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Fumarate reductase (quinol)

Fumarate reductase (quinol)
3D cartoon of the fumarate reductase crystal structure from E. coli.
Identifiers
EC no.1.3.5.4
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Search
PMCarticles
PubMedarticles
NCBIproteins
Fumarate reductase respiratory complex
Cartoon structure of fumarate reductase flavoprotein subunit A.
Identifiers
SymbolFum_red_TM
PfamPF01127
Pfam clanCL0335
InterProIPR004224
SCOP21qla / SCOPe / SUPFAM
OPM superfamily3
OPM protein2bs3
CDDcd03494
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1qlaF:1-243 2bs3F:1-243 1qlbC:1-243 2bs4F:1-243
Fumarate reductase subunit C
Cartoon structure of fumarate reductase subunits C and D near two menaquinone molecules.
Identifiers
SymbolFumarate_red_C
PfamPF02300
Pfam clanCL0335
InterProIPR003510
SCOP21fum / SCOPe / SUPFAM
CDDcd00546
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Fumarate reductase subunit D
Cartoon structure of fumarate reductase subunits C and D near two menaquinone molecules.
Identifiers
SymbolFumarate_red_D
PfamPF02313
Pfam clanCL0335
InterProIPR003418
SCOP21fum / SCOPe / SUPFAM
CDDcd00547
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Fumarate reductase (quinol) (EC 1.3.5.4, QFR, FRD, menaquinol-fumarate oxidoreductase, quinol:fumarate reductase) is an enzyme with systematic name succinate:quinone oxidoreductase.[1][2][3] This enzyme catalyzes the following chemical reaction:

fumarate + quinol succinate + quinone

Fumarate reductase (QFR) is a key enzyme induced by anaerobic growth of bacteria.[4] By partaking in fumarate respiration, fumarate reductase performs the last step in the microbial anaerobic respiration. It is a membrane bound protein capable of oxidizing a quinone and passing the released electrons to an awaiting fumarate to be reduced. It is activated and synthesized under low oxygen conditions, when aerobic respiration cannot be performed and the cell must perform anaerobic respiration to grow.[5] This reaction is opposite to the reaction that is catalyzed by the related complex II of the respiratory chain (succinate dehydrogenase (SQR)).[6][7]

Enzyme Structure

To date, a number of QFR enzymes have been crystalized and the specifics of enzyme structure varies between organisms; however, the overall structure remains similar across different species.[1][7][8] Fumarate reductase complexes include four subunits.[1] Subunit A contains the site of fumarate reduction and a covalently bound flavin adenine dinucleotide (FAD) prosthetic group. It is closely bound to subunit B, which contains three iron-sulfur centers, all placed near to each other and the nearby substrates. Subunit C consists of hydrophobic membrane-spanning, primarily helical segments and is the site of quinol oxidization. In some fumarate reductase structures, one or more heme groups are additionally bound to the C subunit and participate in the electron transfer.[7][5] The D subunit contains hydrophobic alpha helices that span the membrane, but does not participate in the catalytic action of the enzyme. It may be required to anchor the catalytic components of the fumarate reductase complex to the cytoplasmic membrane.[5]

3D cartoon depiction of the QFR subunit B with a menaquinone, three iron sulfur clusters, and an FAD molecule (top to bottom).[1]

Enzyme Mechanism

The reduction of fumarate in fumarate reductase is achieved via the oxidation of a quinol bound to subunit C and the resulting transfer of electrons down a chain of iron-sulfur clusters onto a waiting FAD molecule. The edge-to-edge distances between the quinol, the iron sulfur clusters, and the FAD in this enzyme do not exceed 12.5 Angstroms and can be seen on the image below.[3] These short distances between electron receptors allow electrons to travel down the chain at a physiologically reasonable timescale. Once electrons have travelled down the iron-sulfur clusters, they pass onto the FAD molecule bound to the catalytic site of the enzyme. The final reduction of the fumarate is achieved in the active site where the asymmetrical charges from the nearby amino acids polarize the fumarate and distort its shape.[9] Once the fumarate is no longer planar, a hydride from the bound FAD molecule in the active site attacks the double bond to reduce the fumarate.[9] Thus, in this reaction, the fumarate serves as the terminal electron acceptor.

