A comparison of ceruloplasmin to biological polyanions in promoting the oxidation of Fe2+ under physiologically relevant conditions

Abstract

These findings indicate that the requirement of an enzyme to oxidize iron may only be necessary under conditions of adverse pH or anionic strength, for example from hypoxia. In a normal physiological environment, Fe(3+) incorporation into transferrin would be sufficiently enabled by the biological polyanions that are prevalent within extracellular fluids.

Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics

“…Astrocytes do not express TfR1 but express ferroportin and glycophosphatidylinositol‐anchored CP, which oxidizes ferrous iron and facilitates binding to circulating transferrin (Wong et al . ). Evidence for the major role of astrocytes in relaying iron to neurons is supported by the observation that CP inactivation in mice results in iron accumulation mostly in astrocytes and no iron accumulation in oligodendrocytes and large neurons of the deep nuclei is observed, whereas Purkinje neurons up‐regulate DMT1 indicating signs of iron deprivation probably because of iron sequestration in astrocytes (Patel et al .…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Superoxide dismutase is a major copper binding protein and antioxidant in neurons, which utilizes copper to convert the superoxide free radical into hydrogen peroxide [167]. Ceruloplasmin is another major copper-binding protein, which functions as a ferroxidase to promote iron export [168,169]. The protein requires copper binding to perform this function, and low copper levels could lead to iron accumulation by impairing ceruloplasminmediated iron export [170].…”

Evaluating Iron Flux in the Brain

“…1b) and has been designed to accurately measure iron oxidation in CSF and total protein extraction from brain. In so doing, variations between the ferric gain and Tf loading components of the assay have elucidated that Tf itself can modulate enzymatic ferroxidase activity [54] and that for brain tissue samples, only the ferric gain component of the assay can reliably be used. Sub-fractionation of biological samples has also provided stronger evidence that a substantial proportion of ferroxidase activity in CSF and brain tissue does not originate from CP or other large MW proteins, but instead from a <10 kDa component most likely derived from polyanions such as citrates, phosphates, and bicarbonates that are abundantly present within the extracellular fluid of the brain.…”

“…But its sole use in measuring ferroxidase activity has recently been brought into doubt as it does not measure all points in the full enzymatic equation (Fig. 1a) and the addition of Tf provides a rate-limiting step in the assay [54].…”

“…When cellular homeostatic regulation requires iron to be exported, all brain cell types use Fpn [50] and the stabilization of Fpn for iron export at the cellular membrane is provided by glycophosphatidylinositol-anchored ceruloplasmin (CP) in astrocytes and endothelial cells [51]; hephaestin in oligodendrocytes [52] and microglia; and amyloid β precursor protein (APP) in neurons [53]. Fe 2+ remains in the pore of Fpn and is only released to be incorporated into Tf when it is oxidized to Fe 3+ by ferroxidases such as CP and hephaestin or auto-oxidized by the presence of electrolytic anions such as citrates, phosphates, and bicarbonates to fortify the NBTI concentration [54,55].…”