Succinate Dehydrogenase: Difference between revisions
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<StructureSection load='3ae1' size='350' side='right' caption='Succinate dehydrogenase containing flavoprotein subunit (Sdha) (grey), iron-sulfur subunit (Sdhb) (green), cytochrome B560 subunit (Sdhc) (pink) and cytochrome B small subunit (Sdhd) (yellow), FAD, Fe2S2, Fe4S4 and Fe3S4 complex with protoporphyrin, malonate, benzamide derivative and α-phosphatidyl-β-oleoyl-γ-palmitoyl-phosphatidylethanolamine, [[3ae1]] ' scene=''> | <StructureSection load='3ae1' size='350' side='right' caption='Succinate dehydrogenase containing flavoprotein subunit (Sdha) (grey), iron-sulfur subunit (Sdhb) (green), cytochrome B560 subunit (Sdhc) (pink) and cytochrome B small subunit (Sdhd) (yellow), FAD, Fe2S2, Fe4S4 and Fe3S4 complex with protoporphyrin, malonate, benzamide derivative and α-phosphatidyl-β-oleoyl-γ-palmitoyl-phosphatidylethanolamine, [[3ae1]] ' scene=''> | ||
[[Image:Succinate Dehydrogenase.png|left|250px]] | [[Image:Succinate Dehydrogenase.png|left|250px]] | ||
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== Function == | == Function == | ||
[[Succinate Dehydrogenase]] (PDB = [[2wdv]] with empty ubiquinone binding site; PDB = [[1nek]] with ubiquinone bound), also called '''succinate-coenzyme Q reductase''' (SQR) or '''Complex II''', is a tetrameric enzyme found in the cell membrane of | [[Succinate Dehydrogenase]] (PDB = [[2wdv]] with empty ubiquinone binding site; PDB = [[1nek]] with ubiquinone bound), also called '''succinate-coenzyme Q reductase''' (SQR) or '''Complex II''', is a tetrameric enzyme found in the cell membrane of http://proteopedia.org/wiki/index.php?title=Succinate_Dehydrogenase&action=editsome bacteria and the inner mitochondrial membrane of mammalian cells. It is classified as an α+β protein, as it contains <scene name='Michael_Vick_Sandbox_2/2wdv_sec_structure/1'>segregated regions</scene> of α helices and antiparallel β sheets. It is involved in two aspects of digestion; it catalyzes the oxidation of succinate to fumarate in the [[The_Citric_Acid_Cycle|citric acid cycle]] by simultaneously reducing ubiquinone to ubiquinol in the electron transport chain <ref>PMID:14672929</ref>. See also:<br /> | ||
*[[Krebs cycle carbons]] | *[[Krebs cycle carbons]] | ||
*[[Krebs cycle importance]] | *[[Krebs cycle importance]] | ||
*[[Krebs cycle overview]] | *[[Krebs cycle overview]] | ||
*[[Krebs cycle reactions]] | |||
*[[Citric Acid Cycle]] | |||
*[[Krebs cycle step 6]] | *[[Krebs cycle step 6]] | ||
*[[Glyoxylate cycle]] | |||
==Structure== | ==Structure== | ||
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The exact mechanism for the oxidation of succinate to fumarate has not yet been elucidated. The initial deprotonation may be performed by FAD, Glu255, Arg286, or His242 of SdhA, and the following elimination may be a concerted E2 or E1cb elimination. In the concerted mechanism, the α-carbon is deprotonated by a base as FAD removes a hydride from the β-carbon; this is shown in image 1 <ref name="ghi">PMID:16950775</ref>. | The exact mechanism for the oxidation of succinate to fumarate has not yet been elucidated. The initial deprotonation may be performed by FAD, Glu255, Arg286, or His242 of SdhA, and the following elimination may be a concerted E2 or E1cb elimination. In the concerted mechanism, the α-carbon is deprotonated by a base as FAD removes a hydride from the β-carbon; this is shown in image 1 <ref name="ghi">PMID:16950775</ref>. | ||
[[Image:S.D.Oxidation_of_Succinate_E2.gif|left| | [[Image:S.D.Oxidation_of_Succinate_E2.gif|left|600px]] | ||
{{Clear}} | {{Clear}} | ||
'''Image 1: Oxidation of succinate to fumarate through E2 elimination''' (from Adamandalex in ''Wikimedia Commons'' http://en.wikipedia.org/wiki/File:S.D.Oxidation_of_Succinate_E2.gif). | '''Image 1: Oxidation of succinate to fumarate through E2 elimination''' (from Adamandalex in ''Wikimedia Commons'' http://en.wikipedia.org/wiki/File:S.D.Oxidation_of_Succinate_E2.gif). | ||
