PDBsum entry 2hrc

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Lyase PDB id
Protein chain
359 a.a. *
FES ×2
IMD ×2
CHD ×6
_CL ×2
Waters ×604
* Residue conservation analysis
PDB id:
Name: Lyase
Title: 1.7 angstrom structure of human ferrochelatase variant r115l
Structure: Ferrochelatase. Chain: a, b. Synonym: protoheme ferro-lyase, heme synthetase. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Strain: jm109. Gene: fech. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.70Å     R-factor:   0.221     R-free:   0.242
Authors: A.Medlock,L.Swartz,T.A.Dailey,H.A.Dailey,W.N.Lanzilotta
Key ref:
A.Medlock et al. (2007). Substrate interactions with human ferrochelatase. Proc Natl Acad Sci U S A, 104, 1789-1793. PubMed id: 17261801 DOI: 10.1073/pnas.0606144104
20-Jul-06     Release date:   13-Mar-07    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P22830  (HEMH_HUMAN) -  Ferrochelatase, mitochondrial
423 a.a.
359 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Ferrochelatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Heme and Chlorophyll Biosynthesis
      Reaction: Protoheme + 2 H+ = protoporphyrin + Fe2+
+ 2 × H(+)
Bound ligand (Het Group name = CHD)
matches with 57.78% similarity
+ Fe(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     heme biosynthetic process   1 term 
  Biochemical function     ferrochelatase activity     1 term  


    Added reference    
DOI no: 10.1073/pnas.0606144104 Proc Natl Acad Sci U S A 104:1789-1793 (2007)
PubMed id: 17261801  
Substrate interactions with human ferrochelatase.
A.Medlock, L.Swartz, T.A.Dailey, H.A.Dailey, W.N.Lanzilotta.
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 approximately 100 degrees and is buried an additional 4.5 A 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.
  Selected figure(s)  
Figure 1.
Fig. 1. Overall backbone trace of the asymmetric unit for the E343K human ferrochelatase. The C^ trace for monomers A, B, C, and D are colored green, yellow, magenta, and cyan, respectively. The two detergent molecules and six protoporphyrin IX molecules are also shown with the carbon, oxygen, and nitrogen atoms colored yellow, red, and blue, respectively. Only the detergent molecules are labeled. The [2Fe-2S] clusters are represented as spheres and colored bright red.
Figure 2.
Fig. 2. Structural alignment of the substrate-bound (E343K) and substrate-free (R115L) forms of human ferrochelatase. The substrate-free form of human ferrochelatase is shown in green, and the substrate-bound form of human ferrochelatase is shown in magenta. Regions of significant movement in the substrate-bound form have been highlighted in red for clarity and include residues 90–115, 302–313, and 349–361. The [2Fe-2S] clusters for the substrate-free and substrate-bound forms are shown in yellow and orange, respectively.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21173279 C.V.Romão, D.Ladakis, S.A.Lobo, M.A.Carrondo, A.A.Brindley, E.Deery, P.M.Matias, R.W.Pickersgill, L.M.Saraiva, and M.J.Warren (2011).
Evolution in a family of chelatases facilitated by the introduction of active site asymmetry and protein oligomerization.
  Proc Natl Acad Sci U S A, 108, 97.
PDB codes: 2xvx 2xvz 2xwp 2xwq 2xws
21052751 M.D.Hansson, T.Karlberg, C.A.Söderberg, S.Rajan, M.J.Warren, S.Al-Karadaghi, S.E.Rigby, and M.Hansson (2011).
Bacterial ferrochelatase turns human: Tyr13 determines the apparent metal specificity of Bacillus subtilis ferrochelatase.
  J Biol Inorg Chem, 16, 235-242.  
21222436 N.R.McIntyre, R.Franco, J.A.Shelnutt, and G.C.Ferreira (2011).
Nickel(II) chelatase variants directly evolved from murine ferrochelatase: porphyrin distortion and kinetic mechanism.
  Biochemistry, 50, 1535-1544.  
20506125 G.Layer, J.Reichelt, D.Jahn, and D.W.Heinz (2010).
Structure and function of enzymes in heme biosynthesis.
  Protein Sci, 19, 1137-1161.  
19703464 A.E.Medlock, M.Carter, T.A.Dailey, H.A.Dailey, and W.N.Lanzilotta (2009).
Product release rather than chelation determines metal specificity for ferrochelatase.
  J Mol Biol, 393, 308-319.
PDB codes: 3hcn 3hco 3hcp 3hcr
19543923 B.Szefczyk, M.N.Cordeiro, R.Franco, and J.A.Gomes (2009).
Molecular dynamics simulations of mouse ferrochelatase variants: what distorts and orientates the porphyrin?
  J Biol Inorg Chem, 14, 1119-1128.  
19767646 R.E.Davidson, C.J.Chesters, and J.D.Reid (2009).
Metal ion selectivity and substrate inhibition in the metal ion chelation catalyzed by human ferrochelatase.
  J Biol Chem, 284, 33795-33799.  
18423489 T.Karlberg, M.D.Hansson, R.K.Yengo, R.Johansson, H.O.Thorvaldsen, G.C.Ferreira, M.Hansson, and S.Al-Karadaghi (2008).
Porphyrin binding and distortion and substrate specificity in the ferrochelatase reaction: the role of active site residues.
  J Mol Biol, 378, 1074-1083.
PDB codes: 2q2n 2q2o 2q3j
17884090 A.E.Medlock, T.A.Dailey, T.A.Ross, H.A.Dailey, and W.N.Lanzilotta (2007).
A pi-helix switch selective for porphyrin deprotonation and product release in human ferrochelatase.
  J Mol Biol, 373, 1006-1016.
PDB codes: 2qd1 2qd2 2qd3 2qd4 2qd5
17567154 H.A.Dailey, C.K.Wu, P.Horanyi, A.E.Medlock, W.Najahi-Missaoui, A.E.Burden, T.A.Dailey, and J.Rose (2007).
Altered orientation of active site residues in variants of human ferrochelatase. Evidence for a hydrogen bond network involved in catalysis.
  Biochemistry, 46, 7973-7979.
PDB codes: 2pnj 2po5 2po7
17566985 M.Hoggins, H.A.Dailey, C.N.Hunter, and J.D.Reid (2007).
Direct measurement of metal ion chelation in the active site of human ferrochelatase.
  Biochemistry, 46, 8121-8127.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.