k

Ferrochelatase catalyses the eighth and terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme B

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.

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+

Function

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.

  • 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 Biology297 (1): 221–232. doi:10.1006/jmbi.2000.3569PMID 10704318.

For example, magnesium chelatase adds magnesium to protoporphyrin IX in the first step of bacteriochlorophyll biosynthesis.

  • Leeper, F. J. (1985). “The biosynthesis of porphyrins, chlorophylls, and vitamin B12”. Natural Product Reports2 (1): 19–47. doi:10.1039/NP9850200019PMID 3895052.

Bacteriochlorophyll Notes

Bacteriochlorophylls (BChl) are photosynthetic pigments that occur in various phototrophicbacteria. They were discovered by C. B. van Niel in 1932.[Niel, C. B. (1932). “On the morphology and physiology of the purple and green sulphur bacteria”. Archiv für Mikrobiologie3: 1–112. doi:10.1007/BF00454965S2CID 19597530.] They are related to chlorophylls, which are the primary pigments in plantsalgae, and cyanobacteria. Organisms that contain bacteriochlorophyll conduct photosynthesis to sustain their energy requirements, but the process is anoxygenic and does not produce oxygen as a byproduct. They use wavelengths of light not absorbed by plants or cyanobacteria. Replacement of Mg2+ with protons gives bacteriophaeophytin (BPh), the phaeophytin form.

There are a large number of known bacteriochlorophylls[Senge, Mathias O.; Smith, Kevin M. (2004). “Biosynthesis and Structures of the Bacteriochlorophylls”. Anoxygenic Photosynthetic Bacteria. Advances in Photosynthesis and Respiration. Vol. 2. pp. 137–151. doi:10.1007/0-306-47954-0_8ISBN 0-7923-3681-X.][Chew, Aline Gomez Maqueo; Bryant, Donald A. (2007). “Chlorophyll Biosynthesis in Bacteria: The Origins of Structural and Functional Diversity”. Annual Review of Microbiology. 61: 113–129. doi:10.1146/annurev.micro.61.080706.093242PMID 17506685.] but all have features in common since the biosynthetic pathway involves chlorophyllide a (Chlide a) as an intermediate.[Willows, Robert D. (2003). “Biosynthesis of chlorophylls from protoporphyrin IX”. Natural Product Reports. 20 (6): 327–341. doi:10.1039/B110549NPMID 12828371.]

Chlorin-cored BChls (c to f) are produced by a series of enzymatic modifications on the sidechain of Chlide a, much like how Chl b, d, e are made. The bacteriochlorin-cored BChls a, b, g require a unique step to reduce the double bound between C7 and C8, which is performed by Chlorophyllide a reductase (COR).[Chew, Aline Gomez Maqueo; Bryant, Donald A. (2007). “Chlorophyll Biosynthesis in Bacteria: The Origins of Structural and Functional Diversity”. Annual Review of Microbiology. 61: 113–129. doi:10.1146/annurev.micro.61.080706.093242PMID 17506685.]

Isobacteriochlorins, in contrast, are biosynthesised from uroporphyrinogen III in a separate pathway that leads, for example, to sirohemecofactor F430 and cobalamin. The common intermediate is sirohydrochlorin.[Battersby, Alan R. (2000). “Tetrapyrroles: The pigments of life: A Millennium review”. Natural Product Reports. 17 (6): 507–526. doi:10.1039/B002635MPMID 11152419.]

Pigment & Taxain vivo infrared absorption maximum (nm)
BChl a
Purple bacteria
Heliobacteria, 
Green Sulfur Bacteria
Chloroflexota
Chloracidobacterium thermophilum[Bryant DA, et al. (2007-07-27), “Candidatus Chloracidobacterium thermophilum: An Aerobic Phototrophic Acidobacterium” (PDF), Science317 (5837): 523–526, Bibcode:2007Sci…317..523Bdoi:10.1126/science.1143236PMID 17656724S2CID 20419870]
805, 830–890
BChl b
Purple bacteria
835–850, 1020–1040
BChl c
Green sulfur bacteria, 
Chloroflexota
C. thermophilum,[Bryant DA, et al. (2007-07-27), “Candidatus Chloracidobacterium thermophilum: An Aerobic Phototrophic Acidobacterium” (PDF), Science317 (5837): 523–526, Bibcode:2007Sci…317..523Bdoi:10.1126/science.1143236PMID 17656724S2CID 20419870] 
C. tepidum
745–755
BChl d
Green sulfur bacteria
705–740
BChl e
Green sulfur bacteria
719–726
BChl f
(Discovered by mutation of BChl e synthesis by analogy to BChl c/d. Not evolutionarily favorable.)[Vogl K, et al. (2012-08-10). “Bacteriochlorophyll f: properties of chlorosomes containing the “forbidden chlorophyll””Front. Microbiol3: article 298, pages 1–12. doi:10.3389/fmicb.2012.00298PMC 3415949PMID 22908012.]
700–710
BChl g
Heliobacteria
670, 788
List of major bacteriochlorophylls

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.

  • Berg, Jeremy; Tymoczko, John; Stryer, Lubert (2012). Biochemistry (7th ed.). New York: W.H. Freeman. ISBN 9781429229364.

Cytochrome b Notes

Cytochrome b within both molecular and cell biology, is a protein found in the mitochondria of eukaryotic cells. It functions as part of the electron transport chain and is the main subunit of transmembrane cytochrome bc1 and b6f complexes.[Howell N (August 1989). “Evolutionary conservation of protein regions in the proton motive cytochrome b and their possible roles in redox catalysis”. J. Mol. Evol29 (2): 157–69. Bibcode:1989JMolE..29..157Hdoi:10.1007/BF02100114PMID 2509716S2CID 7298013.][Esposti MD, De Vries S, Crimi M, Ghelli A, Patarnello T, Meyer A (July 1993). “Mitochondrial cytochrome b: evolution and structure of the protein” (PDF). Biochim. Biophys. Acta1143 (3): 243–71. doi:10.1016/0005-2728(93)90197-NPMID 8329437.]

Cytochrome b Function

In the mitochondrion of eukaryotes and in aerobic prokaryotes, cytochrome b is a component of respiratory chain complex III (EC 1.10.2.2) — also known as the bc1 complex or ubiquinol-cytochrome c reductase. In plant chloroplasts and cyanobacteria, there is an analogous protein, cytochrome b6, a component of the plastoquinone-plastocyanin reductase (EC 1.10.99.1), also known as the b6f complex. These complexes are involved in electron transport, the pumping of protons to create a proton-motive force (PMF). This proton gradient is used for the generation of ATP. These complexes play a vital role in cells.[Blankenship, Robert (2009). Molecular Mechanisms of Photosynthesis. Blackwell Publishing. pp. 124–132.]

Cytochrome b Structure

Cytochrome b/b6[Howell N (1989). “Evolutionary conservation of protein regions in the protonmotive cytochrome b and their possible roles in redox catalysis”. J. Mol. Evol29 (2): 157–169. Bibcode:1989JMolE..29..157Hdoi:10.1007/BF02100114PMID 2509716S2CID 7298013.][Esposti MD, Crimi M, Ghelli A, Patarnello T, Meyer A, De Vries S (1993). “Mitochondrial cytochrome b: evolution and structure of the protein” (PDF). Biochim. Biophys. Acta1143 (3): 243–271. doi:10.1016/0005-2728(93)90197-NPMID 8329437.] is an integral membrane protein of approximately 400 amino acid residues that probably has 8 transmembrane segments. In plants and cyanobacteria, cytochrome b6 consists of two protein subunits encoded by the petB and petD genes. Cytochrome b/b6 non-covalently binds two heme groups, known as b562 and b566. Four conserved histidine residues are postulated to be the ligands of the iron atoms of these two heme groups.

