Mechanisms of biosynthesis of the human multicopper oxidase, ceruloplasmin. Tamika Keisha Samuel

ISBN: 9780549839255

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NOOKstudy eTextbook

127 pages


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Mechanisms of biosynthesis of the human multicopper oxidase, ceruloplasmin.  by  Tamika Keisha Samuel

Mechanisms of biosynthesis of the human multicopper oxidase, ceruloplasmin. by Tamika Keisha Samuel
| NOOKstudy eTextbook | PDF, EPUB, FB2, DjVu, AUDIO, mp3, RTF | 127 pages | ISBN: 9780549839255 | 10.80 Mb

The human multicopper oxidases are part of a family of enzymes that utilize the facile electron chemistry of bound copper ions to catalyze the four-electron reduction of oxygen concomitantly with the oxidation of ferrous (Fe 2+) to ferric (Fe3+)MoreThe human multicopper oxidases are part of a family of enzymes that utilize the facile electron chemistry of bound copper ions to catalyze the four-electron reduction of oxygen concomitantly with the oxidation of ferrous (Fe 2+) to ferric (Fe3+) iron.

In humans, the multicopper oxidases are ceruloplasmin, which is expressed as a secreted isoform in hepatocytes or as a glycosylphosphatidylinositol-anchored protein expressed mainly in astrocytes, and the homologous type I membrane bound protein, hephaestin.

Both ceruloplasmin and hephaestin are critical for maintaining iron homeostasis by enabling iron uptake and efflux. Ceruloplasmin was demonstrated to be essential for iron mobilization by the discovery of the autosomal recessive disorder aceruloplasminemia. Patients with aceruloplasminemia present with diabetes mellitus, retinal degeneration and neurological symptoms due to parenchymal iron accumulation.-A number of missense mutations found in patients with aceruloplasminemia were biochemically analyzed and led to the identification of four distinct classes of missense mutations.

These mutations revealed that copper incorporation into apoceruloplasmin requires precise folding and quality control in the late secretory pathway. Additionally, holoceruloplasmin synthesis was affected by treatment with the vacuolar ATPase inhibitor bafilomycin, revealing that pH plays a critical role in copper incorporation in vivo.

These findings support the concept that copper incorporation into ceruloplasmin is dependent upon both protein structure and the intracellular conditions of the late secretory pathway.-Analysis of GPI-anchored ceruloplasmin revealed that the intracellular copper concentration affected the stability of the protein on the cell surface. Furthermore, apoGPI-anchored ceruloplasmin mutants exhibited more rapid cell surface turnover, although trafficking to and localization on the cell surface were unaffected. In addition, these studies indicated that the turnover of GPI-anchored ceruloplasmin is not regulated by the glycosylphosphatidylinositol anchor and is not altered when ceruloplasmin is expressed as a transmembrane protein.

Taken together, these data revealed that GPI-anchored ceruloplasmin is regulated at the cell surface. These studies provide further insight into the biosynthesis and regulation of ceruloplasmin and point to novel therapeutic approaches that could benefit patients with aceruloplasminemia.



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