The Ca(2+)-dependent precursor convertase
furin is abundantly expressed in epidermal keratinocytes and melanocytes. In this context, it is noteworthy that
proopiomelanocortin (
POMC) cleavage is also processed by
furin, leading to
ACTH,
beta-lipotropin, and
beta-endorphin. All
prohormone convertases including
furin are regulated by Ca(2+). Because numerous epidermal
peptides and
enzymes are affected by H(2)O(2)-mediated oxidation, including the
POMC-derived
peptides alpha-MSH and
beta-endorphin as shown in the epidermis of patients with
vitiligo, we here asked the question of whether
furin could also be a possible target for this oxidation mechanism by using immunofluorescence, RT-PCR, Western blotting, Ca(2+)-binding studies, and computer modeling. Our results demonstrate significantly decreased in situ immunoreactivity of
furin in the epidermis of patients with progressive
vitiligo (n = 10), suggesting H(2)O(2)-mediated oxidation. This was confirmed by (45)Ca(2+)-binding studies with human recombinant
furin identifying the loss of one Ca(2+)-binding site from the
enzyme after oxidation with H(2)O(2). Computer simulation supported alteration of one of the two Ca(2+)-binding sites on
furin. Taken together, our results implicate that the Ca(2+)-dependent proteolytic activity of this convertase is targeted by H(2)O(2), which in turn could contribute to the reduced epidermal expression of the
POMC-derived
peptides alpha-MSH and
beta-endorphin as documented earlier in patients with
vitiligo.