Cytochrome b Use in phylogenetics

Cytochrome b is commonly used as a region of mitochondrial DNA for determining phylogenetic relationships between organisms, due to its sequence variability. It is considered to be most useful in determining relationships within families and genera. Comparative studies involving cytochrome b have resulted in new classification schemes and have been used to assign newly described species to a genus as well as to deepen the understanding of evolutionary relationships.[Castresana, J. (2001). “Cytochrome b Phylogeny and the Taxonomy of Great Apes and Mammals”Molecular Biology and Evolution18 (4): 465–471. doi:10.1093/oxfordjournals.molbev.a003825PMID 11264397.]

Cytochrome b Clinical significance

Mutations in cytochrome b primarily result in exercise intolerance in human patients; though more rare, severe multi-system pathologies have also been reported.[Blakely EL, Mitchell AL, Fisher N, Meunier B, Nijtmans LG, Schaefer AM, Jackson MJ, Turnbull DM, Taylor RW (July 2005). “A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast”FEBS J272 (14): 3583–92. doi:10.1111/j.1742-4658.2005.04779.xPMID 16008558S2CID 13938075.]

Single-point mutations in cytochrome b of Plasmodium falciparum and P. berghei are associated with resistance to the anti-malarial drug atovaquone.[Siregar JE, Syafruddin D, Matsuoka H, Kita K, Marzuki S (June 2008). “Mutation underlying resistance of Plasmodium berghei to atovaquone in the quinone binding domain 2 (Qo(2)) of the cytochrome b gene”. Parasitology International57 (2): 229–32. doi:10.1016/j.parint.2007.12.002PMID 18248769]

Cytochrome b Human genes

Human genes encoding cytochrome b proteins include:

Cytochrome b Fungicide target

Cyt b is targeted by the QoI class of fungicides, Fungicide Resistance Action Committee group 11. The cyt b mutations G143A and F129L provide resistance against the main body of group 11, although G143A does not work against metyltetraprole (11A).[FRAC (Fungicide Resistance Action Committee) (March 2021). “FRAC Code List ©*2021: Fungal control agents sorted by cross resistance pattern and mode of action (including coding for FRAC Groups on product labels)” (PDF).] G143A is significant in Botrytis cinerea in California strawberry production.[Petrasch, Stefan; Knapp, Steven J.; van Kan, Jan A. L.; Blanco‐Ulate, Barbara (2019-04-04). “Grey mould of strawberry, a devastating disease caused by the ubiquitous necrotrophic fungal pathogen Botrytis cinereaMolecular Plant PathologyBritish Society for Plant Pathology (W-B). 20 (6): 877–892. doi:10.1111/mpp.12794ISSN 1464-6722PMC 6637890PMID 30945788S2CID 93002697. Cosseboom, Scott D.; Ivors, Kelly L.; Schnabel, Guido; Bryson, Patricia K.; Holmes, Gerald J. (2019). “Within-Season Shift in Fungicide Resistance Profiles of Botrytis cinerea in California Strawberry Fields”Plant DiseaseAmerican Phytopathological Society103 (1): 59–64. doi:10.1094/pdis-03-18-0406-reISSN 0191-2917PMID 30422743S2CID 205345358.]

Almost all these fungicides are in the same cross-resistance group (FRAC 11) and must be managed carefully to avoid the appearance of fungicide resistance. All group 11s are cross-resistant with each other.[FRAC (Fungicide Resistance Action Committee) (March 2021). “FRAC Code List ©*2021: Fungal control agents sorted by cross resistance pattern and mode of action (including coding for FRAC Groups on product labels)” (PDF). pp. 1–17.] Some fungicide resistance has been observed in many crop pathogens[ Zeng, F; Arnao, E; Zhang, G; Olaya, G; Wullschleger, J; Sierotzki, H; Ming, R; Bluhm, B. H; Bond, J. P; Fakhoury, A. M; Bradley, C. A (2015). “Characterization of Quinone Outside Inhibitor Fungicide Resistance in Cercospora sojina and Development of Diagnostic Tools for its Identification”Plant Disease99 (4): 544–550. doi:10.1094/PDIS-05-14-0460-RE.] (such as in the case of wheat powdery mildew), so the application of QoI products should respect effective rates and intervals to provides time and space when the pathogen population is not influenced by the product selection pressure.[clarification needed][“Recommendations for QoI”FRAC (Fungicide Resistance Action Committee). 2020-01-31. Retrieved 2021-06-16.] Resistance to group 11 is conferred by cytochrome b mutations G143A and F129L, and by other mechanisms.[FRAC (Fungicide Resistance Action Committee) (March 2021). “FRAC Code List ©*2021: Fungal control agents sorted by cross resistance pattern and mode of action (including coding for FRAC Groups on product labels)” (PDF). pp. 1–17.]

The tetrazolinones consist of only one molecule, metyltetraprole. This constitutes FRAC 11A. 11A is not cross-resistant with 11 resistance conferred by G143A.[3]

See also:

Cytochrome b References

  1. Howell N (August 1989). “Evolutionary conservation of protein regions in the proton motive cytochrome b and their possible roles in redox catalysis”. J. Mol. Evol. 29 (2): 157–69. Bibcode:1989JMolE..29..157Hdoi:10.1007/BF02100114PMID 2509716S2CID 7298013.
  2. Esposti MD, De Vries S, Crimi M, Ghelli A, Patarnello T, Meyer A (July 1993). “Mitochondrial cytochrome b: evolution and structure of the protein” (PDF). Biochim. Biophys. Acta. 1143 (3): 243–71. doi:10.1016/0005-2728(93)90197-NPMID 8329437.
  3. Blankenship, Robert (2009). Molecular Mechanisms of Photosynthesis. Blackwell Publishing. pp. 124–132.
  4. Howell N (1989). “Evolutionary conservation of protein regions in the protonmotive cytochrome b and their possible roles in redox catalysis”. J. Mol. Evol. 29 (2): 157–169. Bibcode:1989JMolE..29..157Hdoi:10.1007/BF02100114PMID 2509716S2CID 7298013.
  5. Esposti MD, Crimi M, Ghelli A, Patarnello T, Meyer A, De Vries S (1993). “Mitochondrial cytochrome b: evolution and structure of the protein” (PDF). Biochim. Biophys. Acta. 1143 (3): 243–271. doi:10.1016/0005-2728(93)90197-NPMID 8329437.
  6. Castresana, J. (2001). “Cytochrome b Phylogeny and the Taxonomy of Great Apes and Mammals”. Molecular Biology and Evolution. 18 (4): 465–471. doi:10.1093/oxfordjournals.molbev.a003825PMID 11264397.
  7. Blakely EL, Mitchell AL, Fisher N, Meunier B, Nijtmans LG, Schaefer AM, Jackson MJ, Turnbull DM, Taylor RW (July 2005). “A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast”. FEBS J. 272 (14): 3583–92. doi:10.1111/j.1742-4658.2005.04779.xPMID 16008558S2CID 13938075.
  8. Siregar JE, Syafruddin D, Matsuoka H, Kita K, Marzuki S (June 2008). “Mutation underlying resistance of Plasmodium berghei to atovaquone in the quinone binding domain 2 (Qo(2)) of the cytochrome b gene”. Parasitology International. 57 (2): 229–32. doi:10.1016/j.parint.2007.12.002PMID 18248769.
  9. FRAC (Fungicide Resistance Action Committee) (March 2021). “FRAC Code List ©*2021: Fungal control agents sorted by cross resistance pattern and mode of action (including coding for FRAC Groups on product labels)” (PDF).
  10. Petrasch, Stefan; Knapp, Steven J.; van Kan, Jan A. L.; Blanco‐Ulate, Barbara (2019-04-04). “Grey mould of strawberry, a devastating disease caused by the ubiquitous necrotrophic fungal pathogen Botrytis cinerea”. Molecular Plant PathologyBritish Society for Plant Pathology (W-B). 20 (6): 877–892. doi:10.1111/mpp.12794ISSN 1464-6722PMC 6637890PMID 30945788S2CID 93002697.
  11. Cosseboom, Scott D.; Ivors, Kelly L.; Schnabel, Guido; Bryson, Patricia K.; Holmes, Gerald J. (2019). “Within-Season Shift in Fungicide Resistance Profiles of Botrytis cinerea in California Strawberry Fields”Plant DiseaseAmerican Phytopathological Society103 (1): 59–64. doi:10.1094/pdis-03-18-0406-reISSN 0191-2917PMID 30422743S2CID 205345358.

