Fumarate reductase (quinol)

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Fumarate reductase (quinol)
QFR Crystal.png
3D cartoon of the fumarate reductase crystal structure from E. coli.
Identifiers
EC no. 1.3.5.4
Databases
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BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
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PMC articles
PubMed articles
NCBI proteins
Fumarate reductase respiratory complex
QFR Subunit A.png
Cartoon structure of fumarate reductase flavoprotein subunit A.
Identifiers
SymbolFum_red_TM
Pfam PF01127
Pfam clan CL0335
InterPro IPR004224
SCOP2 1qla / SCOPe / SUPFAM
OPM superfamily 3
OPM protein 2bs3
CDD cd03494
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1qla F:1-243 2bs3 F:1-243 1qlb C:1-243 2bs4 F:1-243
Fumarate reductase subunit C
QFR Subunit C-D.png
Cartoon structure of fumarate reductase subunits C and D near two menaquinone molecules.
Identifiers
SymbolFumarate_red_C
Pfam PF02300
Pfam clan CL0335
InterPro IPR003510
SCOP2 1fum / SCOPe / SUPFAM
CDD cd00546
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Fumarate reductase subunit D
QFR Subunit C-D.png
Cartoon structure of fumarate reductase subunits C and D near two menaquinone molecules.
Identifiers
SymbolFumarate_red_D
Pfam PF02313
Pfam clan CL0335
InterPro IPR003418
SCOP2 1fum / SCOPe / SUPFAM
CDD cd00547
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure 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:

Contents

Fumarate Reductase.png

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

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. QFR Electron Transport Chain Labeled.png
Pathway for electron tunneling across the fumarate reductase with distances labeled in Angstroms.

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

Related Research Articles

<span class="mw-page-title-main">Oxidative phosphorylation</span> Metabolic pathway

Oxidative phosphorylation or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine triphosphate (ATP). In eukaryotes, this takes place inside mitochondria. Almost all aerobic organisms carry out oxidative phosphorylation. This pathway is so pervasive because it releases more energy than alternative fermentation processes such as anaerobic glycolysis.

An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H+ ions) across a membrane. Many of the enzymes in the electron transport chain are embedded within the membrane.

<span class="mw-page-title-main">Respiratory complex I</span> Protein complex involved in cellular respiration

Respiratory complex I, EC 7.1.1.2 is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the transfer of electrons from NADH to coenzyme Q10 (CoQ10) and translocates protons across the inner mitochondrial membrane in eukaryotes or the plasma membrane of bacteria.

<span class="mw-page-title-main">Succinate dehydrogenase</span> Enzyme

Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates in both the citric acid cycle and oxidative phosphorylation. Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential.

<span class="mw-page-title-main">Succinate dehydrogenase complex subunit C</span> Protein found in humans

Succinate dehydrogenase complex subunit C, also known as succinate dehydrogenase cytochrome b560 subunit, mitochondrial, is a protein that in humans is encoded by the SDHC gene. This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with pheochromocytomas and paragangliomas. Alternatively spliced transcript variants have been described.

<span class="mw-page-title-main">Flavin adenine dinucleotide</span> Redox-active coenzyme

In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which may be in the form of FAD or flavin mononucleotide (FMN). Many flavoproteins are known: components of the succinate dehydrogenase complex, α-ketoglutarate dehydrogenase, and a component of the pyruvate dehydrogenase complex.

<span class="mw-page-title-main">SDHB</span> Protein-coding gene in the species Homo sapiens

Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHB gene.

<span class="mw-page-title-main">Mixed acid fermentation</span> Biochemical conversion of six-carbon sugars into acids in bacteria

In biochemistry, mixed acid fermentation is the metabolic process by which a six-carbon sugar is converted into a complex and variable mixture of acids. It is an anaerobic (non-oxygen-requiring) fermentation reaction that is common in bacteria. It is characteristic for members of the Enterobacteriaceae, a large family of Gram-negative bacteria that includes E. coli.

Microbial metabolism is the means by which a microbe obtains the energy and nutrients it needs to live and reproduce. Microbes use many different types of metabolic strategies and species can often be differentiated from each other based on metabolic characteristics. The specific metabolic properties of a microbe are the major factors in determining that microbe's ecological niche, and often allow for that microbe to be useful in industrial processes or responsible for biogeochemical cycles.

<span class="mw-page-title-main">Nitrate reductase</span> Class of enzymes

Nitrate reductases are molybdoenzymes that reduce nitrate to nitrite. This reaction is critical for the production of protein in most crop plants, as nitrate is the predominant source of nitrogen in fertilized soils.

