Fumarate reductase (quinol)

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. This enzyme catalyzes the following chemical reaction:

fumarate + quinol

\longrightarrow

succinate + quinone

Fumarate reductase (QFR) is a key enzyme induced by anaerobic growth of bacteria. 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. This reaction is opposite to the reaction that is catalyzed by the related complex II of the respiratory chain (succinate dehydrogenase (SQR)).

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. Fumarate reductase complexes include four subunits. 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. 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.

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. 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. 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. Thus, in this reaction, the fumarate serves as the terminal electron acceptor.

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. 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.

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. It has been shown that the A and B subunits of both proteins likely evolved from a common ancestral gene. 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. And it has been shown that in Bacillus subtilis, SQR is able to successfully perform the function of fumarate reductase.

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. 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. 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. 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. 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.

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.

References

^ 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.
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.
^ 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.
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^ 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.
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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.
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^ 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.
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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.
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.
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External links

Fumarate reductase / succinate dehydrogenase FAD-binding site in PROSITE
Fumarate+reductase+(menaquinone) at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

v t e Oxidoreductases: CH–CH oxidoreductases (EC 1.3)
1.3.1: NAD/NADP acceptor	Enoyl-acyl carrier protein reductase/Enoyl ACP reductase 7-Dehydrocholesterol reductase Biliverdin reductase 2,4 Dienoyl-CoA reductase Dihydroxymethyloxo-tetrahydroquinoline dehydrogenase
1.3.3: Oxygen acceptor	Dihydroorotate dehydrogenase Coproporphyrinogen III oxidase Protoporphyrinogen oxidase Bilirubin oxidase Acyl-CoA oxidase Dihydrouracil oxidase Tetrahydroberberine oxidase Secologanin synthase Tryptophan alpha,beta-oxidase Pyrroloquinoline-quinone synthase L-galactonolactone oxidase
1.3.5: Quinone	Succinate dehydrogenase SDHA SDHB SDHC SDHD
1.3.99: Other acceptors	Fumarate reductase Butyryl-CoA dehydrogenase Acyl CoA dehydrogenase ACADSB ACADS 5α-reductase SRD5A1 SRD5A2 SRD5A3 Glutaryl-CoA dehydrogenase Isovaleryl coenzyme A dehydrogenase 3-oxo-5beta-steroid 4-dehydrogenase

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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