Substrate interactions with human ferrochelatase

Amy Medlock, Larkin Swartz, Tamara A. Dailey, Harry A. Dailey, William N. Lanzilotta

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Ferrochelatase, the terminal enzyme in heme biosynthesis, catalyzes the insertion of ferrous iron into protoporphyrin IX to form protoheme IX. Human ferrochelatase is a homodimeric, inner mitochondrial membrane-associated enzyme that possesses an essential [2Fe-2S] cluster. In this work, we report the crystal structure of human ferrochelatase with the substrate protoporphyrin IX bound as well as a higher resolution structure of the R115L variant without bound substrate. The data presented reveal that the porphyrin substrate is bound deep within an enclosed pocket. When compared with the location of N-methylmesoporphyrin in the Bacillus subtilis ferrochelatase, the porphyrin is rotated by ≈100° and is buried an additional 4.5 Å deeper within the active site. The propionate groups of the substrate do not protrude into solvent and are bound in a manner similar to what has been observed in uroporphyrinogen decarboxylase. Furthermore, in the substrate-bound form, the jaws of the active site mouth are closed so that the porphyrin substrate is completely engulfed in the pocket. These data provide insights that will aid in the determination of the mechanism for ferrochelatase.

Original languageEnglish (US)
Pages (from-to)1789-1793
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number6
DOIs
StatePublished - Feb 6 2007

Fingerprint

Ferrochelatase
Porphyrins
Heme
Catalytic Domain
Uroporphyrinogen Decarboxylase
Propionates
Mitochondrial Membranes
Enzymes
Bacillus subtilis
Jaw
Mouth

Keywords

  • Heme biosynthesis
  • Metal insertion
  • Protoporphyrin IX
  • X-ray crystallography

ASJC Scopus subject areas

  • General

Cite this

Substrate interactions with human ferrochelatase. / Medlock, Amy; Swartz, Larkin; Dailey, Tamara A.; Dailey, Harry A.; Lanzilotta, William N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 6, 06.02.2007, p. 1789-1793.

Research output: Contribution to journalArticle

Medlock, Amy ; Swartz, Larkin ; Dailey, Tamara A. ; Dailey, Harry A. ; Lanzilotta, William N. / Substrate interactions with human ferrochelatase. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 6. pp. 1789-1793.
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