Ceruloplasmin and the reactions forming differic transferrin

Chidambaram, M. V.; Barnes, Grady; Frieden, Earl

doi:10.1016/0014-5793(83)80432-3

Cited by 29 publications

(17 citation statements)

References 11 publications

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“…The complete absence of Cp, because of inherited mutations (17) or targeted disruption of the Cp gene (18), leads to a long term accumulation of parenchyma iron due to an impaired iron efflux from cells. The oxidation of the Fe(II) released from cells and its subsequent incorporation into apotransferrin would be the mechanism whereby Cp is involved in mediating iron release from cellular stores (19,20). Analogously, the ferroxidase reaction performed by Fet3 is also an essential reaction for the high affinity iron uptake in yeasts (13,21).…”

Section: Ceruloplasmin (Cp)mentioning

confidence: 99%

Site-directed Mutagenesis of Human Ceruloplasmin

Bielli¹,

Bellenchi²,

Calabrese³

2001

Journal of Biological Chemistry

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A fully active recombinant human ceruloplasmin was obtained, and it was mutated to produce a ceruloplasmin stable to proteolysis. The stable ceruloplasmin was further mutated to perturb the environment of copper at the type 1 copper sites in two different domains. The wild type and the mutated ceruloplasmin were produced in the yeast Pichia pastoris and characterized. The mutations R481A, R701A, and K887A were at the proteolytic sites, did not alter the enzymatic activity, and were all necessary to protect ceruloplasmin from degradation. The mutation L329M was at the tricoordinate type 1 site of the domain 2 and was ineffective to induce modifications of the spectroscopic and catalytic properties of ceruloplasmin, supporting the hypothesis that this site is reduced and locked in a rigid frame. In contrast the mutation C1021S at the type 1 site of domain 6 substantially altered the molecular properties of the protein, leaving a small fraction endowed with oxidase activity. This result, while indicating the importance of this site in stabilizing the overall protein structure, suggests that another type 1 site is competent for dioxygen reduction. During the expression of ceruloplasmin, the yeast maintained a high level of Fet3 that was released from membranes of yeast not harboring the ceruloplasmin gene. This indicates that expression of ceruloplasmin induces a state of iron deficiency in yeast because the ferric iron produced in the medium by its ferroxidase activity is not available for the uptake.

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Section: Ceruloplasmin (Cp)mentioning

confidence: 99%

Site-directed Mutagenesis of Human Ceruloplasmin

Bielli¹,

Bellenchi²,

Calabrese³

2001

Journal of Biological Chemistry

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“…Furthermore, in vitro ferroxidase catalysis of iron release from the liver was demonstrated, as was the formation of holo-Tf from a mixture of Fe(II) and apo-Tf (22)(23)(24). Recent experiments show that this ferroxidase-dependent release of iron from cells is associated with Fpn iron transport catalyzed by Cp or Hp (25).…”

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confidence: 99%

Redox Cycling in Iron Uptake, Efflux, and Trafficking

Kosman

2010

Journal of Biological Chemistry

106

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Aerobic organisms are faced with a dilemma. Environmental iron is found primarily in the relatively inert Fe(III) form, whereas the more metabolically active ferrous form is a strong pro-oxidant. This conundrum is solved by the redox cycling of iron between Fe(III) and Fe(II) at every step in the iron metabolic pathway. As a transition metal ion, iron can be "metabolized" only by this redox cycling, which is catalyzed in aerobes by the coupled activities of ferric iron reductases (ferrireductases) and ferrous iron oxidases (ferroxidases).Following the first crystallization of a protein, jack bean urease, reported by Sumner in 1926 (1), the evolution of protein chemistry remained a slow process, hampered by limitations in techniques for protein resolution and analysis. Not surprisingly, many proteins obtained in relatively pure form were those with prosthetic metal ion groups that imparted a visible absorbance to guide the purification. Some were copper proteins whose Cu(II) spectral properties gave their protein host a greenish blue to bright blue hue. Two of these were from mammalian whole blood: hemocuprein (cupric species from erythrocytes, superoxide dismutase) and ceruloplasmin (cerulean blue species from plasma). Superoxide dismutase was first isolated in 1938 by Mann and Keilin (5); Cp 2 was first isolated in 1948 by Holmberg and Laurell (6). Both proteins play essential roles in aerobic homeostasis. In the case of ceruloplasmin and the other copper proteins that share its substrate specificity, this role is to manage the redox state of iron in the metabolism of this essential yet potentially cytotoxic transition metal ion. These proteins, all of which are members of the MCO family (7-9), and the mechanism by which they provide this function are a focus of this minireview.

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“…This coupling of the ferroxidase activity of hCp to its iron-binding sites suggests a molecular basis for the link between Cp and iron homeostasis in mammals, i.e. in the plasma, Cp catalyzes the oxidation of Fe(II) released from both erythrocytes and other cell types so that the resulting Fe(III) can be bound by transferrin, thus suppressing the level of "free" Fe(II) in the circulation (12,13). The correlation between the absence of serum hCp (and its ferroxidase activity) and lipid peroxidation on the one hand (14) and cellular degeneration in the substantia nigra on the other (15,16), is consistent with this suggestion.…”

mentioning

confidence: 99%