Cytochrome b External links

Proteins that contain heme (hemoproteins)

Cytochrome b Categories: 

Coenzyme Q : cytochrome c – oxidoreductase Notes

The coenzyme Q : cytochrome c – oxidoreductase, sometimes called the cytochrome bc1 complex, and at other times complex III, is the third complex in the electron transport chain (EC 1.10.2.2), playing a critical role in biochemical generation of ATP (oxidative phosphorylation). Complex III is a multisubunit transmembrane protein encoded by both the mitochondrial (cytochrome b) and the nuclear genomes (all other subunits). Complex III is present in the mitochondria of all animals and all aerobic eukaryotes and the inner membranes of most eubacteria. Mutations in Complex III cause exercise intolerance as well as multisystem disorders. The bc1 complex contains 11 subunits, 3 respiratory subunits (cytochrome B, cytochrome C1, Rieske protein), 2 core proteins and 6 low-molecular weight proteins.

Ubiquinol—cytochrome-c reductase catalyzes the chemical reaction

QH2 + 2 ferricytochrome c ⇌\rightleftharpoons  Q + 2 ferrocytochrome c + 2 H+

Thus, the two substrates of this enzyme are quinol (QH2) and ferri- (Fe3+cytochrome c, whereas its 3 products are quinone (Q), ferro- (Fe2+) cytochrome c, and H+.

This enzyme belongs to the family of oxidoreductases, specifically those acting on diphenols and related substances as donor with a cytochrome as acceptor. This enzyme participates in oxidative phosphorylation. It has four cofactorscytochrome c1cytochrome b-562, cytochrome b-566, and a 2-Iron ferredoxin of the Rieske type.

Coenzyme Q : cytochrome c – oxidoreductase Nomenclature

The systematic name of this enzyme class is ubiquinol:ferricytochrome-c oxidoreductase. Other names in common use include:

  • coenzyme Q-cytochrome c reductase,
  • dihydrocoenzyme Q-cytochrome c reductase,
  • reduced ubiquinone-cytochrome c reductase, complex III,
  • (mitochondrial electron transport),
  • ubiquinone-cytochrome c reductase,
  • ubiquinol-cytochrome c oxidoreductase,
  • reduced coenzyme Q-cytochrome c reductase,
  • ubiquinone-cytochrome c oxidoreductase,
  • reduced ubiquinone-cytochrome c oxidoreductase,
  • mitochondrial electron transport complex III,
  • ubiquinol-cytochrome c-2 oxidoreductase,
  • ubiquinone-cytochrome b-c1 oxidoreductase,
  • ubiquinol-cytochrome c2 reductase,
  • ubiquinol-cytochrome c1 oxidoreductase,
  • CoQH2-cytochrome c oxidoreductase,
  • ubihydroquinol:cytochrome c oxidoreductase,
  • coenzyme QH2-cytochrome c reductase, and
  • QH2:cytochrome c oxidoreductase.

Coenzyme Q : cytochrome c – oxidoreductase Structure

Structure of complex III

Compared to the other major proton-pumping subunits of the electron transport chain, the number of subunits found can be small, as small as three polypeptide chains. This number does increase, and eleven subunits are found in higher animals.[ Iwata S, Lee JW, Okada K, Lee JK, Iwata M, Rasmussen B, Link TA, Ramaswamy S, Jap BK (July 1998). “Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex”. Science281 (5373): 64–71. Bibcode:1998Sci…281…64Idoi:10.1126/science.281.5373.64PMID 9651245.] Three subunits have prosthetic groups. The cytochrome b subunit has two b-type hemes (bL and bH), the cytochrome c subunit has one c-type heme (c1), and the Rieske Iron Sulfur Protein subunit (ISP) has a two iron, two sulfur iron-sulfur cluster (2Fe•2S).

Structures of complex III: PDB1KYO​, PDB1L0L

Coenzyme Q – cytochrome c reductase Composition of complex

In vertebrates the bc1 complex, or Complex III, contains 11 subunits: 3 respiratory subunits, 2 core proteins and 6 low-molecular weight proteins.[Zhang Z, Huang L, Shulmeister VM, Chi YI, Kim KK, Hung LW, et al. (1998). “Electron transfer by domain movement in cytochrome bc1”. Nature392 (6677): 677–84. Bibcode:1998Natur.392..677Zdoi:10.1038/33612PMID 9565029S2CID 4380033.][Hao GF, Wang F, Li H, Zhu XL, Yang WC, Huang LS, et al. (2012). “Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex”. J Am Chem Soc134 (27): 11168–76. doi:10.1021/ja3001908PMID 22690928.] Proteobacterial complexes may contain as few as three subunits.[Yang XH, Trumpower BL (1986). “Purification of a three-subunit ubiquinol-cytochrome c oxidoreductase complex from Paracoccus denitrificans”J Biol Chem261 (26): 12282–9. doi:10.1016/S0021-9258(18)67236-9PMID 3017970.]

Table of subunit composition of complex III

No.Subunit nameHuman proteinProtein description from UniProtPfam family
with Human protein
Respiratory subunit proteins
1MT-CYB / Cyt bCYB_HUMANCytochrome bPfam PF13631
2CYC1 / Cyt c1CY1_HUMANCytochrome c1, heme protein, mitochondrialPfam PF02167
3Rieske / UCR1UCRI_HUMANCytochrome b-c1 complex subunit Rieske, mitochondrial EC 1.10.2.2Pfam PF02921 
Pfam PF00355
Core protein subunits
4QCR1 / SU1QCR1_HUMANCytochrome b-c1 complex subunit 1, mitochondrialPfam PF00675
Pfam PF05193
5QCR2 / SU2QCR2_HUMANCytochrome b-c1 complex subunit 2, mitochondrialPfam PF00675
Pfam PF05193
Low-molecular weight protein subunits
6QCR6 / SU6QCR6_HUMANCytochrome b-c1 complex subunit 6, mitochondrialPfam PF02320
7QCR7 / SU7QCR7_HUMANCytochrome b-c1 complex subunit 7Pfam PF02271
8QCR8 / SU8QCR8_HUMANCytochrome b-c1 complex subunit 8Pfam PF02939
9QCR9 / SU9 / UCRCQCR9_HUMANaCytochrome b-c1 complex subunit 9Pfam PF09165
10QCR10 / SU10QCR10_HUMANCytochrome b-c1 complex subunit 10Pfam PF05365
11QCR11 / SU11QCR11_HUMANCytochrome b-c1 complex subunit 11Pfam PF08997
a In vertebrates, a cleavage product of 8 kDa from the N-terminus of the Rieske protein (Signal peptide) is retained in the complex as subunit 9. Thus subunits 10 and 11 correspond to fungal QCR9p and QCR10p.

