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EcoSal Plus

Domain 3:

Metabolism

Succinate as Donor; Fumarate as Acceptor

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  • Authors: Thomas M. Tomasiak1, Gary Cecchini2, and Tina M. Iverson
  • Editor: Valley Stewart3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600; 2: Molecular Biology Division, VA Medical Center, San Francisco, CA 94121, and Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143; 3: University of California, Davis, Davis, CA
  • Received 02 March 2007 Accepted 07 May 2007 Published 13 August 2007
  • Address correspondence to Gary Cecchini gary.cecchini@ucsf.edu and Tina M. Iverson tina.iverson@vanderbilt.edu
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  • Abstract:

    Succinate and fumarate are four-carbon dicarboxylates that differ in the identity of their central bond (single or double). The oxidoreduction of these small molecules plays a central role in both aerobic and anaerobic respiration. During aerobic respiration, succinate is oxidized, donating two reducing equivalents, while in anaerobic respiration, fumarate is reduced, accepting two reducing equivalents. Two related integral membrane Complex II superfamily members catalyze these reactions, succinate:ubiquinone oxidoreductase (SQR) and fumarate:menaquinol oxidoreductase (QFR). The structure, function, and regulation of these integral-membrane enzymes are summarized here. The overall architecture of these Complex II enzymes has been found to consist of four subunits: two integral membrane subunits, and a soluble domain consisting of an iron-sulfur protein subunit, and a flavoprotein subunit. This architecture provides a scaffold that houses one active site in the membrane and another in the soluble milieu, making a linear electron transfer chain that facilities shuttling of reducing equivalents between the two active sites. A combination of kinetic measurements, mutagenesis, electron paramagnetic resonance spectroscopy, UV/Vis spectroscopy, and x-ray crystallography have suggested mechanisms for succinate:fumarate interconversion, electron transfer, and quinone:quinol interconversion. Of particular interest are the structural details that control directionality and make SQR and QFR primed for preferential catalysis each in different favored directions.

  • Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6

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ecosal.3.2.6.citations
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content/journal/ecosalplus/10.1128/ecosal.3.2.6
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/content/journal/ecosalplus/10.1128/ecosal.3.2.6
2007-08-13
2017-04-26

Abstract:

Succinate and fumarate are four-carbon dicarboxylates that differ in the identity of their central bond (single or double). The oxidoreduction of these small molecules plays a central role in both aerobic and anaerobic respiration. During aerobic respiration, succinate is oxidized, donating two reducing equivalents, while in anaerobic respiration, fumarate is reduced, accepting two reducing equivalents. Two related integral membrane Complex II superfamily members catalyze these reactions, succinate:ubiquinone oxidoreductase (SQR) and fumarate:menaquinol oxidoreductase (QFR). The structure, function, and regulation of these integral-membrane enzymes are summarized here. The overall architecture of these Complex II enzymes has been found to consist of four subunits: two integral membrane subunits, and a soluble domain consisting of an iron-sulfur protein subunit, and a flavoprotein subunit. This architecture provides a scaffold that houses one active site in the membrane and another in the soluble milieu, making a linear electron transfer chain that facilities shuttling of reducing equivalents between the two active sites. A combination of kinetic measurements, mutagenesis, electron paramagnetic resonance spectroscopy, UV/Vis spectroscopy, and x-ray crystallography have suggested mechanisms for succinate:fumarate interconversion, electron transfer, and quinone:quinol interconversion. Of particular interest are the structural details that control directionality and make SQR and QFR primed for preferential catalysis each in different favored directions.

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Figures

Image of Figure 1
Figure 1

(a) Aerobic respiratory chain. In aerobic respiration, reduced ubiquinol passes electrons from upstream reductases such as SQR and NADH oxidase I ( 9 , 10 ) to cytochrome oxidase and ultimately to oxygen ( 11 , 12 , 13 ). Cytochrome oxidase, omitted for clarity, is expressed at levels similar to those of cytochrome oxidase under microaerophilic conditions ( 14 ). NDH-I also participates in anaerobic respiration ( 15 ). (b) Anaerobic respiratory chain. In anaerobic respiration, reduced menaquinol passes electrons from hydrogenase-2 ( 16 , 17 ) and anaerobic 3-phosphate dehydrogenase ( 18 , 19 ) to terminal oxidases such as QFR.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 2
Figure 2

