TYROSINASE INHIBITION DUE TO INTERACTION OF HOMOCYST(E)INE WITH COPPER - THE MECHANISM FOR REVERSIBLE HYPOPIGMENTATION IN HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY

Deficiency of cystathionine B-synthase (CBS) is a genetic disorder of transsulfuration resulting in elevated plasma homocyst(e)ine and methi onine and decreased cysteine. Affected patients have multisystem invol vement, which may include light skin and hair. Reversible hypopigmenta tion in treated homocystinuric patients has been infrequently reported , and the mechanism is undefined. Two CBS-deficient homocystinuric pat ients manifested darkening of their hypopigmented hair following treat ment that decreased plasma homocyst(e)ine. We hypothesized that homocy st(e)ine inhibits tyrosinase, the major pigment enzyme. The activity o f tyrosinase extracted from pigmented human melanoma cells (MNT-1) tha t were grown in the presence of homocysteine was reduced in comparison to that extracted from cells grown without homocysteine. Copper sulfa te restored homocyst(e)ine-inhibited tyrosinase activity when added to the culture cell media at a proportion of 1.25 mol of copper sulfate per 1 mol of DL-homocysteine. Holo-tyrosinase activity was inhibited b y adding DL-homocysteine to the assay reaction mixture, and the additi on of copper sulfate to the reaction mixture prevented this inhibition . Other tested compounds, L-cystine and betaine did not affect tyrosin ase activity. Our data suggest that reversible hypopigmentation in hom ocystinuria is the result of tyrosinase inhibition by homocyst(e)ine a nd that the probable mechanism of this inhibition is the interaction o f homocyst(e)ine with copper at the active site of tyrosinase.