The Biology of Human Ceruloplasmin

Zl, Harris; Morita, Hayato; Gitlin, Jd; Harris, Z. Leah

doi:10.1142/9789812830081_0010

Cited by 11 publications

(15 citation statements)

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“…Unchanged ceruloplasmin oxidative activity, in the presence of increased levels of ceruloplasmin, resulted in lower specific activity (activity related to mass) in the oldest patients as compared with the younger patients but not when the patients were compared as a whole group with their controls (Results and table 3). Increased ceruloplasmin levels with concomitant increase in copper levels, although not mathced by significantly increased ceruloplasmin oxidative activity, might tentatively be explained as a stress-related compensatory phenomenon (Harris et al 1997) or, perhaps, as compensatory increase oriented towards lower specific activity (table 3). These results, irrespective of cause, are different from what we have previously found in patients with Alzheimer's disease (Snaedal et al 1998).…”

Section: Discussionmentioning

confidence: 98%

Copper, Ceruloplasmin and Superoxide Dismutase (SOD1) in Patients with Down's Syndrome

Tórsdóttir

Kristinsson

Hreidarsson

et al. 2001

Pharmacology & Toxicology

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The aim of this study was primarily to investigate whether similar signs of copper dyshomeostasis occur in dementia with age in Down's syndrome as previously found in Alzheimer's disease. Copper was accordingly determined in plasma, ceruloplasmin concentration in serum, ceruloplasmin oxidative activity and ceruloplasmin specific oxidative activity (activity related to mass) in serum, and superoxide dismutase (SOD1) in erythrocytes in 35 (27 males, 8 females) 18-53 years old (average 37 years) patients with Down's syndrome (Down's patients) and their age- and gender-matched controls. SOD1 activity was on an average almost 50% higher in the patients than in their controls but the evidence of a causal relationship between increased SOD1 activity and Down's syndrome appears at best equivocal. Copper and ceruloplasmin levels and ceruloplasmin activities were similar in the patients and their controls. Ceruloplasmin and copper levels increased significantly with age in the patients but not in the controls. Ceruloplasmin activities or SOD1 activity did not change significantly with age, neither in the patients nor in the controls as whole groups. When SOD1 activity and ceruloplasmin activities of the oldest in the patients group (40 years or older) were compared with those of the younger patients, respectively, SOD1 activity and specific oxidative activity, but not ceruloplasmin oxidative activity were found to decrease significantly with age. The results thus suggest that development of dementia in Down's patients with age is paralleled with decrease in SOD1 activity and specific oxidative activity but not with decrease in ceruloplasmin oxidative activity itself as was also found in Alzheimer's patients.

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Section: Discussionmentioning

confidence: 98%

Copper, Ceruloplasmin and Superoxide Dismutase (SOD1) in Patients with Down's Syndrome

Tórsdóttir

Kristinsson

Hreidarsson

et al. 2001

Pharmacology & Toxicology

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“…Our findings could be of physiological relevance. After decades of debate, it is now clear that, in vivo , CP exerts a ferroxidase activity, as demonstrated by clinical studies on patients lacking a functional CP gene and having severe iron dismetabolism [2,51]. This recent achievement of knowledge, however, still has not ruled out the hypothesis that CP has multifunctional roles.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of CP, a number of substrates, including phenols and aromatic amines can be oxidized by the protein [1], and the oxidation of p ‐phenylenediamine ( p PD) constitutes in fact a classic assay for the enzymatic activity of CP. However, Fe(II) is by far the best substrate in vitro , in terms of both K m and V max [1] and the ferroxidase activity of CP is now considered one of the main functions of the protein in vivo [2].…”

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confidence: 99%

The multifunctional oxidase activity of ceruloplasmin as revealed by anion binding studies