<span class="mw-page-title-main">SDHA</span> Protein-coding gene in humans

Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene. This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. SDHA contains the FAD binding site where succinate is deprotonated and converted to fumarate. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Fumarate reductase is the enzyme that converts fumarate to succinate, and is important in microbial metabolism as a part of anaerobic respiration. The catalyzed reaction is:

<span class="mw-page-title-main">Formate dehydrogenase</span>

Formate dehydrogenases are a set of enzymes that catalyse the oxidation of formate to carbon dioxide, donating the electrons to a second substrate, such as NAD+ in formate:NAD+ oxidoreductase (EC 1.17.1.9) or to a cytochrome in formate:ferricytochrome-b1 oxidoreductase (EC 1.2.2.1). This family of enzymes has attracted attention as inspiration or guidance on methods for the carbon dioxide fixation, relevant to global warming.

<span class="mw-page-title-main">Cytochrome c nitrite reductase</span> Class of enzymes

Cytochrome c nitrite reductase (ccNiR) is a bacterial enzyme that catalyzes the six electron reduction of nitrite to ammonia; an important step in the biological nitrogen cycle. The enzyme catalyses the second step in the two step conversion of nitrate to ammonia, which allows certain bacteria to use nitrite as a terminal electron acceptor, rather than oxygen, during anaerobic conditions. During this process, ccNiR draws electrons from the quinol pool, which are ultimately provided by a dehydrogenase such as formate dehydrogenase or hydrogenase. These dehydrogenases are responsible for generating a proton motive force.

The Arc system is a two-component system found in some bacteria that regulates gene expression in faculatative anaerobes such as Escheria coli. Two-component system means that it has a sensor molecule and a response regulator. Arc is an abbreviation for Anoxic Redox Control system. Arc systems are instrumental in maintaining energy metabolism during transcription of bacteria. The ArcA response regulator looks at growth conditions and expresses genes to best suit the bacteria. The Arc B sensor kinase, which is a tripartite protein, is membrane bound and can autophosphorylate.

The fnr gene of Escherichia coli encodes a transcriptional activator (FNR) which is required for the expression of a number of genes involved in anaerobic respiratory pathways. The FNR protein of E. coli is an oxygen – responsive transcriptional regulator required for the switch from aerobic to anaerobic metabolism.

"Type III mutants, originally frdB, were designated fnr because they were defective in fumarate and nitrate reduction and impaired in their ability to produce gas." - Lambden and Guest, 1976 Journal of General Microbiology97, 145-160

<span class="mw-page-title-main">NADH:ubiquinone reductase (non-electrogenic)</span> Class of enzymes

NADH:ubiquinone reductase (non-electrogenic) (EC 1.6.5.9, NDH-2, ubiquinone reductase, coenzyme Q reductase, dihydronicotinamide adenine dinucleotide-coenzyme Q reductase, DPNH-coenzyme Q reductase, DPNH-ubiquinone reductase, NADH-coenzyme Q oxidoreductase, NADH-coenzyme Q reductase, NADH-CoQ oxidoreductase, NADH-CoQ reductase) is an enzyme with systematic name NADH:ubiquinone oxidoreductase. This enzyme catalyses the following chemical reaction:

Nitrate reductase (quinone) (EC 1.7.5.1, nitrate reductase A, nitrate reductase Z, quinol/nitrate oxidoreductase, quinol-nitrate oxidoreductase, quinol:nitrate oxidoreductase, NarA, NarZ, NarGHI) is an enzyme with systematic name nitrite:quinone oxidoreductase. This enzyme catalyses the following chemical reaction

Sulfide:quinone reductase is an enzyme with systematic name sulfide:quinone oxidoreductase. This enzyme catalyses the following chemical reaction

The H+-translocating F420H2 Dehydrogenase (F420H2DH) Family(TC# 3.D.9) is a member of the Na+ transporting Mrp superfamily. A single F420H2 dehydrogenase (also referred to as F420H2:quinol oxidoreductase) from the methanogenic archaeon, Methanosarcina mazei Gö1, has been shown to be a redox driven proton pump. The F420H2DH of M. mazei has a molecular size of about 120 kDa and contains Fe-S clusters and FAD. A similar five-subunit enzyme has been isolated from Methanolobus tindarius. The sulfate-reducing Archaeoglobus fulgidus (and several other archaea) also have this enzyme.

References

  1. 1 2 3 4 5 6 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. 1 2 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. 1 2 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. 1 2 3 4 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. 1 2 3 4 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. 1 2 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. 1 2 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
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