Pathway for electron tunneling across the fumarate reductase with distances labeled in Angstroms.[1]

Relation to Succinate Dehydrogenase

Succinate dehydrogenase (SQR) is a key enzyme in both the citric acid cycle and the electron transport chain in the mitochondria of eukaryotes and single celled organisms.[10] It is a key enzyme in aerobic respiration and it performs the opposite reaction of QFR, by coupling the reduction of a quinone to the formation of succinate for use in the citric acid cycle.[11]

Both SQR and QFR are highly related and have been shown to have some functional overlap and redundancy in various organisms. QFR and SQR are both members of the conserved protein domain family SQR_QFR_TM and have highly similar structures.[12] It has been shown that the A and B subunits of both proteins likely evolved from a common ancestral gene.[5] Both enzymes have a common subunit arrangement containing a catalytic site, an iron-sulfur cluster containing subunit and one or two transmembrane subunits with quinone binding sites and heme binding sites if applicable. Additionally, Based on a study performed in E. coli, researchers have concluded that under some circumstances fumarate reductase is capable of replacing succinate dehydrogenase by oxidizing succinate to produce fumarate.[13] And it has been shown that in Bacillus subtilis, SQR is able to successfully perform the function of fumarate reductase.[14]

Biological Function

Fumarate reductase is involved in anaerobic respiration of multiple different organisms. Most of the information gathered about fumarate reductase is from the Escherichia coli fumarate reductase; however, fumarate reductase has also been studied in other organisms including Wolinella succinogenes, Helicobacter pylori, and Bacteroides fragilis.[1][7][4][15] Each of these organisms has slightly different gene regulation and function in addition to different enzyme structures.

In E. coli, fumarate is the terminal electron acceptor of the energy producing electron transport chain and fumarate reductase performs the crucial last step in this energy producing process that allows E. coli to grow when aerobic respiration and/or fermentation is not feasible.[16] Because of its role in cellular energy production, its function is closely regulated by multiple conditions to ensure optimal production of energy based on current cellular needs. In addition to low oxygen conditions, fumarate reductase genes are also activated by high concentrations of fumarate and repressed in the presence of other terminal electron acceptors including nicotinamide adenine dinucleotide (NAD) and nitrate.[16][17] Nitrate suppression of fumarate reductase is common in E.coli and is carried out by two genes, narL a gene that encodes for nitrate reductase regulator proteins and narX that encodes for a nitrate sensor protein.[18] Other man-made antibiotics, including Chalcones have also been proven to successfully inhibit fumarate reductase in addition to other cellular enzymes in order to cripple bacterial growth.[19]

Fumarate reductase also has a notably high production of superoxide and hydrogen peroxide in E. coli. The single electron reactivity of FAD, iron-sulfur clusters, and quinones in the fumarate reductase could all contribute to electron transfer to oxygen. However, FAD has been shown to be the most significant cause of superoxide and peroxide formation in fumarate reductase, due to higher solvent accessibility in the active site than in the locations of the quinone and iron-sulfur clusters.[20]

