conspectus of researchon copper metabolism and requirements

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1984 KARL E. MASON oxidase, diamine oxidase, benzylamineoxidase, etc.) but their significance in hu man metabolism is rather obscure. These proteins will be discussed in the general order mentioned. It may be noted that this panorama of cuproproteins has been sub ject to frequent changes in identification, description, terminology and functional at tributes over recent years. Hence, some statements and views expressed may be con sidered in a state of flux subject to consid erable revision as new advances are made. Ceruloplasmin (ferroxidase I) The classic studies of Holmberg and Laurell (346, 347 ) described a blue plasma copper-containing protein which they named "ceruloplasmin." They reported that it was an Â«-globulinrepresenting almost all the copper present in mammalian plasma, and differed remarkably from all other such proteins in its molecular weight of about 151,000 daltons, its copper content of about 0.32% and its content of eight atoms of copper per molecule. Human ceruloplasmin has been highly purified and crystallized as tetragonal crystals (537). According to Scheinberg and Morell (676), who provide an excellent review of the sub ject, its molecular weight may vary from 132,000 to 160,000, depending upon the method employed. More recently, it has been reported that its molecular weight is 134,000 Â±3,000, and that the number of copper atoms varies from 6 to 6.6 (653). Of these, about one-half are in the cupric and the other half in the cuprous state (395). The nature of the copper-protein bond is not known. It is also recognized that ceruloplasmins from different animals show some cross-reactivity (395) and that they differ in p-phenylenediamine oxidase activity (502). Two other blue oxidases, ascorbate oxidase and lacease are enzymes found only in the plant world, where ceruloplasmin does not exist. An excellent comparison of the chemical structure and physiological properties of these three ox idases is given by Dawson et al. (151). Ceruloplasmin contains about 8% car bohydrate, composed principally of glucosamine, mannose and galactose. Almost, if not all, of its oligosaccharide side chains are terminated by a sialic acid residue, ap parently essential for its survival in the cir culation (550). Copper is incorporated into ceruloplasmin only at the time of its syn thesis in the liver and the liver is its only site of synthesis (439, 742, 824). In the blood stream ceruloplasmin does not ex change its copper with other copper com plexes in the serum or blood cells. In vitro, copper is released from ceruloplasmin only after acidification, indicating strong protein binding of copper. Ceruloplasmin is hetero geneous, existing in several forms depend ing upon its prosthetic carbohydrate groups (65, 535). A moderate oxidase activity of cerulo plasmin toward a variety of substrates, of which p-phenylenediamine is the best, was recognized by Holmberg and Laurell (348) in 1951. This enzyme reaction, as employed in the method of Ravin (629), has pro vided a useful means of qualitatively mea suring ceruloplasmin in body fluids. There has also been developed an immunological method using highly purified human ceru loplasmin as an antigen to incite specific antibody, usually in rabbits (339, 490, 674). Careful studies of Rosenberg et al. (644) demonstrate that both methods yield com parable results. Although ceruloplasmin is primarily a plasma protein, it is found also in synovial, ascitic and cerebrospinal fluids (744). Much interest has centered around this protein not only because of the mystery surrounding its true physiological functions but also because of impairment of its syn thesis and other possible derangements in Wilson's disease (p. 2009) and its low plasma levels associated with Menkes' kinky-hair (steely-hair) syndrome, a genetically de termined copper-deficiency disease in chil dren (p. 2005). It is of interest that in the early studies of Holmberg and Laurell, who were aware of recent evidence of abnormalities of copper metabolism in Wilson's disease, ceruloplasmin plasma levels were found to be normal in a pa tient said to have Wilson's disease but who, several years later, was found not to be a victim of that disease. Hence, as stated by Scheinberg (671 ), "The capstone of physi ological significance to these discoveries ironically and undeservedly eluded them/' This same type of study carried out by Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 1985 Scheinberg and Gitlin (674) laid the basis of the concept that Wilson's disease is usually characterized by a lifelong defi ciency