Coenzyme Q – cytochrome c reductase Reaction

It catalyzes the reduction of cytochrome c by oxidation of coenzyme Q (CoQ) and the concomitant pumping of 4 protons from the mitochondrial matrix to the intermembrane space:

QH2 + 2 cytochrome c (FeIII) + 2 H+
in → Q + 2 cytochrome c (FeII) + 4 H+
out

In the process called Q cycle,[Kramer DM, Roberts AG, Muller F, Cape J, Bowman MK (2004). “Q-cycle bypass reactions at the Qo site of the cytochrome bc1 (and related) complexes”. Quinones and Quinone Enzymes, Part BMeth. Enzymol. Methods in Enzymology. Vol. 382. pp. 21–45. doi:10.1016/S0076-6879(04)82002-0ISBN 978-0-12-182786-1PMID 15047094.][Crofts AR (2004). “The cytochrome bc1 complex: function in the context of structure”. Annu. Rev. Physiol66: 689–733. doi:10.1146/annurev.physiol.66.032102.150251PMID 14977419.] two protons are consumed from the matrix (M), four protons are released into the inter membrane space (IM) and two electrons are passed to cytochrome c.

Coenzyme Q – cytochrome c reductase Reaction mechanism

The Q cycle

The reaction mechanism for complex III (cytochrome bc1, coenzyme Q: cytochrome C oxidoreductase) is known as the ubiquinone (“Q”) cycle. In this cycle four protons get released into the positive “P” side (inter membrane space), but only two protons get taken up from the negative “N” side (matrix). As a result, a proton gradient is formed across the membrane. In the overall reaction, two ubiquinols are oxidized to ubiquinones and one ubiquinone is reduced to ubiquinol. In the complete mechanism, two electrons are transferred from ubiquinol to ubiquinone, via two cytochrome c intermediates.

Overall:

  • 2 x QH2 oxidised to Q
  • 1 x Q reduced to QH2
  • 2 x Cyt c reduced
  • 4 x H+ released into intermembrane space
  • 2 x H+ picked up from matrix

The reaction proceeds according to the following steps:

Round 1:

  1. Cytochrome b binds a ubiquinol and a ubiquinone.
  2. The 2Fe/2S center and BL heme each pull an electron off the bound ubiquinol, releasing two protons into the intermembrane space.
  3. One electron is transferred to cytochrome c1 from the 2Fe/2S centre, whilst another is transferred from the BL heme to the BH Heme.
  4. Cytochrome c1 transfers its electron to cytochrome c (not to be confused with cytochrome c1), and the BH Heme transfers its electron to a nearby ubiquinone, resulting in the formation of a ubisemiquinone.
  5. Cytochrome c diffuses. The first ubiquinol (now oxidised to ubiquinone) is released, whilst the semiquinone remains bound.

Round 2:

  1. A second ubiquinol is bound by cytochrome b.
  2. The 2Fe/2S center and BL heme each pull an electron off the bound ubiquinol, releasing two protons into the intermembrane space.
  3. One electron is transferred to cytochrome c1 from the 2Fe/2S centre, whilst another is transferred from the BL heme to the BH Heme.
  4. Cytochrome c1 then transfers its electron to cytochrome c, whilst the nearby semiquinone produced from round 1 picks up a second electron from the BH heme, along with two protons from the matrix.
  5. The second ubiquinol (now oxidised to ubiquinone), along with the newly formed ubiquinol are released.[ Ferguson SJ, Nicholls D, Ferguson S (2002). Bioenergetics (3rd ed.). San Diego: Academic. pp. 114–117. ISBN 978-0-12-518121-1.]

Coenzyme Q – cytochrome c reductaseInhibitors of complex III

There are three distinct groups of Complex III inhibitors.

  • Antimycin A binds to the Qi site and inhibits the transfer of electrons in Complex III from heme bH to oxidized Q (Qi site inhibitor).
  • Myxothiazol and stigmatellin binds to the Qo site and inhibits the transfer of electrons from reduced QH2 to the Rieske Iron sulfur protein. Myxothiazol and stigmatellin bind to distinct but overlapping pockets within the Qo site.
    • Myxothiazol binds nearer to cytochrome bL (hence termed a “proximal” inhibitor).
    • Stigmatellin binds farther from heme bL and nearer the Rieske Iron sulfur protein, with which it strongly interacts.

Some have been commercialized as fungicides (the strobilurin derivatives, best known of which is azoxystrobinQoI inhibitors) and as anti-malaria agents (atovaquone).

Also propylhexedrine inhibits cytochrome c reductase.[Holmes, J. H.; Sapeika, N; Zwarenstein, H (1975). “Inhibitory effect of anti-obesity drugs on NADH dehydrogenase of mouse heart homogenates”. Research Communications in Chemical Pathology and Pharmacology11 (4): 645–6. PMID 241101.]

Coenzyme Q – cytochrome c reductase Oxygen free radicals

A small fraction of electrons leave the electron transport chain before reaching complex IV. Premature electron leakage to oxygen results in the formation of superoxide. The relevance of this otherwise minor side reaction is that superoxide and other reactive oxygen species are highly toxic and are thought to play a role in several pathologies, as well as aging (the free radical theory of aging).[Muller, F. L.; Lustgarten, M. S.; Jang, Y.; Richardson, A. & Van Remmen, H. (2007). “Trends in oxidative aging theories”. Free Radic. Biol. Med43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034PMID 17640558.] Electron leakage occurs mainly at the Qo site and is stimulated by antimycin AAntimycin A locks the b hemes in the reduced state by preventing their re-oxidation at the Qi site, which, in turn, causes the steady-state concentrations of the Qo semiquinone to rise, the latter species reacting with oxygen to form superoxide. The effect of high membrane potential is thought to have a similar effect.[Skulachev VP (May 1996). “Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants”. Q. Rev. Biophys29 (2): 169–202. doi:10.1017/s0033583500005795PMID 8870073.] Superoxide produced at the Qo site can be released both into the mitochondrial matrix[Muller F (2000). “The nature and mechanism of superoxide production by the electron transport chain: Its relevance to aging”AGE23 (4): 227–253. doi:10.1007/s11357-000-0022-9PMC 3455268PMID 23604868.][Muller FL, Liu Y, Van Remmen H (November 2004). “Complex III releases superoxide to both sides of the inner mitochondrial membrane”J. Biol. Chem279 (47): 49064–73. doi:10.1074/jbc.M407715200PMID 15317809.] and into the intermembrane space, where it can then reach the cytosol.[Muller F (2000). “The nature and mechanism of superoxide production by the electron transport chain: Its relevance to aging”AGE23 (4): 227–253. doi:10.1007/s11357-000-0022-9PMC 3455268PMID 23604868.][Han D, Williams E, Cadenas E (January 2001). “Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space”Biochem. J353 (Pt 2): 411–6. doi:10.1042/0264-6021:3530411PMC 1221585PMID 11139407.] This could be explained by the fact that Complex III might produce superoxide as membrane permeable HOO rather than as membrane impermeable O−.
2
.[Muller FL, Liu Y, Van Remmen H (November 2004). “Complex III releases superoxide to both sides of the inner mitochondrial membrane”J. Biol. Chem279 (47): 49064–73. doi:10.1074/jbc.M407715200PMID 15317809.]