See also

References

  1. ^ a b c d e f Iverson TM, Luna-Chavez C, Cecchini G, Rees DC (June 1999). "Structure of the Escherichia coli fumarate reductase respiratory complex". Science. 284 (5422): 1961–6. doi:10.1126/science.284.5422.1961. PMID 10373108.
  2. ^ Cecchini G, Schröder I, Gunsalus RP, Maklashina E (January 2002). "Succinate dehydrogenase and fumarate reductase from Escherichia coli". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1553 (1–2): 140–57. doi:10.1016/S0005-2728(01)00238-9. PMID 11803023.
  3. ^ a b Iverson TM, Luna-Chavez C, Croal LR, Cecchini G, Rees DC (May 2002). "Crystallographic studies of the Escherichia coli quinol-fumarate reductase with inhibitors bound to the quinol-binding site". The Journal of Biological Chemistry. 277 (18): 16124–30. doi:10.1074/jbc.M200815200. PMID 11850430.
  4. ^ a b Ge Z, Feng Y, Dangler CA, Xu S, Taylor NS, Fox JG (November 2000). "Fumarate reductase is essential for Helicobacter pylori colonization of the mouse stomach". Microbial Pathogenesis. 29 (5): 279–87. doi:10.1006/mpat.2000.0391. PMID 11031122.
  5. ^ a b c d Cecchini G, Ackrell BA, Deshler JO, Gunsalus RP (February 1986). "Reconstitution of quinone reduction and characterization of Escherichia coli fumarate reductase activity". The Journal of Biological Chemistry. 261 (4): 1808–14. doi:10.1016/S0021-9258(17)36012-X. PMID 3511050.
  6. ^ Cook GM, Greening C, Hards K, Berney M (2014). "Energetics of pathogenic bacteria and opportunities for drug development". Advances in Microbial Physiology. 65: 1–62. doi:10.1016/bs.ampbs.2014.08.001. ISBN 9780128001424. PMID 25476763.
  7. ^ a b c d Lancaster CR, Kröger A, Auer M, Michel H (November 1999). "Structure of fumarate reductase from Wolinella succinogenes at 2.2 A resolution". Nature. 402 (6760): 377–85. Bibcode:1999Natur.402..377L. doi:10.1038/46483. PMID 10586875. S2CID 4403278.
  8. ^ Shimizu H, Osanai A, Sakamoto K, Inaoka DK, Shiba T, Harada S, Kita K (June 2012). "Crystal structure of mitochondrial quinol-fumarate reductase from the parasitic nematode Ascaris suum". Journal of Biochemistry. 151 (6): 589–92. doi:10.1093/jb/mvs051. PMID 22577165.
  9. ^ a b Reid GA, Miles CS, Moysey RK, Pankhurst KL, Chapman SK (August 2000). "Catalysis in fumarate reductase". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1459 (2–3): 310–5. doi:10.1016/s0005-2728(00)00166-3. PMID 11004445.
  10. ^ Rutter J, Winge DR, Schiffman JD (June 2010). "Succinate dehydrogenase - Assembly, regulation and role in human disease". Mitochondrion. 10 (4): 393–401. doi:10.1016/j.mito.2010.03.001. PMC 2874626. PMID 20226277.
  11. ^ Horsefield R, Yankovskaya V, Sexton G, Whittingham W, Shiomi K, Omura S, Byrne B, Cecchini G, Iwata S (March 2006). "Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction". The Journal of Biological Chemistry. 281 (11): 7309–16. doi:10.1074/jbc.M508173200. PMID 16407191.
  12. ^ NCBI. "NCBI CDD Conserved Protein Domain SQR_QFR_TM". www.ncbi.nlm.nih.gov. Retrieved 2018-03-06.
  13. ^ Guest JR (February 1981). "Partial replacement of succinate dehydrogenase function by phage- and plasmid-specified fumarate reductase in Escherichia coli". Journal of General Microbiology. 122 (2): 171–9. doi:10.1099/00221287-122-2-171. PMID 6274999.
  14. ^ Lemma E, Hägerhäll C, Geisler V, Brandt U, von Jagow G, Kröger A (September 1991). "Reactivity of the Bacillus subtilis succinate dehydrogenase complex with quinones". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1059 (3): 281–5. doi:10.1016/s0005-2728(05)80213-0. PMID 1655027.
  15. ^ Meehan BM, Malamy MH (February 2012). "Fumarate reductase is a major contributor to the generation of reactive oxygen species in the anaerobe Bacteroides fragilis". Microbiology. 158 (Pt 2): 539–46. doi:10.1099/mic.0.054403-0. PMC 3352283. PMID 22075026.
  16. ^ a b Kalman LV, Gunsalus RP (July 1989). "Identification of a second gene involved in global regulation of fumarate reductase and other nitrate-controlled genes for anaerobic respiration in Escherichia coli". Journal of Bacteriology. 171 (7): 3810–6. doi:10.1128/jb.171.7.3810-3816.1989. PMC 210129. PMID 2544557.
  17. ^ Tran QH, Bongaerts J, Vlad D, Unden G (February 1997). "Requirement for the proton-pumping NADH dehydrogenase I of Escherichia coli in respiration of NADH to fumarate and its bioenergetic implications". European Journal of Biochemistry. 244 (1): 155–60. doi:10.1111/j.1432-1033.1997.00155.x. PMID 9063459.
  18. ^ Stewart V, Parales J (April 1988). "Identification and expression of genes narL and narX of the nar (nitrate reductase) locus in Escherichia coli K-12". Journal of Bacteriology. 170 (4): 1589–97. doi:10.1128/jb.170.4.1589-1597.1988. PMC 211006. PMID 2832370.
  19. ^ Chen M, Zhai L, Christensen SB, Theander TG, Kharazmi A (July 2001). "Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones". Antimicrobial Agents and Chemotherapy. 45 (7): 2023–9. doi:10.1128/AAC.45.7.2023-2029.2001. PMC 90595. PMID 11408218.
  20. ^ Messner KR, Imlay JA (November 2002). "Mechanism of superoxide and hydrogen peroxide formation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase". The Journal of Biological Chemistry. 277 (45): 42563–71. doi:10.1074/jbc.M204958200. PMID 12200425.
This article incorporates text from the public domain Pfam and InterPro: IPR004224
This article incorporates text from the public domain Pfam and InterPro: IPR003510
This article incorporates text from the public domain Pfam and InterPro: IPR003418
Quelle: http://en.wikipedia.org/wiki/Fumarate_reductase_(quinol)