Copper Enzyme Must Preload

A study of a copper enzyme that misfolds and malfunctions in copper- and iron-metabolism diseases indicates that it can't be fixed simply by inducing the copper-deficient misfolded version to take up more copper (Biochemistry, DOI: 10.1021/bi700715e). Ceruloplasmin, an oxidase normally containing six copper atoms, lacks copper and therefore misfolds in disorders such as Wilson's disease, aceruloplasminemia, and anemia. Researchers speculated that these diseases could be treated by supplying copper, which might be taken up by the enzyme and permit it to refold properly. However, a chemical unfolding study of the enzyme by Erik Sedlak and Pernilla Wittung-Stafshede of Rice University now suggests that copper-free ceruloplasmin adopts an irretrievably misfolded globular structure in cells and that the related diseases can be treated only by inducing ceruloplasmin to take up copper when it is first biosynthesized, not after it has already misfolded. The findings "may facilitate new approaches to incorporate copper into copper-lacking ceruloplasmin variants found in affected patients," the researchers note.