or absence of ceruloplasmin, and that this deficiency is autosomal recessive in nature. Advances in knowledge concerning ceru loplasmin, as well as the role of copper in human metabolism, have in large part been the consequence of intensive research on the nature, cause and treatment of Wilson's disease, resulting in truly voluminous lit erature. In contrast, investigations con cerning Menkes" disease have focused largely on the role of metallothionein-like cuproproteins and defects in intestinal ab sorption of copper. Here also, in the in terim since its first recognition in 1962 (513), an extensive literature has evolved. On the other side of the ledger are ad vances made during the past 12 years in elucidating the role of copper in iron me tabolism. These have, in large part, re solved questions in the minds of those investigators of 50 years ago (311, 313) who first recognized the important role of copper in nutrition. The role of ceruloplasmin in biological processes began to receive some rational explanation about 1960, with evidence that in vitro it catalyzed the oxidation of fer rous iron ( 141). Further investigation of this oxidase activity of ceruloplasmin pro vided indications that it represented an enzyme in human plasma responsible for oxidation of ferrous iron, and that the latter was the substrate for its greatest activity (504, 583, 585). Based on these findings, Osaki et al. (583) proposed that the name ferroxidase may be more useful than desig nating this enzyme as a "sky-blue substance from plasma." Since then, ceruloplasmin and ferroxidase I have become synonymous terms. However, in the discussion to follow the more common designation "ceruloplas min" will be used. The hypothesis proposed was that by this mechanism ceruloplasmin may play an important biological role in the release and transfer of iron from storage cells to plasma transferrin. This concept was promptly supported by studies on copper-deficient swine (445, 446, 625), and by liver per fusion studies on dogs and swine (584). The studies on copper-deficient swine clearly demonstrated the effectiveness of ceruloplasmin in counteracting the defec tive movement of iron from hepatic cells, reticuloendothelial cells and the intestinal mucosa to the plasma. This general subject has been extensively discussed and re viewed elsewhere (211, 226-230, 390, 446). The current concept of ceruloplasmin function in iron metabolism appears to be as follows. For normal hemoglobin syn thesis iron must be transported from stor age sites in the liver, reticuloendothelial system and intestine to the bone marrow by transferrin. In the storage sites iron is present in the ferric state, as ferritin. This iron can be reduced by reduced riboflavin and riboflavin derivatives, liberating fer rous iron from the ferritin. This ferrous iron is then oxidized catalytically back to ferric iron by virtue of the ferroxidase ac tivity of ceruloplasmin, allowing the Fe3* to combine with apotransferrin, as the initial step in the mobilization of stored iron. The mechanism of iron transfer from the storage cell to transferrin has not been clearly established. It is possible that Fe2+ and ceruloplasmin interact to form a ferric intermediate that transfers iron to apo transferrin by a specific ligand exchange reaction (850). In any case, Fe3* combines with transferrin and provides the progeni tors of the erythrocytes in the bone mar row with the necessary iron for hemoglobin synthesis. As has been expressed (230), the life cycle of the copper in ceruloplas min is a one-time journey to the tissues or a return to the liver for resynthesis. Ceruloplasmin is a multifunctional pro tein involved not only in the mobilization of plasma iron but also in copper transport and in regulation of biogenic amines. The suggestion of Broman (65) that it func tions as a copper-transport protein has been well substantiated by animal studies indi cating that its copper atoms are trans ferred to cytochrome c oxidase and prob ably to other copper-containing proteins of body tissues (230, 365). Close correla tions between low serum ceruloplasmin and low cytochrome c oxidase in leuco cytes in Wilson's disease (715) suggest that the same is true in man. Ceruloplas- Downloaded from jn.nutrition.org by guest on February 27, 2013
Page 1 and 2: A CONSPECTUS OF RESEARCH ON COPPER
Page 3 and 4: INTRODUCTION The discovery of coppe
Page 5: COPPER METABOLISM AND REQUIREMENTS
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Page 55 and 56: Ã®1co 1stW Â»aÂ«a3 COPPER MET
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COPPER METABOLISM AND REQUIREMENTS
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