Product release rather than chelation determines metal specificity for ferrochelatase.

Full Abstract

Ferrochelatase (protoheme ferrolyase, E.C. 4.99.1.1) 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.

Author information

Author/s: Medlock, Amy E (AE); Carter, Michael (M); Dailey, Tamara A (TA); Dailey, Harry A (HA); Lanzilotta, William N (WN);

Affiliation: Biomedical and Health Sciences Institute, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, 30602, USA.

Grants: DK 32303 (Agency:NIDDK NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.

Journal: Journal of molecular biology (J Mol Biol), published in England. (Language: eng)

Reference: 2009-Oct; vol 393 (issue 2) : pp 308-19

Dates: Created 2009/10/05; Completed 2009/10/20; Revised 2009/11/05;

PMID: 19703464, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Cadmium - chemistry; metabolism
Cobalt - chemistry; metabolism
Crystallography, X-Ray
Ferrochelatase - chemistry; genetics; metabolism
Heme - chemistry; metabolism
Humans
Iron - chemistry; metabolism
Lead - chemistry; metabolism

Associated Chemicals: Metals (0) ; Protoporphyrins (0) ; Heme (14875-96-8) ; protoporphyrin IX (553-12-8) ; Iron (7439-89-6) ; Lead (7439-92-1) ; Mercury (7439-97-6) ; Nickel (7440-02-0) ; Cadmium (7440-43-9) ; Cobalt (7440-48-4) ; Zinc (7440-66-6) ; Ferrochelatase (EC 4.99.1.1)

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