Coenzyme Q – cytochrome c reductase Human gene names

MT-CYBmtDNA encoded cytochrome b; mutations associated with exercise intolerance

CYC1: cytochrome c1

CYCS: cytochrome c

UQCRFS1: Rieske iron sulfur protein

UQCRB: Ubiquinone binding protein, mutation linked with mitochondrial complex III deficiency nuclear type 3

UQCRH: hinge protein

UQCRC2: Core 2, mutations linked to mitochondrial complex III deficiency, nuclear type 5

UQCRC1: Core 1

UQCR: 6.4KD subunit

UQCR10: 7.2KD subunit

TTC19: Newly identified subunit, mutations linked to complex III deficiency nuclear type 2.

Coenzyme Q – cytochrome c reductase Mutations in complex III genes in human disease

Mutations in complex III-related genes typically manifest as exercise intolerance.[DiMauro S (November 2006). “Mitochondrial myopathies” (PDF). Curr Opin Rheumatol18 (6): 636–41. doi:10.1097/01.bor.0000245729.17759.f2PMID 17053512S2CID 29140366.][DiMauro S (June 2007). “Mitochondrial DNA medicine”. Biosci. Rep27 (1–3): 5–9. doi:10.1007/s10540-007-9032-5PMID 17484047S2CID 5849380.] Other mutations have been reported to cause septo-optic dysplasia[Schuelke M, Krude H, Finckh B, Mayatepek E, Janssen A, Schmelz M, Trefz F, Trijbels F, Smeitink J (March 2002). “Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation”. Ann. Neurol51 (3): 388–92. doi:10.1002/ana.10151PMID 11891837S2CID 12425236.] and multisystem disorders.[Wibrand F, Ravn K, Schwartz M, Rosenberg T, Horn N, Vissing J (October 2001). “Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene”. Ann. Neurol50 (4): 540–3. doi:10.1002/ana.1224PMID 11601507S2CID 8944744.] However, mutations in BCS1L, a gene responsible for proper maturation of complex III, can result in Björnstad syndrome and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. The pathogenicity of several mutations has been verified in model systems such as yeast.[Fisher N, Castleden CK, Bourges I, Brasseur G, Dujardin G, Meunier B (March 2004). “Human disease-related mutations in cytochrome b studied in yeast”J. Biol. Chem279 (13): 12951–8. doi:10.1074/jbc.M313866200PMID 14718526.] The extent to which these various pathologies are due to bioenergetic deficits or overproduction of superoxide is presently unknown.

See also

Additional images

    Coenzyme Q – cytochrome c reductase References

    1. PDB1ntz​; Gao X, Wen X, Esser L, Quinn B, Yu L, Yu CA, Xia D (August 2003). “Structural basis for the quinone reduction in the bc1 complex: a comparative analysis of crystal structures of mitochondrial cytochrome bc1 with bound substrate and inhibitors at the Qi site”. Biochemistry. 42 (30): 9067–80. doi:10.1021/bi0341814PMID 12885240.
    2. Iwata S, Lee JW, Okada K, Lee JK, Iwata M, Rasmussen B, Link TA, Ramaswamy S, Jap BK (July 1998). “Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex”. Science. 281 (5373): 64–71. Bibcode:1998Sci…281…64Idoi:10.1126/science.281.5373.64PMID 9651245.
    3. Zhang Z, Huang L, Shulmeister VM, Chi YI, Kim KK, Hung LW, et al. (1998). “Electron transfer by domain movement in cytochrome bc1”. Nature. 392 (6677): 677–84. Bibcode:1998Natur.392..677Zdoi:10.1038/33612PMID 9565029S2CID 4380033.
    4. Hao GF, Wang F, Li H, Zhu XL, Yang WC, Huang LS, et al. (2012). “Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex”. J Am Chem Soc. 134 (27): 11168–76. doi:10.1021/ja3001908PMID 22690928.
    5. Yang XH, Trumpower BL (1986). “Purification of a three-subunit ubiquinol-cytochrome c oxidoreductase complex from Paracoccus denitrificans”. J Biol Chem. 261 (26): 12282–9. doi:10.1016/S0021-9258(18)67236-9PMID 3017970.
    6. Kramer DM, Roberts AG, Muller F, Cape J, Bowman MK (2004). “Q-cycle bypass reactions at the Qo site of the cytochrome bc1 (and related) complexes”. Quinones and Quinone Enzymes, Part B. Meth. Enzymol. Methods in Enzymology. Vol. 382. pp. 21–45. doi:10.1016/S0076-6879(04)82002-0ISBN 978-0-12-182786-1PMID 15047094.
    7. Crofts AR (2004). “The cytochrome bc1 complex: function in the context of structure”. Annu. Rev. Physiol. 66: 689–733. doi:10.1146/annurev.physiol.66.032102.150251PMID 14977419.
    8. Ferguson SJ, Nicholls D, Ferguson S (2002). Bioenergetics (3rd ed.). San Diego: Academic. pp. 114–117. ISBN 978-0-12-518121-1.
    9. Holmes, J. H.; Sapeika, N; Zwarenstein, H (1975). “Inhibitory effect of anti-obesity drugs on NADH dehydrogenase of mouse heart homogenates”. Research Communications in Chemical Pathology and Pharmacology. 11 (4): 645–6. PMID 241101.
    10. Muller, F. L.; Lustgarten, M. S.; Jang, Y.; Richardson, A. & Van Remmen, H. (2007). “Trends in oxidative aging theories”. Free Radic. Biol. Med. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034PMID 17640558.
    11. Skulachev VP (May 1996). “Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants”. Q. Rev. Biophys. 29 (2): 169–202. doi:10.1017/s0033583500005795PMID 8870073.
    12. Muller F (2000). “The nature and mechanism of superoxide production by the electron transport chain: Its relevance to aging”. AGE. 23 (4): 227–253. doi:10.1007/s11357-000-0022-9PMC 3455268PMID 23604868.
    13. Muller FL, Liu Y, Van Remmen H (November 2004). “Complex III releases superoxide to both sides of the inner mitochondrial membrane”. J. Biol. Chem. 279 (47): 49064–73. doi:10.1074/jbc.M407715200PMID 15317809.
    14. Han D, Williams E, Cadenas E (January 2001). “Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space”. Biochem. J. 353 (Pt 2): 411–6. doi:10.1042/0264-6021:3530411PMC 1221585PMID 11139407.
    15. DiMauro S (November 2006). “Mitochondrial myopathies” (PDF). Curr Opin Rheumatol. 18 (6): 636–41. doi:10.1097/01.bor.0000245729.17759.f2PMID 17053512S2CID 29140366.
    16. DiMauro S (June 2007). “Mitochondrial DNA medicine”. Biosci. Rep. 27 (1–3): 5–9. doi:10.1007/s10540-007-9032-5PMID 17484047S2CID 5849380.
    17. Schuelke M, Krude H, Finckh B, Mayatepek E, Janssen A, Schmelz M, Trefz F, Trijbels F, Smeitink J (March 2002). “Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation”. Ann. Neurol. 51 (3): 388–92. doi:10.1002/ana.10151PMID 11891837S2CID 12425236.
    18. Wibrand F, Ravn K, Schwartz M, Rosenberg T, Horn N, Vissing J (October 2001). “Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene”. Ann. Neurol. 50 (4): 540–3. doi:10.1002/ana.1224PMID 11601507S2CID 8944744.
    19. Fisher N, Castleden CK, Bourges I, Brasseur G, Dujardin G, Meunier B (March 2004). “Human disease-related mutations in cytochrome b studied in yeast”. J. Biol. Chem. 279 (13): 12951–8. doi:10.1074/jbc.M313866200PMID 14718526.

