Bactericidal effect of Fe2+, ceruloplasmin, and phosphate

doi:10.1016/0003-9861(92)90522-X

Archives of Biochemistry and Biophysics

Volume 295, Issue 2, June 1992, Pages 302-308

https://doi.org/10.1016/0003-9861(92)90522-X Get rights and content

Abstract

Fe²⁺, when combined with ceruloplasmin or phosphate, was bactericidal to Escherichia coli at pH 5.0, and when Fe²⁺, ceruloplasmin, and phosphate were combined, a bactericidal effect was observed under conditions, i.e., short incubation period, in which Fe²⁺ plus ceruloplasmin and Fe²⁺ plus phosphate were ineffective. Bactericidal activity increased with the ceruloplasmin or phosphate concentration to a maximum and then decreased as their concentration was further increased. Fe²⁺ was oxidized in the presence of ceruloplasmin, phosphate, or, in particular, a combination of the two. A bactericidal effect was observed when there was only a partial loss of Fe²⁺, with more extensive oxidation resulting in a loss of bactericidal activity. The bactericidal effect of Fe²⁺ plus ceruloplasmin and/or phosphate was unaffected by catalase or superoxide dismutase and was not associated with iodination. Fe-EDTA was also bactericidal at an Fe²⁺: EDTA molar ratio of 1:0.5, where Fe²⁺ was partially oxidized. However, in contrast to Fe²⁺ plus ceruloplasmin and/or phosphate, bactericidal activity was inhibited by catalase and was associated with iodination. Combinations of Fe²⁺ and Fe³⁺ were not bactericidal under the conditions employed. A requirement for Fe²⁺ plus either a product of Fe²⁺ oxidation or an iron ceruloplasmin and/ or phosphate chelate for bactericidal activity is proposed.

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CP suppresses Fe2+-mediated production of reactive oxygen species and is widely accepted as an effective protective agent against oxidative stress [14]. It also exhibits ferroxidase-dependent bactericidal activity [15]. Furthermore, CP was shown to be the primary copper transporter in the blood [16].
Ferroptosis is a regulated form of cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Ceruloplasmin (CP) is a glycoprotein that plays an essential role in iron homeostasis. However, whether CP regulates ferroptosis has not been reported. Here, we show that CP suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma (HCC) cells. Depletion of CP promoted erastin- and RSL3-induced ferroptotic cell death and resulted in the accumulation of intracellular ferrous iron (Fe²⁺) and lipid reactive oxygen species (ROS). Moreover, overexpression of CP suppressed erastin- and RSL3-induced ferroptosis in HCC cells. In addition, a novel frameshift mutation (c.1192-1196del, p.leu398serfs) of CP gene newly identified in patients with iron accumulation and neurodegenerative diseases lost its ability to regulate iron homeostasis and thus failed to participate in the regulation of ferroptosis. Collectively, these data suggest that CP plays an indispensable role in ferroptosis by regulating iron metabolism and indicate a potential therapeutic approach for hepatocellular carcinoma.
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The physiological function(s) of Cp is uncertain. The fact that it is an acute-phase reactant protein with bactericidal activity [42] suggests that Cp may participate in inflammatory responses to foreign agents. Moreover, Cp antioxidant activity also blocks protein [43] and DNA damage [44] and may protect cells against free radical-initiated cell injury and lysis [45].
In a randomized clinical trial of calorie restriction (CR), we demonstrated that important cardiovascular disease (CVD) biomarkers were favorably influenced by CR alone and in conjunction with physical exercise. The aim of this study was to examine the effects of CR with or without exercise on copper bound to ceruloplasmin (CuCp), a well-known biomarker for CVD, in overweight men and women enrolled in the CALERIE phase 1 study. Forty-six individuals were randomized to one of four groups for 6 months: control, healthy weight maintenance; CR, 25% CR from baseline energy requirements; CR+exercise, 12.5% CR and 12.5% through aerobic exercise; and low-calorie diet, low-calorie diet until 15% reduction in body weight followed by weight maintenance diet. CuCp was determined in fasting blood samples by a high-performance liquid chromatography–inductively coupled plasma mass spectrometry methodology and compared with changes in body composition and markers of CVD.
After 6 months, CR combined with exercise induced a decrease in plasma concentration of CuCp. CuCp was inversely correlated with insulin sensitivity at baseline and after 6 months of intervention. A cluster analysis showed that the percent change of weight after 6 months of intervention was the most important variable that could discriminate the intervention groups. The percent change of CuCp was the only other variable selected by the analysis.
Decreased CuCp in overweight subjects by CR combined with exercise suggests a positive effect of this intervention on metabolic health. Further studies to explain the relationship between weight loss and CuCp and its relevance for cardiovascular health are needed.
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Cp inhibits ferrous ion-mediated production of reactive oxygen species and, therefore, is widely accepted as an important antioxidant. It also exhibits ferroxidase-dependent bactericidal activity [8]. Cp is 132 kD single polypeptide that contains about seven copper atoms in its structure and folds into three homologous domains [9].
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Ceruloplasmin is an abundant plasma protein that contains seven copper atoms per molecule and accounts for 95% of the total circulating copper in healthy adults [2]. Although the physiologic functions of ceruloplasmin are uncertain, the roles in copper transport [3], iron homeostasis [4], and bactericidal activity as an acute-phase reactant have been proposed [5]. In addition to these roles, elevated serum ceruloplasmin levels could represent abnormally high oxidative stress due to its ferroxidase activity [6,7].

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^☆: This work was supported by United States Public Health Service Grants AI-07763 and AI-17758.

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Bactericidal effect of Fe2+, ceruloplasmin, and phosphate☆

Abstract

Biochem. Biophys. Res. Commun

J. Biol. Chem

J. Biol. Chem

J. Biol. Chem

Biochim. Biophys. Acta

J. Biol. Chem

Biochim. Biophys. Acta

Int. J. Biochem

J. Biol. Chem

FEBS Lett

Chem. Biol. Interact

J. Biol. Chem

FEBS Lett

Biochim. Biophys. Acta

Biochimie

Biochim. Biophys. Acta

FEBS Lett

Arch. Biochem. Biophys

J. Biol. Chem

J. Biol. Chem

Free Radicals Biol. Med

Free Radicals Biol. Med

Bactericidal effect of Fe²⁺, ceruloplasmin, and phosphate☆