3HCP: Human Ferrochelatase With Mn And Deuteroporphyrin Bound

Ferrochelatase (protoheme ferrolyase, E.C. is the terminal enzyme in heme biosynthesis and catalyzes the insertion of ferrous iron into protoporphyrin IX to form protoheme IX (heme). Within the past two years, X-ray crystallographic data obtained with human ferrochelatase have clearly shown that significant structural changes occur during catalysis that are predicted to facilitate metal insertion and product release. One unanswered question about ferrochelatase involves defining the mechanism whereby some metals, such as divalent Fe, Co, Ni, and Zn, can be used by the enzyme in vitro to produce the corresponding metalloporphyrins, while other metals, such as divalent Mn, Hg, Cd, or Pb, are inhibitors of the enzyme. Through the use of high-resolution X-ray crystallography along with characterization of metal species via their anomalous diffraction, the identity and position of Hg, Cd, Ni, or Mn in the center of enzyme-bound porphyrin macrocycle were determined. When Pb, Hg, Cd, or Ni was present in the macrocycle, the conserved pi helix was in the extended, partially unwound "product release" state. Interestingly, in the structure of ferrochelatase with Mn-porphyrin bound, the pi helix is not extended or unwound and is in the "substrate-bound" conformation. These findings show that at least in the cases of Mn, Pb, Cd, and Hg, metal "inhibition" of ferrochelatase is not due to the inability of the enzyme to insert the metal into the macrocycle or by binding to a second metal binding site as has been previously proposed. Rather, inhibition occurs after metal insertion and results from poor or diminished product release. Possible explanations for the lack of product release are proposed herein.
PDB ID: 3HCPDownload
MMDB ID: 77998
PDB Deposition Date: 2009/5/6
Updated in MMDB: 2009/11
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 3HCP: dimeric; determined by author and by software (PISA)
Molecular Components in 3HCP
Label Count Molecule
Proteins (2 molecules)
Ferrochelatase, Mitochondrial(Gene symbol: FECH)
Molecule annotation
Chemicals (11 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB