Structural and mechanistic basis of porphyrin metallation by ferrochelatase

Ferrochelatase, the enzyme catalyzing metallation of protoporphyrin IX at t he terminal step of heme biosynthesis, was co-crystallized with an isomer m ixture of the potent inhibitor N-methylmesoporphyrin (N-MeMP). The X-ray st ructure revealed the active site of the enzyme, to which only one of the is omers was bound, and for the first time allowed characterization of the mod e of porphyrin macrocycle distortion by ferrochelatase. Crystallization of ferrochelatase and N-MeMP in the presence of Cu2+ leads to metallation and demethylation of N-MeMP. A mechanism of porphyrin distortion is proposed, w hich assumes that the enzyme holds pyrrole rings B, C and D in a vice-like grip and forces a 36 degrees tilt on ring A. (C) 2000 Academic Press.