Musci¹,

Bellenchi²,

Calabrese³

1999

European Journal of Biochemistry

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The effect of multiple binding of azide, N 3 2 , on the structural and functional properties of ceruloplasmin (CP) has been reinvestigated by means of both spectroscopic and enzymatic techniques. High affinity binding of the anion to human CP resulted in a dramatic increase of the absorbance at 610 nm and in a concomitant decrease of the optical density at 330 nm. The oxidase activity toward Fe(II) was essentially unaffected, while turnover parameters versus nonferrous substrates dramatically changed, with an < 100-fold enhancement of the k cat /K m parameter. Chloride at physiological concentration proved to behave very similarly to N 3 2 bound with high affinity, in that it not only induced the spectroscopic changes previously interpreted in terms of an intramolecular electron transfer from reduced type 1 to type 3 copper ions [Musci, G., Bonaccorsi di Patti, M.C. & Calabrese, L. (1995) J. Protein Chem. 14, 611±617], but it also enhanced some 60-fold the k cat /K m value. A different behavior was observed with chicken CP, where a decrease at 330 nm occurred without a concomitant modification at 603 nm. The chicken enzyme was less sensitive also in terms of enzymatic activity, which was nearly unchanged in the presence of either high affinity N 3 2 or Cl 2 . At higher N 3 2 concentrations, optical changes of both human and chicken CP were mainly focussed on the appearance of ligand-to-metal charge transfer bands below 500 nm, and the anion behaved as an inhibitor of the oxidase activity versus Fe(II) as well as noniron substrates. The well known bleaching of the blue chromophore could be observed, at neutral pH, only at very high N 3 2 /CP ratios. The data presented in this paper are consistent with a mechanism of structural and functional modulation of CP by anions, that would be able to dictate the substrate specificity of the cuproprotein, and suggest the possibility that CP may act in vivo as a multifunctional oxidase.Keywords: ceruloplasmin; azide; chloride; anions; iron.Ceruloplasmin (CP), the blue oxidase of vertebrate plasma, is a complex, multidomain protein which regulates iron and copper metabolism. Blue oxidases couple the oxidation of a reducing substrate to the four-electron reduction of dioxygen to water. In the case of CP, a number of substrates, including phenols and aromatic amines can be oxidized by the protein [1], and the oxidation of p-phenylenediamine (pPD) constitutes in fact a classic assay for the enzymatic activity of CP. However, Fe(II) is by far the best substrate in vitro, in terms of both K m and V max [1] and the ferroxidase activity of CP is now considered one of the main functions of the protein in vivo [2].The crystallography of human CP has confirmed the presence of six copper ions [3]. Three mononuclear sites contain type 1`blue' ions that are characterized, in their oxidized state, by a strong absorption band at around 600 nm (1 <5000 m 21´c m 21 ) and by unusual magnetic parameters in the EPR spectrum (A k # 95 Â 10 24 cm 21 ) [4]. Type 1 sites act as the route of entry fo...

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“…Ceruloplasmin is the mayor acceptor of Cu in liver, and liver is its major producer (Figure 4). The biosynthesis of ceruloplasmin is unaffected by Cu accessibility, but the turnover of apoceruloplasmin is much faster (4-5 h) than the turnover of holoceruloplasmin (4-5 d) (187). Little information is available on the mechanism of Cu transfer from ATP7B to ceruloplasmin.…”

Section: Cu Capture Storage and Distribution In The Liver Excretionmentioning

confidence: 99%

Molecular mechanisms of copper homeostasis

Lalioti

Muruáis²,

Tsuchiya³

et al. 2009

Front Biosci

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The transition metal copper (Cu) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and potentially damaging to the cell. Free Cu is virtually absent in the cell. The descriptions of the structural and functional organization of the metallothioneins, Cu-chaperones and P-type ATPases as well as of the mechanisms that regulate their distribution and functioning in the cell have enormously advanced our understanding of the Cu homeostasis and metabolism in the last decade. Cu is stored by metallothioneins and distributed by specialized chaperones to specific cell targets that make use of its redox properties. Transfer of Cu to newly synthesized cuproenzymes and Cu disposal is performed by the individual or concerted actions of the P-type ATPases ATP7A and ATP7B expressed in tissues. In mammalians liver is the major captor, distributor and excreter of Cu. Mutations in the P-type ATPases that interfere with their functioning and traffic are cause of the life-threatening Wilson (ATP7B) and Menkes (ATP7A) diseases.

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The Biology of Human Ceruloplasmin

Cited by 11 publications

References 0 publications

Copper, Ceruloplasmin and Superoxide Dismutase (SOD1) in Patients with Down's Syndrome

Copper, Ceruloplasmin and Superoxide Dismutase (SOD1) in Patients with Down's Syndrome

The multifunctional oxidase activity of ceruloplasmin as revealed by anion binding studies

Molecular mechanisms of copper homeostasis

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