conspectus of researchon copper metabolism and requirements

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1988 KARL E. MASON and has a molecular weight of about 33,000 daltons. Actually it may represent a series of cuproproteins which catalyze a series of reactions that convert tyrosine to melanin (213, 479). The enzymatic activity is thought to be associated with the mitochondrial component of cells. The skin and uveal tissues of the eye in human albinos have no demonstrable tyresinase activity; hence, the absence of melanin. Decreased production of tyrosinase is responsible for the loss of hair pigmentation in animals deficient in copper and in infants with Menkes' steely-hair syndrome. Dopamine ÃŸ-hijdroxylase This cuproprotein (3,4-dihydroxyphenylethylamine ÃŸ-hydroxylase) is an oxidase containing 4 to 7 copper atoms per mole cule and having a molecular weight of about 290,000 daltons (232). It was origi nally isolated from beef adrenals and later from cattle brain and hearts. In experimen tal animals it appears to serve a function in catalyzing the conversion of dopamine to form norepinephrine (568, 570). A com parable role in man may be assumed but has not been proven. Metallothionein The rather tortuous history of identifica tion and nomenclature of copper proteins leading up to the proper recognition of Superoxide dismutase has been somewhat paralleled by the history of metallothionein. This designation was given by Kagi and Vallee (392, 393) to a protein iso lated from equine and human kidney, with a molecular weight of about 10,000 daltons, a content of 26 sulfhydryl groups per mole, and a capacity to bind zinc and cadmium as well as copper. Metallothionein is not an enzyme. By virtue of its high content of sulfhydryl groups it binds copper by forming mercaptides. In fact, it may repre sent a family of metallothioneins specifi cally designed for the binding of either one metal or specific groups of metals such as copper, zinc and cadmium. Accumulating knowledge of metallothionein or metallothionein-like proteins, with variable affinities for copper, especially as they occur and function in the intestinal mucosa and liver, may well add greatly to our understanding of the two clinical dis orders of copper metabolism in man; namely, Wilson's disease and Menkes' steely-hair syndrome. For example, one recognized and basic defect in Menkes' disease is an inadequate transport of cop per across the intestinal mucosa (145, 147). It is possible that the retention of abnormal amounts of copper in the in testinal mucosa involves increased affinity of a mucosal metallothionein or of another protein not normally involved in copper transport (351). Furthermore, there is evi dence that the usual metallothionein con cerned with storage and release of ab sorbed copper in the liver may, in Wilson's disease, be of an abnormal type with a binding constant about four times greater than normal ( 197). An unusual variant of metallothionein, referred to as neonatal hepatomitochondrocuprein, has been isolated from immature bovine liver and from human newborn liver (615). It contains 25% cystine and about 49Â¿copper, which is at least 10 times that of adult hepatocuprein. It increases just before birth and decreases rapidly during the first few months of postnatal life, as it is released for synthesis of ceruloplasmin, which is present in plasma in small amounts at birth. It is thought to represent a special storage type of protein to tide the newborn infant over the early period of life when breast milk does not meet normal requirements (610 ). Although concentrated in the heavy mitochondrial fraction, it is not a true mitochondrial con stituent in that some of it may be localized in lysosomes of a "heavy" type, and prob ably represents a polymer of metallothio nein (614). Other cuproproteins Since the identification and characteriza tion of a sulfhydryl-rich cuproprotein in human liver with a molecular weight of 8,000 to 10,000 daltons, designated L-6D (536, 703), there have been described similar cuproproteins derived from chick intesane (733), rat liver (856), rat intes tine ( 198), adult human liver ( 74 ) and human fetal liver (654). These proteins differ somewhat with respect to estimated molecular weight, copper content and amino-acid components, especially cysteine Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 1989 and thionein, which may reflect differences in methods employed in isolation and analysis as well as species differences in composition. There is good reason to be lieve that they have important functions in copper-homeostatic mechanisms such as storage, transport and detoxification, espe cially in the intestine and liver. Unques tionably, future research will clarify many of these differences and delineate more clearly the physiological and biochemical role(s) of these low-molecular weight cuproproteins. Monoamine oxidases. Aside from lysyl oxidase, there are other amine oxidases that are present in connective tissues (116, 330, 334, 335). It is now presumed that these oxidases serve in deamination of norepinephrine, serotonin and histamine. Amine oxidases, presumably containing copper, derived from beef and swine plasma have been highly purified and crystallized (73, 308, 649, 807, 867). A monoamine oxidase from human plasma has also been purified (505) and is said to increase in states of congestive heart failure and parenchymal liver disease (506). However, whether or not this enzyme is copper dependent is not clear. Diamine oxidase. Purification of diamine oxidase from pig kidney has been carried out by many investigators since 1943. Its crystallization was first reported by Yamada et al. (866) who described it as a pink copper-protein containing 2.17 atoms of copper per molecule, capable of oxidiz ing histamine, cadaverine, putrescine and other like substances. The identity of this enzyme with histiminase had previously been proposed by Mondovi et al. (534). Whether this enzyme plays a role in human metabolism remains to be determined. Albocuprein I and II. These two color less cuproproteins, neither of which possess enzyme activity or undergo alterations in pathological states, have been isolated from human brains (238). Both contain hexoses. Albocuprein II may be the pri mary copper-containing protein of the brain (550). Uncase (urate oxidase}. This cuproprotein, found in the kidney and liver of lower mammals, has a molecular weight of about 110,000, a copper content of 0.6% and is involved in the catabolism of uric acid. There are no recognized effects of its de ficiency or excess in animals. It does not occur in primates (478). Tryptophan-2,3-dioxygenase. This heme protein with a molecular weight of 167,000 daltons and 2 cuprous atoms per molecule, isolated from rat liver cytosol (694), is said to catalyze the insertion of molecular oxygen into the pyrrole ring of L-tryptophan (58). Pink copper protein. A pink copper pro tein with a molecular weight of about 32,000 has been isolated from human erythrocytes (631). The biological function of this protein still remains to be demon strated. Mitochondrial monoamine oxidase. This enzyme, previously obtained in highly puri fied form from many sources (beef and hog plasma, human plasma, rabbit serum, liver and kidney of several animal species, and human placenta) has been isolated from human liver, and identified as a flavoprotein with a molecular weight of 64,000 (563). It is said to have the ability to oxidize epinephrine and serotonin. On the other hand, its status as a cuproenzyme has since been questioned (730). The large number of cuproproteins and the multiplicity of their enzymatic func tions, as well as the homeostatic mecha nisms involved in normal metabolism of copper, emphasize its great importance in mammalian nutrition. For further aspects of cuproproteins, the reader is referred to a series of reviews (191-195, 211, 308, 309, 350, 458, 550, 568-570, 634, 650, 663, 671, 676). ABSORPTION OF COPPER As is true of most metals, absorption of copper is regulated at the level of the in testinal mucosa and excretion is predomi nantly through the intestinal tract, either via the bile or as nonabsorbed copper. Urinary excretion is negligible in normal healthy man, amounting to about 1 to 2% of the intake. Although the site of maximal absorption of copper varies among different mam malian species, in man absorption occurs primarily in the stomach and duodenum. This conclusion is based upon observations 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 and 6: 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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