Biology:Ferrochelatase

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Protoporphyrin ferrochelatase
1hrk.jpg
Ferrochelatase homodimer, Human
Identifiers
EC number4.98.1.1
CAS number9012-93-5
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Ferrochelatase
Human Ferrochelatase 2 angstrom crystal structure.png
Human ferrochelatase
Identifiers
SymbolFerrochelatase
PfamPF00762
InterProIPR001015
PROSITEPDOC00462
SCOP21ak1 / SCOPe / SUPFAM
OPM superfamily129
OPM protein1hrk

Protoporphyrin ferrochelatase (EC 4.98.1.1, formerly EC 4.99.1.1, or ferrochelatase; systematic name protoheme ferro-lyase (protoporphyrin-forming)) is an enzyme encoded by the FECH gene in humans.[1] Ferrochelatase catalyses the eighth and terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme B. It catalyses the reaction:

protoheme + 2 H+ = protoporphyrin + Fe2+
Hemeb-formation.svg

Function

Summary of heme B biosynthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX in the heme biosynthesis pathway to form heme B. The enzyme is localized to the matrix-facing side of the inner mitochondrial membrane. Ferrochelatase is the best known member of a family of enzymes that add divalent metal cations to tetrapyrrole structures.[2] For example, magnesium chelatase adds magnesium to protoporphyrin IX in the first step of bacteriochlorophyll biosynthesis.[3]

Heme B is an essential cofactor in many proteins and enzymes. In particular, heme b plays a key role as the oxygen carrier in hemoglobin in red blood cells and myoglobin in muscle cells. Furthermore, heme B is found in cytochrome b, a key component in Q-cytochrome c oxidoreductase (complex III) in oxidative phosphorylation.[4]

Structure

Human ferrochelatase is a homodimer composed of two 359 amino acid polypeptide chains. It has a total molecular weight of 85.07 kDa.[5] Each subunit is composed of five regions: a mitochondrial localization sequence, the N terminal domain, two folded domains, and a C terminal extension. Residues 1–62 form a mitochondrial localization domain that is cleaved in post-translational modification. The folded domains contain a total of 17 α-helices and 8 β-sheets. The C terminal extension contains three of the four cysteine residues (Cys403, Cys406, Cys411) that coordinate the catalytic iron–sulfur cluster (2Fe-2S). The fourth coordinating cysteine resides in the N-terminal domain (Cys196).[6]

The active pocket of ferrocheltase consists of two hydrophobic "lips" and a hydrophilic interior. The hydrophobic lips, consisting of the highly conserved residues 300–311, face the inner mitochondrial membrane and facilitate the passage of the poorly soluble protoporphyrin IX substrate and the heme product via the membrane. The interior of the active site pocket contains a highly conserved acidic surface that facilitates proton extraction from protoporphyrin. Histidine and aspartate residues roughly 20 angstroms from the center of the active site on the mitochondrial matrix side of the enzyme coordinate metal binding.[6]

Mechanism

Protoporphyrin IX with pyrrole rings lettered.

The mechanism of human protoporphyrin metalation remains under investigation. Many researchers have hypothesized distortion of the porphyrin macrocycle as key to catalysis. Researchers studying Bacillus subtilis ferrochelatase propose a mechanism for iron insertion into protoporphyrin in which the enzyme tightly grips rings B, C, and D while bending ring A 36o. Normally planar, this distortion exposes the lone pair of electrons on the nitrogen in ring A to the Fe+2 ion.[2] Subsequent investigation revealed a 100o distortion in protoporphyrin bound to human ferrochelatase. A highly conserved histidine residue (His183 in B. subtilis, His263 in humans) is essential for determining the type of distortion, as well as acting as the initial proton acceptor from protoporphyrin.[6][7] Anionic residues form a pathway facilitating proton movement away from the catalytic histidine.[6] Frataxin chaperones iron to the matrix side of ferrochelatase, where aspartate and histidine residues on both proteins coordinate iron transfer into ferrochelatase.[8] Two arginine and tyrosine residues in the active site (Arg164, Tyr165) may perform the final metalation.[6]

Ferrochelatase active site with protoporphyrin IX substrate in green. Residues shown are: hydrophobic groups holding protoporphyrin IX (yellow), anionic proton transfer path (dark blue), metalation residues (cyan), catalytic histidine (red).

Clinical significance

Defects in ferrochelatase create a buildup of protoporphyrin IX, causing erythropoietic protoporphyria (EPP).[9] The disease can result from a variety of mutations in FECH, most of which behave in an autosomal dominant manner with low clinical penetrance. Clinically, patients with EPP present with a range of symptoms, from asymptomatic to suffering from an extremely painful photosensitivity. In less than five percent of cases, accumulation of protoporphyrin in the liver results in cholestasis (blockage of bile flow from the liver to the small intestine) and terminal liver failure.[10]

In cases of lead poisoning, lead inhibits ferrochelatase activity, in part resulting in porphyria.[11]

Interactions

Ferrochelatase interacts with numerous other enzymes involved in heme biosynthesis, catabolism, and transport, including protoporphyrinogen oxidase, 5-aminolevulinate synthase, ABCB10, ABCB7, succinyl-CoA synthetase,[12] and mitoferrin-1.[13] Multiple studies have suggested the existence of an oligomeric complex that enables substrate channeling and coordination of overall iron and porphyrin metabolism throughout the cell.[12][13] N-methylmesoporphyrin (N-MeMP) is a competitive inhibitor with protoporphyrin IX and is thought to be a transition state analog. As such, N-MeMP has been used extensively as a stabilizing ligand for x-ray crystallography structure determination.[14] Frataxin acts as the Fe+2 chaperone and complexes with ferrochelatase on its mitochondrial matrix side.[8] Ferrochelatase can also insert other divalent metal ions into protoporphyrin. Some ions, such as Zn+2, Ni, and Co form other metalloporphyrins while heavier metal ions such as Mn, Pb, Hg, and Cd inhibit product release after metallation.[15]

