mechanisms of tissue-specific regulation are presented in this review along with the key features of the porphyric disorders.
Keywords: Iron; Heme; Porphyrin; Porphyrias
Copper homeostasis in eukaryotes: Teetering on a tightrope by Kuppusamy Balamurugan; Walter Schaffner (pp. 737-746).
The transition metal copper is an essential trace element for both prokaryotes and eukaryotes. However, intracellular free copper has to be strictly limited due to its toxic side effects, not least the generation of reactive oxygen species (ROS) via redox cycling. Thus, all organisms have sophisticated copper homeostasis mechanisms that regulate uptake, distribution, sequestration and export of copper. From insects to mammals, metal-responsive transcription factor (MTF-1), a zinc finger transcription factor, controls expression of metallothioneins and other components involved in heavy metal homeostasis. In the fruit fly Drosophila, MTF-1 paradoxically acts as an activator under both high and low copper concentrations. Namely, under high copper conditions, MTF-1 activates metallothioneins in order to protect the cell, while under low copper conditions MTF-1 activates the copper importer Ctr1B in order to acquire scarce copper from the surroundings. This review highlights the current knowledge of copper homeostasis in eukaryotes with a focus on Drosophila and the role of MTF-1.
Keywords: Copper scarcity; Copper importers; Ctr1B; Copper load; Metallothioneins; Copper detoxification; MTF-1
Activation of superoxide dismutases: Putting the metal to the pedal by Valeria Cizewski Culotta; Mei Yang; Thomas V. O'Halloran (pp. 747-758).
Superoxide dismutases (SOD) are important anti-oxidant enzymes that guard against superoxide toxicity. Various SOD enzymes have been characterized that employ either a copper, manganese, iron or nickel co-factor to carry out the disproportionation of superoxide. This review focuses on the copper and manganese forms, with particular emphasis on how the metal is inserted in vivo into the active site of SOD. Copper and manganese SODs diverge greatly in sequence and also in the metal insertion process. The intracellular copper SODs of eukaryotes (SOD1) can obtain copper post-translationally, by way of interactions with the CCS copper chaperone. CCS also oxidizes an intrasubunit disulfide in SOD1. Adventitious oxidation of the disulfide can lead to gross misfolding of immature forms of SOD1, particularly with SOD1 mutants linked to amyotrophic lateral sclerosis. In the case of mitochondrial MnSOD of eukaryotes (SOD2), metal insertion cannot occur post-translationally, but requires new synthesis and mitochondrial import of the SOD2 polypeptide. SOD2 can also bind iron in vivo, but is inactive with iron. Such metal ion mis-incorporation with SOD2 can become prevalent upon disruption of mitochondrial metal homeostasis. Accurate and regulated metallation of copper and manganese SOD molecules is vital to cell survival in an oxygenated environment.
Keywords: Copper; Manganese; Iron; Mitochondria; ALS; Superoxide dismutase; SOD; CCS; Copper chaperone; Posttranslational modification; Disulfide isomerase; SOD1; SOD2; EC-SOD
Copper trafficking to the mitochondrion and assembly of copper metalloenzymes by Paul A. Cobine; Fabien Pierrel; Dennis R. Winge (pp. 759-772).
Copper is required within the mitochondrion for the function of two metalloenzymes, cytochrome c oxidase (CcO) and superoxide dismutase (Sod1). Copper metallation of these two enzymes occurs within the mitochondrial intermembrane space and is mediated by metallochaperone proteins. Cox17 is a key copper donor to two accessory proteins, Sco1 and Cox11, to form the two copper centers in the mature CcO complex. Ccs1 is the necessary metallochaperone for the copper metallation of Sod1 in the IMS as well as within the cytoplasm where the bulk of Sod1 resides. Copper ions used in the metallation of CcO and Sod1 appear to be provided by a novel copper pool within the mitochondrial matrix. This review documents copper ion shuttling within the mitochondrion and the proteins that mediate assembly of active CcO and Sod1.
Keywords: Copper; Mitochondrion; Cytochrome oxidase; Metallochaperone