Approximately one dozen cuproenzymes have been characterized in mammals. The highaffinity iron uptake systems in the opportunistic pathogen candida albicans are activated under iron limited conditions and are also required for virulence. Ceruloplasmin is a member of the multicopper oxidase family, an evolutionarily conserved group of proteins that utilize copper to couple substrate oxidation with the 4electron reduction of oxygen to water. Novel insight into the expression and function of the. Iron acquisition is a critical aspect of the virulence of many pathogenic microbes. Multicopper oxidases and human iron metabolism mdpi. T1 and t2 types containing one copper atom and the diatomic t3 type. Multicopper oxidases are an important class of oxidases reducing dioxygen in a fourelectron reduction to water with concomitant oneelectron oxidation of the reducing substrate. The progress in the characterization and understanding of the structure and function of these enzymes has advanced so tremendously over the last ten years that the. The multicopper oxidase mco family of enzymes includes laccases, which oxidize a broad range of substrates including polyphenols and phenylendiamines.
Multicopper oxidases and human iron metabolism europe pmc. Mcos are descended from the family of small blue copper proteins cupredoxins that likely arose as a complement to the hemeironbased cytochromes involved in electron transport. Iron is essential for oxidationreduction catalysis and bioenergetics, but unless appropriately shielded, iron plays a key role in the formation of toxic oxygen radicals that can attack all biological molecules. To date, three multicopper oxidases have been detected in humansceruloplasmin. Aging results in iron accumulations in the nonhuman primate choroid of the eye without an associated increase. Multicopper oxidases and human iron metabolism europe. The human transferrin shell by itself has a molecular mass between 430 and 460. A multicopper oxidase cj1516 and a copa homologue cj1161.
The results indicate that iron accumulates in hotspots in the choroid with age with. Biomolecular nmr facility 37 chalmers hall 7855322345. Mcos include laccases and several oxidases with specific substrates, such as ascorbate, metal ions and bilirubin. Taken together with recent work indicating an essential role for a homologous copper protein in gastrointestinal iron absorption 11, these clinical observations reveal a critical function for multicopper oxidases in human iron metabolism. Iron and copper transport in yeast and its relevance to human. The work presented in this thesis describes the occurrence and properties of two multicopper oxidases derived from lichens. Ferrous binding to the multicopper oxidases saccharomyces.
The highaffinity ironuptake systems in the opportunistic pathogen candida albicans are activated under ironlimited conditions and are also required for virulence. Iron metabolism disorders most common form of anemia symptom of pathologic process primary manifestation is hematologic treatment requires. However, the role of mcfs in renal metabolism remains unclear. Redox cycling between the two oxidation states is a critical aspect of iron metabolism because the two forms of iron have different properties. Multicopper oxidases and human iron metabolism ganna vashchenko 1 and ross t. Hephaestin is involved in the metabolism and homeostasis of iron and possibly copper. The three multicopper oxidases important for human iron metabolism. Hephaestin and ceruloplasmin facilitate iron metabolism in. Neither of these proteins nor their corresponding genes have been isolated. Xray crystallographic techniques have been used to elucidate the structure of human ceruloplasmin at a resolution of 3.
To date, three mcos have been identified in human body. Jun 27, 20 multicopper oxidases and human iron metabolism. As multicopper oxidases like cp are thought to be the major metabolic link between copper and iron, additional research is needed to determine the impact, if any, of lower gpicp on iron flux and the development of anemia when copper is limiting. It is remarkable the profusion of oxidases suppliers of hydrogen peroxide in fungi.
Aging results in iron accumulations in the nonhuman. The involvement of a multicopper oxidase in iron uptake by. Characterization of the multicopper oxidase gene family in. Department of biochemistry and molecular biophysics. Phylogenetic comparison and classification of laccase and. They are copper containing proteins characterised by distinctive structural. Aug 14, 2015 iron acquisition is a critical aspect of the virulence of many pathogenic microbes. Metal ion homeostasis mechanisms in the foodborne human pathogen campylobacter jejuni are poorly understood. A common feature of all enzymes included in the mco family is the presence of a catalytic centre composed of at least four copper atoms divided on account of their spectroscopic and magnetic properties into three types. As well as being found in the basolateral membrane of the duodenal enterocyte, ferroportin is also found in macrophages and hepatocytes. Multicopper oxidases and human iron metabolism core. The multicopper oxidase mco family of enzymes includes laccases, ferroxidases, cuprous oxidases, ascorbate oxidases and bilirubin oxidases sakurai and kataoka, 2007. T1 a fungal multicopper oxidase restores iron homeostasis in aceruloplasminemia.
Multicopper oxidase1 is a ferroxidase essential for iron. Multicopper ferroxidases mcfs play an important role in cellular iron homeostasis. Multicopper oxidases mcos are a diverse group of enzymes that couple the oxidation of a variety of substrates to the reduction of dioxygen and include notable members such as ascorbate oxidase, fet3p, cueo, ceruloplasmin, and laccases kosman, 2010. Ferrous binding to the multicopper oxidases saccharomyces cerevisiae fet3p and human. The highest expression of hephaestin is found in small intestine. Their high specificity for feii has been attributed to the existence of a binding site for iron.