Succinate and fumarate are sterically similar dicarboxylate molecules that are interconverted through a two-proton, two-electron transition.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 3
Figure 3

Like succinate and fumarate, quinol (a and c) and quinone (b and d) are interconverted with a two-proton, two-electron transition, making the coupling of succinate/fumarate to quinol/quinone energetically well matched. Specifically, interconversion between quinol and quinone occurs at the hydroxyl/carbonyl, highlighted in red. (a and b) Ubiquinol and ubiquinone interconversion. (c and d) Menaquinol and menaquinone interconversion.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 4
Figure 4

Both SQR (a) and QFR (b) comprise four polypeptide subunits: a flavoprotein subunit (blue: , SQR; , QFR), an iron protein subunit (orange: , SQR; , QFR), and two transmembrane subunits (green [, SQR; , QFR] and purple [, SQR; , QFR]). The respective genes of QFR and SQR comprise two distinct operons with different gene order. The genes are shown in the same color scheme as the structures. Standard nomenclature uses the chain name in addition to the residue number in identifying an amino acid.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Figure 5

(a) Mitchellian loop and proton gradient formation. Two coupled reactions on opposite sides of the membrane (labeled with stars)—uptake protons on one side of the membrane and release protons on the other. This results in a net separation of two protons and establishment of a proton gradient. (b) Non-Mitchellian loop in SQR. SQR and QFR catalyze two reactions with proton release and uptake on the same side of the membrane, resulting in no net charge displacement.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 6
Figure 6

(a) SQR Fe:S clusters. Note the unique ligation of the [2Fe:2S] cluster in SQR due to the replacement of a cysteine ligand with Asp-B63. Other iron-ligating residues include Cys-B55, Cys-B60, and Cys-B75 to the [2Fe:2S] cluster; Cys-B149, Cys-B152, Cys-B155, and Cys-B216 to the [4Fe:4S] cluster; and Cys-B159, Cys-B212, and Cys-B206 to the [3Fe:4S] cluster. (b) QFR Fe:S clusters. Iron-ligating residues include Cys-B57, Cys-B62, Cys-B55, and Cys-B77 to the [2Fe:2S] cluster; Cys-B148, Cys-B151, Cys-B154, and Cys-B214 to the [4Fe:4S] cluster; and Cys-B158, Cys-B204, and Cys-B210 to the [3Fe:4S] cluster. For both clusters, iron atoms are purple and sulfur atoms are yellow. The main-chain ribbon and side-chain carbon atoms are white.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 7
Figure 7

Each cofactor is labeled with its respective midpoint (pH 7) reduction potential, and distances are represented as lines. (a) SQR cofactor arrangements in relation to the entire complex. (b) QFR cofactor composition in relation to the entire complex. FAD, ubiquinone, and heme are yellow, oxygen is red, nitrogen is blue, phosphate is magenta, and iron is purple. Additionally, the FAD adenine ring carbon atoms are gray to distinguish them from flavin. Sulfur is yellow and iron is purple in three Fe:S clusters.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Figure 8

The covalent bond between the 8α carbon of FAD and the Nε of histidine is shown. This is His45 in SQR and His44 in QFR.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 9
Figure 9

(a) Hydride transfer to fumarate by FAD. Bound fumarate forms hydrogen bonds to the side chains of His-A232, His-A355, and Arg-A390. Reduced FAD transfers a hydride to the C-2 carbon on fumarate in a single step. (b) Proton transfer to the carbanion intermediate by Arg-A287 to yield succinate. (c) Regeneration of catalytically competent protein. Arg-A287 is reprotonated through a proton shuttle consisting of Glu-A245 and Arg-A248. FAD is re-reduced by electrons that are transferred from quinol through the Fe:S clusters. How FAD is reprotonated has not been determined.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 10
Figure 10

(a) The fumarate binding site in relation to the rest of the flavoprotein. (b) Close-up of fumarate active site. Fumarate carbon atoms are magenta, and oxygen atoms are red. Carbon atoms of catalytically relevant residues and FAD are yellow, with oxygen atoms being red and nitrogen atoms being blue. Hydrogen bonds are represented as dashed lines.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 11
Figure 11