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In the proposed E1cb mechanism, the deprotonation leads to the formation of an enolate intermediate; FAD then removes the hydride, as shown in Image 2 <ref name="ghi" />. | In the proposed E1cb mechanism, the deprotonation leads to the formation of an enolate intermediate; FAD then removes the hydride, as shown in Image 2 <ref name="ghi" />. | ||
[[Image:S.D.Oxidation_of_Succinate_E1cb.gif|left| | [[Image:S.D.Oxidation_of_Succinate_E1cb.gif|left|700px]] | ||
{{Clear}} | {{Clear}} | ||
'''Image 2: Oxidation of succinate to fumarate via E1cb elimination''' (from Adamandalex in ''Wikimedia Commons'' http://en.wikipedia.org/wiki/File:S.D.Oxidation_of_Succinate_E1cb.gif). | '''Image 2: Oxidation of succinate to fumarate via E1cb elimination''' (from Adamandalex in ''Wikimedia Commons'' http://en.wikipedia.org/wiki/File:S.D.Oxidation_of_Succinate_E1cb.gif). | ||
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Ubiquinone is initially oriented in the active site such that the O1 carbonyl group interacts with Tyr83 of SdhD via hydrogen bonding. The electrons removed during the oxidation reaction are conveyed through the iron-sulfur clusters to 3Fe-4S; their presence on that cluster stimulates the substrate to reorient so that a second hydrogen bond between the <scene name='Michael_Vick_Sandbox_2/Ubq_binding_site/2'>O4 carbonyl group and Ser27</scene> of SdhC may form. The electrons are transferred to the substrate individually, with the addition of the first producing a radical semiquinone and the second completing the reduction to ubiquinol. This mechanism is illustrated in image 3 <ref name="ghi" />. | Ubiquinone is initially oriented in the active site such that the O1 carbonyl group interacts with Tyr83 of SdhD via hydrogen bonding. The electrons removed during the oxidation reaction are conveyed through the iron-sulfur clusters to 3Fe-4S; their presence on that cluster stimulates the substrate to reorient so that a second hydrogen bond between the <scene name='Michael_Vick_Sandbox_2/Ubq_binding_site/2'>O4 carbonyl group and Ser27</scene> of SdhC may form. The electrons are transferred to the substrate individually, with the addition of the first producing a radical semiquinone and the second completing the reduction to ubiquinol. This mechanism is illustrated in image 3 <ref name="ghi" />. | ||
[[Image:QuinoneMechanism.gif|left| | [[Image:QuinoneMechanism.gif|left|700px]] | ||
{{Clear}} | {{Clear}} | ||
'''Image 3: Reduction of ubiquinone to ubiquinol''' (from Adamandalex in ''Wikimedia Commons'' http://en.wikipedia.org/wiki/File:QuinoneMechanism.gif). | '''Image 3: Reduction of ubiquinone to ubiquinol''' (from Adamandalex in ''Wikimedia Commons'' http://en.wikipedia.org/wiki/File:QuinoneMechanism.gif). | ||
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Since succinate dehydrogenase possesses multiple active sites that catalyze two different reactions, two classes of inhibitors function on the enzyme. The first class, which includes succinate analogs--both naturally-occuring TCA cycle intermediates like malate and oxaloacetate and the synthetic analog, malonate--contains some of the strongest succinate dehydrogenase inhibitors. The second class of inhibitors, which includes the ubiquinone analogs thenoyltrifluoroacetone and carboxin, binds to the ubiquinone active site and prevents reduction of the substrate<ref>PMID:17916065</ref>. | Since succinate dehydrogenase possesses multiple active sites that catalyze two different reactions, two classes of inhibitors function on the enzyme. The first class, which includes succinate analogs--both naturally-occuring TCA cycle intermediates like malate and oxaloacetate and the synthetic analog, malonate--contains some of the strongest succinate dehydrogenase inhibitors. The second class of inhibitors, which includes the ubiquinone analogs thenoyltrifluoroacetone and carboxin, binds to the ubiquinone active site and prevents reduction of the substrate<ref>PMID:17916065</ref>. | ||
==3D structures of succinate dehydrogenase== | ==3D structures of succinate dehydrogenase== | ||
[[Succinate dehydrogenase 3D structures]] | |||
</StructureSection> | |||
==References== | ==References== | ||
<references/> | <references/> | ||
[[Category:Topic Page]] | [[Category:Topic Page]] | ||