    Coenzyme Q – cytochrome c reductase Further reading

    External links

    MetabolismCitric acid cycle enzymes
    Ion pumpproton pumps: Oxidoreduction-driven transporters (TC 3D)
    Mitochondrial proteins
    Oxidoreductasesdiphenol family (EC 1.10)
    Enzymes

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    Coenzyme Q – cytochrome c reductase Categories:

    Ferrochelatase Structure

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

    Human ferrochelatase is a homodimer composed of two 359 amino acid polypeptide chains. It has a total molecular weight of 85.07 kDa.

    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).

    • 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 Biology8 (2): 156–160. doi:10.1038/84152PMID 11175906S2CID 9822420.

    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.

    • 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 Biology8 (2): 156–160. doi:10.1038/84152PMID 11175906S2CID 9822420.

    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.

    • 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 Biology297 (1): 221–232. doi:10.1006/jmbi.2000.3569PMID 10704318.

    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. Anionic residues form a pathway facilitating proton movement away from the catalytic histidine.

    Frataxin Notes

    Frataxin is a protein that in humans is encoded by the FXN gene.[Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (Mar 1996). “Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion”. Science271 (5254): 1423–7. Bibcode:1996Sci…271.1423Cdoi:10.1126/science.271.5254.1423PMID 8596916S2CID 20303793.][Carvajal JJ, Pook MA, dos Santos M, Doudney K, Hillermann R, Minogue S, Williamson R, Hsuan JJ, Chamberlain S (Oct 1996). “The Friedreich’s ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase”. Nature Genetics14 (2): 157–62. doi:10.1038/ng1096-157PMID 8841185S2CID 6324358.]

    It is located in the mitochondrion and Frataxin mRNA is mostly expressed in tissues with a high metabolic rate. The function of frataxin is not clear but it is involved in assembly of iron-sulfur clusters. It has been proposed to act as either an iron chaperone or an iron storage protein. Reduced expression of frataxin is the cause of Friedreich’s ataxia.

    Frataxin Structure

    X-ray crystallography has shown that human frataxin consists of a β-sheet that supports a pair of parallel α-helices, forming a compact αβ sandwich. Frataxin homologues in other species are similar, sharing the same core structure. However, the frataxin tail sequences, extending from the end of one helix, diverge in sequence and differ in length. Human frataxin has a longer tail sequence than frataxin found in bacteria or yeast. It is hypothesized that the purpose of the tail is to stabilize the protein.[Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE (Oct 2000). “Crystal structure of human frataxin”The Journal of Biological Chemistry275 (40): 30753–6. doi:10.1074/jbc.C000407200PMID 10900192.]

    Like most mitochondrial proteins, frataxin is synthesized in cytoplasmic ribosomes as large precursor molecules with mitochondrial targeting sequences. Upon entry into mitochondria, the molecules are broken down by a proteolytic reaction to yield mature frataxin.[Stemmler TL, Lesuisse E, Pain, Dancis (August 2010). “Frataxin and Mitochondrial FeS Cluster Biogenesis”Journal of Biological Chemistry285 (35): 26737–26743. doi:10.1074/jbc.R110.118679PMC 2930671PMID 20522547.]

    Frataxin Function

    Frataxin is localized to the mitochondrion. The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters. It has been proposed to act as either an iron chaperone or an iron storage protein.[Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR, Bonomi F, Pastore A (Apr 2009). “Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS”. Nature Structural & Molecular Biology. 16 (4): 390 6. doi:10.1038/nsmb.1579PMID 19305405S2CID 205522816.]

    Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich’s ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin.).[Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (Mar 1996). “Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion”. Science271 (5254): 1423–7. Bibcode:1996Sci…271.1423Cdoi:10.1126/science.271.5254.1423PMID 8596916S2CID 20303793.][Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (Oct 1996). “Clinical and genetic abnormalities in patients with Friedreich’s ataxia”The New England Journal of Medicine335 (16): 1169–75. doi:10.1056/NEJM199610173351601PMID 8815938.][Koutnikova H, Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M (Aug 1997). “Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin”. Nature Genetics16 (4): 345–51. doi:10.1038/ng0897-345PMID 9241270S2CID 5883249.]

    Frataxin Clinical significance

    Reduced expression of frataxin is the cause of Friedreich’s ataxia (FRDA), a neurodegenerative disease. The reduction in frataxin gene expression may be attributable from either the silencing of transcription of the frataxin gene because of epigenetic modifications in the chromosomal entity[Kim E, Napierala M, Dent SY (Oct 2011). “Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich’s ataxia”Nucleic Acids Research39 (19): 8366–77. doi:10.1093/nar/gkr542PMC 3201871PMID 21745819.] or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in bacteria[Pan X, Ding Y, Shi L (Nov 2009). “The roles of SbcCD and RNaseE in the transcription of GAA x TTC repeats in Escherichia coli”. DNA Repair8 (11): 1321–7. doi:10.1016/j.dnarep.2009.08.001PMID 19733517.] and Human cells[Baralle M, Pastor T, Bussani E, Pagani F (Jul 2008). “Influence of Friedreich ataxia GAA noncoding repeat expansions on pre-mRNA processing”American Journal of Human Genetics83 (1): 77–88. doi:10.1016/j.ajhg.2008.06.018PMC 2443835PMID 18597733.] or both. The expansion of intronic trinucleotide repeat GAA results in Friedreich’s ataxia.[“Entrez Gene: FXN frataxin”.] This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression.[Li L, Matsui M, Corey DR (2016-01-01). “Activating frataxin expression by repeat-targeted nucleic acids”Nature Communications7: 10606. Bibcode:2016NatCo…710606Ldoi:10.1038/ncomms10606PMC 4742999PMID 26842135.]

    • Friedreich’s ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of coordination in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop hypertrophic cardiomyopathy and require a mobility aid such as a cane, walker, or wheelchair in their teens. As the disease progresses, some affected people lose their sight and hearing. Other complications may include scoliosis and diabetes mellitus.
    • The condition is caused by mutations in the FXN gene on chromosome 9, which makes a protein called frataxin. In FRDA, cells produce less frataxin. Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum. The spinal cord becomes thinner, and nerve cells lose some myelin sheath.
    • In February 2023, the first approval of a treatment for FA was granted by the FDA. Approval in the EU is pending. There are several additional therapies in trial. FRDA shortens life expectancy due to heart disease, but some people can live into their 60s or older. FRDA affects one in 50,000 people in the United States and is the most common inherited ataxia. Rates are highest in people of Western European descent. The condition is named after German physician Nikolaus Friedreich, who first described it in the 1860s.

    96% of FRDA patients have a GAA trinucleotide repeat expansion in intron 1 of both alleles of their FXN gene.[Clark E, Johnson J, Dong YN, Mercado-Ayon, Warren N, Zhai M, McMillan E, Salovin A, Lin H, Lynch DR (November 2018). “Role of frataxin protein deficiency and metabolic dysfunction in Friedreich ataxia, an autosomal recessive mitochondrial disease”Neuronal Signaling2 (4): NS20180060. doi:10.1042/NS20180060PMC 7373238PMID 32714592.] Overall, this leads to a decrease in frataxin mRNA synthesis and a decrease (but not absence) in frataxin protein in people with FRDA. (A subset of FRDA patients have GAA expansion in one chromosome and a point mutation in the FXN exon in the other chromosome.) In the typical case, the length of the allele with the shorter GAA expansion inversely correlates with frataxin levels. FRDA patients’ peripheral tissues typically have less than 10% of the frataxin levels exhibited by unaffected people.[Clark E, Johnson J, Dong YN, Mercado-Ayon, Warren N, Zhai M, McMillan E, Salovin A, Lin H, Lynch DR (November 2018). “Role of frataxin protein deficiency and metabolic dysfunction in Friedreich ataxia, an autosomal recessive mitochondrial disease”Neuronal Signaling2 (4): NS20180060. doi:10.1042/NS20180060PMC 7373238PMID 32714592.] Lower levels of frataxin result in earlier disease onset and faster progression.