Fumarate binds near the reduced FAD. The distance between the N5 of the FAD and the C-2 atom of the fumarate is 3.4 Å, while the distance from a modeled hydride on FAD and the C-2 atom of fumarate is ~2.9Å. The position of fumarate (carbons are magenta) is shown modeled into the active site. In the hydride donor, FAD, and proton donor, Arg-A287, carbon atoms are yellow, oxygen atoms are red, and nitrogen atoms are blue. The oxidation state of FAD could not be determined unambiguously by the crystal structures and is shown here modeled as the reduced state.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 12
Figure 12

(a) The QFR iron-protein subunit and positions of Fe:S clusters. The iron-protein main chain is orange. (b) Type I ferredoxin. The type I ferredoxin (yellow) contains a single [2Fe:2S] cluster. Shown is the type I ferredoxin from 7120 ( 82 ) (PDB ID 1FRD). (c) Type II ferredoxin. The type II ferredoxin (red) contains two clusters, [4Fe:4S] and [3Fe:4S], in opposite positions compared with QFR. Shown is the type II ferredoxin from ( 83 ) (PDB ID 1A6L). (d) Superposition of the type I and type II ferredoxins and the QFR iron protein subunit. The overlay displays the structural similarity between the ferredoxins and the QFR iron protein subunit (light gray). The root mean square deviation (RMSD) of atom positions in alignment between the 7120 type I ferredoxin ( 82 ) and QFR is 1.3 Å for 68 C atoms, while the RMSD of atom positions in the alignment between the . 7Fe ferredoxin ( 83 ) and QFR is 1.0 Å for 37 C atoms. All iron atoms are purple and sulfur atoms are yellow in the iron-sulfur clusters.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 13
Figure 13

Ribbons shown in bold coloring represent the four-helix bundle motif. The remaining helices are shown with transparency to differentiate them from the four-helix bundle. Ubiquinone (a), heme (a), and menaquinol (b) are yellow. Oxygen atoms are red, nitrogen atoms are blue, and iron is orange.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 14
Figure 14

(a) SQR ubiquinone binding site. (b) QFR menaquinol binding sites. Only the integral membrane domains are shown for clarity (light-gray ribbons). Heme carbon atoms are yellow, iron atoms are brown, ubiquinone carbon atoms are tan, and menaquinol carbon atoms are green. In all the molecules, oxygen atoms are red and nitrogen atoms are blue.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 15
Figure 15

(a) SQR Q-site. Ubiquinone carbon atoms are tan, with oxygen atoms are red. (b) QFR Q-site. Menaquinol carbon atoms are green, with oxygen atoms being red. In both panels, side-chain carbon atoms are yellow, oxygen atoms are red, and nitrogen atoms are green.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 16
Figure 16

(a) The inhibitor atpenin-A5 (carbon atoms are green) in the SQR Q-site and contacts. Carbon atoms of atpenin-A5 are green, with oxygen atoms in red and nitrogen atoms in blue. Side-chain carbon atoms are yellow; oxygen atoms are red, and nitrogen atoms are blue. Careful inspection of the atpenin-A5 binding site and the ubiquinone binding site ( Fig. 15 ) shows a different binding position for these two species. (b) The QFR Q-site inhibitor 2-heptyl-4-hydroxy quinoline -oxide (HQNO; carbon atoms are magenta) with contacts. HQNO carbon atoms are magenta, with oxygen atoms being red and nitrogen atoms being blue. Comparison with Fig. 15 shows that the position of this inhibitor is similar to that of the menaquinol. HQNO is proposed to act as a menasemiquinone analog. Side-chain carbon atoms are yellow, oxygen atoms are red, and nitrogen atoms are blue.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Image of Figure 17
Figure 17

(a) The SQR structure. (b) A close-up of the proton shuttle and ubiquinone binding site. The integral membrane subunits are represented with surface models and are purple (, SQR; , QFR) and green (, SQR; , QFR). The proton shuttle comprises ordered water molecules and residues Lys-B208, Lys-B230, Arg-C31, Asp-C95, Glu-C101, and Asp-D82. Water molecules are shown as red spheres. Side-chain carbons are yellow, oxygen atoms are red, and nitrogen atoms are blue. Ubiquinone is tan, and its oxygen atoms are red. Dashes represent the proposed pathway for the proton shuttle.

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6
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Tables

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Table 1

Catalytic parameters for succinate oxidase and fumarate reductase reactions catalyzed by SQR and QFR

Citation: Tomasiak T, Cecchini G, Iverson T. 2007. Succinate as Donor; Fumarate as Acceptor, EcoSal Plus 2007; doi:10.1128/ecosal.3.2.6

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