See also

References

  1. ↑ "FECH - Ferrochelatase, mitochondrial precursor - Homo sapiens (Human) - FECH gene & protein". https://www.uniprot.org/uniprot/P22830. 
  2. ↑ 2.0 2.1 Lecerof, D.; Fodje, M.; Hansson, A.; Hansson, M.; Al-Karadaghi, S. (March 2000). "Structural and mechanistic basis of porphyrin metallation by ferrochelatase". Journal of Molecular Biology 297 (1): 221–232. doi:10.1006/jmbi.2000.3569. PMID 10704318. 
  3. ↑ Leeper, F. J. (1985). "The biosynthesis of porphyrins, chlorophylls, and vitamin B12". Natural Product Reports 2 (1): 19–47. doi:10.1039/NP9850200019. PMID 3895052. 
  4. ↑ Berg, Jeremy; Tymoczko, John; Stryer, Lubert (2012). Biochemistry (7th ed.). New York: W.H. Freeman. ISBN 9781429229364. 
  5. ↑ "RCSB PDB - 1Hrk: Crystal Structure of Human Ferrochelatase". http://www.rcsb.org/pdb/explore/explore.do?structureId=1HRK. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Wu, Chia-Kuei; Dailey, Harry A.; Rose, John P.; Burden, Amy; Sellers, Vera M.; Wang, Bi-Cheng (1 February 2001). "The 2.0 Å structure of human ferrochelatase, the terminal enzyme of heme biosynthesis". Nature Structural Biology 8 (2): 156–160. doi:10.1038/84152. PMID 11175906. 
  7. ↑ Karlberg, Tobias; Hansson, Mattias D.; Yengo, Raymond K.; Johansson, Renzo; Thorvaldsen, Hege O.; Ferreira, Gloria C.; Hansson, Mats; Al-Karadaghi, Salam (May 2008). "Porphyrin Binding and Distortion and Substrate Specificity in the Ferrochelatase Reaction: The Role of Active Site Residues". Journal of Molecular Biology 378 (5): 1074–1083. doi:10.1016/j.jmb.2008.03.040. PMID 18423489. 
  8. ↑ 8.0 8.1 Bencze, Krisztina Z.; Yoon, Taejin; Mill?n-Pacheco, C?sar; Bradley, Patrick B.; Pastor, Nina; Cowan, J. A.; Stemmler, Timothy L. (2007). "Human frataxin: iron and ferrochelatase binding surface". Chemical Communications (18): 1798–1800. doi:10.1039/B703195E. PMID 17476391. PMC 2862461. http://digitalcommons.wayne.edu/cgi/viewcontent.cgi?article=1014&context=med_biochem. 
  9. ↑ James, William D.; Berger, Timothy G. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 
  10. ↑ Rüfenacht, U.B.; Gouya, L.; Schneider-Yin, X.; Puy, H.; Schäfer, B.W.; Aquaron, R.; Nordmann, Y.; Minder, E.I. et al. (1998). "Systematic Analysis of Molecular Defects in the Ferrochelatase Gene from Patients with Erythropoietic Protoporphyria". The American Journal of Human Genetics 62 (6): 1341–52. doi:10.1086/301870. PMID 9585598. 
  11. ↑ "Lead Toxicity -- What Are Possible Health Effects from Lead Exposure?". Agency for Toxic Substances & Disease Registry. https://www.atsdr.cdc.gov/csem/csem.asp?csem=34&po=10. 
  12. ↑ 12.0 12.1 Medlock, Amy E.; Shiferaw, Mesafint T.; Marcero, Jason R.; Vashisht, Ajay A.; Wohlschlegel, James A.; Phillips, John D.; Dailey, Harry A.; Liesa, Marc (19 August 2015). "Identification of the Mitochondrial Heme Metabolism Complex". PLOS ONE 10 (8): e0135896. doi:10.1371/journal.pone.0135896. PMID 26287972. Bibcode: 2015PLoSO..1035896M. 
  13. ↑ 13.0 13.1 Chen, W.; Dailey, H. A.; Paw, B. H. (28 April 2010). "Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis". Blood 116 (4): 628–630. doi:10.1182/blood-2009-12-259614. PMID 20427704. 
  14. ↑ Medlock, A.; Swartz, L.; Dailey, T. A.; Dailey, H. A.; Lanzilotta, W. N. (29 January 2007). "Substrate interactions with human ferrochelatase". Proceedings of the National Academy of Sciences 104 (6): 1789–1793. doi:10.1073/pnas.0606144104. PMID 17261801. Bibcode: 2007PNAS..104.1789M. 
  15. ↑ Medlock, Amy E.; Carter, Michael; Dailey, Tamara A.; Dailey, Harry A.; Lanzilotta, William N. (October 2009). "Product Release Rather than Chelation Determines Metal Specificity for Ferrochelatase". Journal of Molecular Biology 393 (2): 308–319. doi:10.1016/j.jmb.2009.08.042. PMID 19703464. 

Further reading

External links



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