    FRDA is characterized by ataxia, sensory loss, and cardiomyopathy. The reason frataxin deficiency causes these symptoms is not entirely clear. On a cellular level, it is linked to iron accumulation in the mitochondria and increased oxidant sensitivity. For reasons that are not well understood, this primarily affects the tissue of the dorsal root gangliacerebellum, and heart muscle.[Stemmler TL, Lesuisse E, Pain, Dancis (August 2010). “Frataxin and Mitochondrial FeS Cluster Biogenesis”Journal of Biological Chemistry285 (35): 26737–26743. doi:10.1074/jbc.R110.118679PMC 2930671PMID 20522547.]

    Frataxin Animal studies

    In mice, complete inactivation of the FXN gene is lethal in the early embryonic stage.[Cossée M, Puccio H, Gansmuller A, Koutnikova H, Dierich A, LeMeur M, Fischbeck K, Dollé P, Kœnig M (May 2000). “Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation”Human Molecular Genetics9 (8): 1219–1226. doi:10.1093/hmg/9.8.1219PMID 10767347Archived from the original on 2 June 2018. Retrieved 5 April 2019.] Although nearly all organisms express a frataxin homologue, the GAA repeat in intron 1 only exists in humans and other primates, so the mutation that causes FDRA can’t occur naturally in other animals. Scientists have developed several options to model this disease in mice. One approach is to silence frataxin expression in just one specific tissue type of interest: the heart (mice modified this way are called MCK), all neurons (NSE), or just the spinal cord and cerebellum (PRP).[Perdomini M, Hick A, Puccio H (17 July 2013). “Animal and cellular models of Friedreich ataxia”. Journal of Neurochemistry. 126: 65–79. doi:10.1111/jnc.12219PMID 23859342S2CID 1427817.] 

    Another approach involves inserting a GAA expansion into the first intron of the mouse FXN gene, which should inhibit frataxin production, just like in humans. Mice that are homozygous for this modified gene are called KIKI (knock-in knock-in), and the compound heterozygotes formed by crossing KIKI mice with frataxin knockout mice are called KIKO (knock-in knock-out). However, even KIKO mice still express 25-36% of the normal frataxin level, and show very mild symptoms. The final approach involves creating transgenic mice with a GAA-expanded version of the human frataxin gene. These mice are called YG22R (one GAA sequence of 190 repeats) and YG22R (two GAA sequences of 90 and 190 repeats). These mice show symptoms similar to human patients.[Perdomini M, Hick A, Puccio H (17 July 2013). “Animal and cellular models of Friedreich ataxia”. Journal of Neurochemistry. 126: 65–79. doi:10.1111/jnc.12219PMID 23859342S2CID 1427817.]

    An overexpression of frataxin in Drosophila has shown an increase in antioxidant capability, resistance to oxidative stress insults and longevity,[Runko AP, Griswold AJ, Min KT (March 2008). “Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila”FEBS Letters582 (5): 715–9. doi:10.1016/j.febslet.2008.01.046PMID 18258192S2CID 207603250.] supporting the theory that the role of frataxin is to protect the mitochondria from oxidative stress and the ensuing cellular damage.

    Fibroblasts from a mouse model of FRDA and FRDA patient fibroblasts show increased levels of DNA double-strand breaks.[Khonsari H, Schneider M, Al-Mahdawi S, Chianea YG, Themis M, Parris C, Pook MA, Themis M (December 2016). “Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts”Gene Ther23 (12): 846–856. doi:10.1038/gt.2016.61PMC 5143368PMID 27518705.] 

    lentivirus gene delivery system was used to deliver the frataxin gene to the FRDA mouse model and human patient cells, and this resulted in long-term restored expression of frataxin mRNA and frataxin protein. This restored expression of the frataxin gene was accompanied by a substantial reduction in the number of DNA double-strand breaks.[Khonsari H, Schneider M, Al-Mahdawi S, Chianea YG, Themis M, Parris C, Pook MA, Themis M (December 2016). “Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts”Gene Ther23 (12): 846–856. doi:10.1038/gt.2016.61PMC 5143368PMID 27518705.] 

    The impaired frataxin in FRDA cells appears to cause reduced capacity for repair of DNA damage and this may contribute to neurodegeneration.[Khonsari H, Schneider M, Al-Mahdawi S, Chianea YG, Themis M, Parris C, Pook MA, Themis M (December 2016). “Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts”Gene Ther23 (12): 846–856. doi:10.1038/gt.2016.61PMC 5143368PMID 27518705.]

    Frataxin Interactions

    Frataxin has been shown to biologically interact with the enzyme PMPCB.[Koutnikova H, Campuzano V, Koenig M (Sep 1998). “Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase”Human Molecular Genetics7 (9): 1485–9. doi:10.1093/hmg/7.9.1485PMID 9700204.]

    Frataxin References

    1. GRCh38: Ensembl release 89: ENSG00000165060 – Ensembl, May 2017
    2. GRCm38: Ensembl release 89: ENSMUSG00000059363 – Ensembl, May 2017
    3. “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
    4. “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
    5. Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (Mar 1996). “Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion”. Science. 271 (5254): 1423–7. Bibcode:1996Sci…271.1423Cdoi:10.1126/science.271.5254.1423PMID 8596916S2CID 20303793.
    6. Carvajal JJ, Pook MA, dos Santos M, Doudney K, Hillermann R, Minogue S, Williamson R, Hsuan JJ, Chamberlain S (Oct 1996). “The Friedreich’s ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase”. Nature Genetics. 14 (2): 157–62. doi:10.1038/ng1096-157PMID 8841185S2CID 6324358.
    7. Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE (Oct 2000). “Crystal structure of human frataxin”. The Journal of Biological Chemistry. 275 (40): 30753–6. doi:10.1074/jbc.C000407200PMID 10900192.
    8. Stemmler TL, Lesuisse E, Pain, Dancis (August 2010). “Frataxin and Mitochondrial FeS Cluster Biogenesis”. Journal of Biological Chemistry. 285 (35): 26737–26743. doi:10.1074/jbc.R110.118679PMC 2930671PMID 20522547.
    9. Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR, Bonomi F, Pastore A (Apr 2009). “Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS”. Nature Structural & Molecular Biology. 16 (4): 390–6. doi:10.1038/nsmb.1579PMID 19305405S2CID 205522816.
    10. Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (Oct 1996). “Clinical and genetic abnormalities in patients with Friedreich’s ataxia”. The New England Journal of Medicine. 335 (16): 1169–75. doi:10.1056/NEJM199610173351601PMID 8815938.
    11. Koutnikova H, Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M (Aug 1997). “Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin”. Nature Genetics. 16 (4): 345–51. doi:10.1038/ng0897-345PMID 9241270S2CID 5883249.
    12. Kim E, Napierala M, Dent SY (Oct 2011). “Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich’s ataxia”. Nucleic Acids Research. 39 (19): 8366–77. doi:10.1093/nar/gkr542PMC 3201871PMID 21745819.
    13. Pan X, Ding Y, Shi L (Nov 2009). “The roles of SbcCD and RNaseE in the transcription of GAA x TTC repeats in Escherichia coli”. DNA Repair. 8 (11): 1321–7. doi:10.1016/j.dnarep.2009.08.001PMID 19733517.
    14. Baralle M, Pastor T, Bussani E, Pagani F (Jul 2008). “Influence of Friedreich ataxia GAA noncoding repeat expansions on pre-mRNA processing”. American Journal of Human Genetics. 83 (1): 77–88. doi:10.1016/j.ajhg.2008.06.018PMC 2443835PMID 18597733.
    15. “Entrez Gene: FXN frataxin”.
    16. Li L, Matsui M, Corey DR (2016-01-01). “Activating frataxin expression by repeat-targeted nucleic acids”. Nature Communications. 7: 10606. Bibcode:2016NatCo…710606Ldoi:10.1038/ncomms10606PMC 4742999PMID 26842135.
    17. Clark E, Johnson J, Dong YN, Mercado-Ayon, Warren N, Zhai M, McMillan E, Salovin A, Lin H, Lynch DR (November 2018). “Role of frataxin protein deficiency and metabolic dysfunction in Friedreich ataxia, an autosomal recessive mitochondrial disease”. Neuronal Signaling. 2 (4): NS20180060. doi:10.1042/NS20180060PMC 7373238PMID 32714592.
    18. Cossée M, Puccio H, Gansmuller A, Koutnikova H, Dierich A, LeMeur M, Fischbeck K, Dollé P, Kœnig M (May 2000). “Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation”. Human Molecular Genetics. 9 (8): 1219–1226. doi:10.1093/hmg/9.8.1219PMID 10767347Archived from the original on 2 June 2018. Retrieved 5 April 2019.
    19. Perdomini M, Hick A, Puccio H (17 July 2013). “Animal and cellular models of Friedreich ataxia”. Journal of Neurochemistry. 126: 65–79. doi:10.1111/jnc.12219PMID 23859342S2CID 1427817.
    20. Runko AP, Griswold AJ, Min KT (March 2008). “Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila”. FEBS Letters. 582 (5): 715–9. doi:10.1016/j.febslet.2008.01.046PMID 18258192S2CID 207603250.
    21. Khonsari H, Schneider M, Al-Mahdawi S, Chianea YG, Themis M, Parris C, Pook MA, Themis M (December 2016). “Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts”. Gene Ther. 23 (12): 846–856. doi:10.1038/gt.2016.61PMC 5143368PMID 27518705.
    22. Koutnikova H, Campuzano V, Koenig M (Sep 1998). “Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase”. Human Molecular Genetics. 7 (9): 1485–9. doi:10.1093/hmg/7.9.1485PMID 9700204.