Studies of the yeast homologs of human disease genes involved in metal homeostasis have shed light on the pathophysiology of these disorders. Laccases have exceptionally broad substrate specificity whereas the other family members tend to oxidize a single substrate in vivo. Especially the recent discovery of a key role of the fet3 protein of saccharomyces cerevisae, a multicopper oxidase, in iron metabolism of this eukaryote has underpinned the function of the plasma multicopper oxidase ceruloplasmin in vetebrate iron transport. The presence of multiple mco paralogs confirms their important role in human iron metabolism and grants the additional plasticity in the regulation of iron toxicity and export from the cell. Despite numerous data on laccases and tyrosinases in fungi and flowering plants, this is the first report of the occurrence of these enzymes in lichenized ascomycetes. Next to its function in iron metabolism, it has been suggested a protective role for fet3p by suppressing copper and iron cytotoxicity. Replacement therapy correction of underlying cause if possiblecorrection of underlying cause if possible iron. The cj1516 gene product is homologous to the multicopper oxidase cueo, which is known to contribute to copper tolerance in escherichia coli. A fungal multicopper oxidase restores iron homeostasis in. Multicopper oxidases classification, structure and properties. Saccharomyces cerevisiae fet3p and human ceruloplasmin hcp are members of this family that exhibit ferroxidase activity.
Macgillivray 2, 1 department of cellular and physiological sciences, university of british columbia, 2350 health sciences mall, vancouver, bc, v6t1z3, canada. A recent paper presents in vitro data suggesting that ceruloplasmin also increases cellular iron accumulation14. Multicopper oxidase an overview sciencedirect topics. Generally, multicopper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different species. Here one component of highaffinity iron uptake systems, the multicopper oxidase mco genes, was characterized. Despite the need for copper in ceruloplasmin function, this protein plays no essential. Recent progress in the field of copper and iron metabolism has resulted from a convergence of human and yeast genetics. Multicopper oxidases mcos are enzymes that catalyse the oxidation of a wide range of substrates by reducing o 2 to h 2 o without releasing activated oxygen species 1, 2. A phylogenetic analysis of more than 350 multicopper oxidases mcos from fungi, insects, plants, and bacteria provided the basis for a refined classification of this enzyme family into laccases sensu stricto basidiomycetous and ascomycetous, insect laccases, fungal pigment mcos, fungal ferroxidases, ascorbate oxidases, plant laccase.
N2 mutations that lead to a loss of the coppercontaining plasma enzyme ceruloplasmin disrupt mammalian iron homeostasis. Structural insights into the o2 reduction mechanism of. We previously identified, by analysis of differentially expressed plasma membrane proteins, an approximately 150kd protein whose synthesis was induced under. Ceruloplasmin is a serum ferroxidase that contains greater than 95% of the copper found in plasma. This protein is a member of the multicopper oxidase family, an evolutionarily conserved group of proteins that utilize copper to couple substrate oxidation with the fourelectron reduction of oxygen to water. Impact of copper limitation on expression and function of. Hence, specialized molecules for the acquisition, transport transferrin, and storage ferritin of iron in a soluble nontoxic form have evolved. Targeted gene disruption reveals an essential role for. Ceruloplasmin is the homologue of fet3 that is found in the sera of all vertebrates sato and gitlin, 1991 and has been assigned a number of biological functions over the last 50 years messerschmidt and huber, 1990. It is a transmembrane copperdependent ferroxidase responsible for transporting dietary iron from intestinal enterocytes into the circulatory system.
The mechanisms of iron and copper transport are remarkably conserved between yeast and humans. However, it is now established that the central role for. We previously identified, by analysis of differentially expressed plasma membrane proteins, an approximately 150kd protein whose synthesis was induced under conditions. Iron and copper transport in yeast and its relevance to. The genome of anopheles gambiae, a species of mosquito, encodes five putative multicopper oxidases. To date, three multicopper oxidases have been detected in humansceruloplasmin, hephaestin and zyklopen.
Multicopper oxidases mcos are unique among copper proteins in that they contain at least one each of the three types of biologic copper sites, type 1, type 2, and the binuclear type 3. Aging results in iron accumulations in the nonhuman primate. Jun 27, 20 multicopper oxidases and human iron metabolism ganna vashchenko 1 and ross t. The structure reveals that the molecule is comprised of six plastocyanintype domains arranged in a triangular array. Dec 19, 2016 multicopper ferroxidases mcfs play an important role in cellular iron homeostasis. To a lesser extent hephaestin has been detected in colon, spleen, kidney, breast, placenta and bone trabecular cells but its role in these tissues remains to be established. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter protein in humans. Mcos are descended from the family of small blue copper proteins cupredoxins that likely arose as a complement to the heme iron based cytochromes involved in electron transport. The lately determined xray structure of human ceruloplasmin confirms its close. Iron is an essential element required for most organisms. Anemia of copper deficiency was first described in the 19th century, but the underlying biochemistry remains unknown. Biotechnology core facility 206 burt hall 7855325956 7855326297 fax.
It is limited to enterocytes of the villi where the iron absorption takes place. Their high specificity for feii has been attributed to the existence of a binding. They are found in numerous organisms, from bacteria to humans, and have. Four of these are referred to as multicopper oxidases mco due to their copper binding geometries. Here one component of highaffinity ironuptake systems, the multicopper oxidase mco genes, was characterized. The multicopper oxidase of pseudomonas aeruginosa is a. The multicopper oxidases are a family of enzymes that couple the reduction of o 2 to h 2 o with the oxidation of a range of substrates. In addition to the oxidation of organic substrates, all human mcos can oxidize ferrous iron feii. Mj pippard, in blood and bone marrow pathology second edition, 2011. The multicopper oxidases are a family of enzymes that couple the reduction of o2 to h2o with the oxidation of a range of substrates. Here we show, by optical absorbance and electron paramag. Multicopper oxidases mcos are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules.973 1130 831 532 1539 668 283 217 1444 1536 209 636 1541 1151 978 760 789 431 548 1162 1292 1283 354 1535 500 350 1199 742 35 256 1243 550 1471 151 90 610 565 560 653 203