    Frataxin Further reading

    Frataxin External links

    Mitochondrial proteins

    Frataxin Categories: 

    Frataxin chaperones iron to the matrix side of ferrochelatase, where aspartate and histidine residues on both proteins coordinate iron transfer into ferrochelatase.

    Two arginine and tyrosine residues in the active site (Arg164, Tyr165) may perform the final metalation.

    • 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 Biology8 (2): 156–160. doi:10.1038/84152PMID 11175906S2CID 9822420.
    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).

    • James, William D.; Berger, Timothy G. (2006). Andrews’ Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.

    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.

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

    Interactions

    Ferrochelatase interacts with numerous other enzymes involved in heme biosynthesis, catabolism, and transport, including protoporphyrinogen oxidase5-aminolevulinate synthaseABCB10ABCB7succinyl-CoA synthetase, and mitoferrin-1. 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.

    ATP-binding cassette sub-family B member 7, mitochondrial is a protein that in humans is encoded by the ABCB7gene.[Savary S, Allikmets R, Denizot F, Luciani MF, Mattei MG, Dean M, Chimini G (July 1997). “Isolation and chromosomal mapping of a novel ATP-binding cassette transporter conserved in mouse and human”. Genomics. 41 (2): 275–8. doi:10.1006/geno.1997.4658PMID 9143506][“Entrez Gene: ABCB7 ATP-binding cassette, sub-family B (MDR/TAP), member 7”.] The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). Forty eight ABC genes have been reported in humans. Among these, many have been characterized and shown to be causally related to diseases present in humans such as cystic fibrosisadrenoleukodystrophyStargardt disease, drug-resistant tumors, Dubin–Johnson syndrome, Byler’s disease, progressive familiar intrahepatic cholestasis, X-linked sideroblastic anemiaataxia, and persistent and hyperinsulimenic hypoglycemia.[Choi CH (Oct 2005). “ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal”Cancer Cell International5: 30. doi:10.1186/1475-2867-5-30PMC 1277830PMID 16202168.] ABC transporters are also involved in multiple drug resistance, and this is how some of them were first identified. When the ABC transport proteins are overexpressed in cancer cells, they can export anticancer drugs and render tumors resistant.[Scott MP, Lodish HF, Berk A, Kaiser, C, Krieger M, Bretscher A, Ploegh H, Amon A (2012). Molecular Cell Biology. San Francisco: W. H. Freeman. ISBN 978-1-4292-3413-9.]

    This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a half-transporter involved in the transport of heme from the mitochondria to the cytosol. With iron/sulfur cluster precursors as its substrates, this protein may play a role in metal homeostasis.

    Mutations in this gene have been implicated in X-linked sideroblastic anemia with ataxia.[“Entrez Gene: ABCB7 ATP-binding cassette, sub-family B (MDR/TAP), member 7”.]

    ABCB7 has been shown to interact with Ferrochelatase.[Taketani S, Kakimoto K, Ueta H, Masaki R, Furukawa T (April 2003). “Involvement of ABC7 in the biosynthesis of heme in erythroid cells: interaction of ABC7 with ferrochelatase”. Blood101 (8): 3274–80. doi:10.1182/blood-2002-04-1212PMID 12480705S2CID 18599174.]

    See also: ATP-binding cassette transporter

    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.

    Frataxin acts as the Fe+2 chaperone and complexes with ferrochelatase on its mitochondrial matrix side.

    Ferrochelatase can also insert other divalent metal ions into protoporphyrin. Some ions, such as Zn+2Ni, and Co form other metalloporphyrins while heavier metal ions such as MnPbHg, and Cd inhibit product release after metallation.

    See also

    References

    1. “FECH – Ferrochelatase, mitochondrial precursor – Homo sapiens (Human) – FECH gene & protein”.
    2. 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 Biology297 (1): 221–232. doi:10.1006/jmbi.2000.3569PMID 10704318.
    3. Leeper, F. J. (1985). “The biosynthesis of porphyrins, chlorophylls, and vitamin B12”. Natural Product Reports2 (1): 19–47. doi:10.1039/NP9850200019PMID 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”.
    6. 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 Biology8 (2): 156–160. doi:10.1038/84152PMID 11175906S2CID 9822420.
    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 Biology378 (5): 1074–1083. doi:10.1016/j.jmb.2008.03.040PMC 2852141PMID 18423489.
    8. 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/B703195EPMC 2862461PMID 17476391.
    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.; Deybach, J.C. (1998). “Systematic Analysis of Molecular Defects in the Ferrochelatase Gene from Patients with Erythropoietic Protoporphyria”The American Journal of Human Genetics62 (6): 1341–52. doi:10.1086/301870PMC 1377149PMID 9585598.
    11. “Lead Toxicity — What Are Possible Health Effects from Lead Exposure?”. Agency for Toxic Substances & Disease Registry. Retrieved 9 February 2021.
    12. 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 ONE10 (8): e0135896. Bibcode:2015PLoSO..1035896Mdoi:10.1371/journal.pone.0135896PMC 4545792PMID 26287972.
    13. 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”Blood116 (4): 628–630. doi:10.1182/blood-2009-12-259614PMC 3324294PMID 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 Sciences104 (6): 1789–1793. Bibcode:2007PNAS..104.1789Mdoi:10.1073/pnas.0606144104PMC 1794275PMID 17261801.
    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 Biology393 (2): 308–319. doi:10.1016/j.jmb.2009.08.042PMC 2771925PMID 19703464.

    Further reading

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    Enzymes involved in the metabolism of heme and porphyrin
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