Succinate dehydrogenase

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succinate dehydrogenase (succinate-ubiquinone oxidoreductase)
Succinate Dehydrogenase 1YQ3 and Membrane.png
The structure of SQR in a phospholipid membrane. SDHA, SDHB, SDHC and SDHD
Identifiers
EC no. 1.3.5.1
CAS no. 9028-11-9
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Succinate dehydrogenase
Identifiers
SymbolRespiratory complex II
OPM superfamily 3
OPM protein 1zoy
Membranome 656

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. [1] Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential. [2]

Contents

In step 6 of the citric acid cycle, SQR catalyzes the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol. This occurs in the inner mitochondrial membrane by coupling the two reactions together.

Structure

Image 5: Subunits of succinate dehydrogenase SuccDeh.svg
Image 5: Subunits of succinate dehydrogenase

Subunits

Mitochondrial and many bacterial SQRs are composed of four structurally different subunits: two hydrophilic and two hydrophobic. The first two subunits, a flavoprotein (SDHA) and an iron-sulfur protein (SDHB), form a hydrophilic head where enzymatic activity of the complex takes place. SDHA contains a covalently attached flavin adenine dinucleotide (FAD) cofactor and the succinate binding site and SDHB contains three iron-sulfur clusters: [2Fe-2S], [4Fe-4S], and [3Fe-4S]. The second two subunits are hydrophobic membrane anchor subunits, SDHC and SDHD. Human mitochondria contain two distinct isoforms of SDHA (Fp subunits type I and type II), these isoforms are also found in Ascaris suum and Caenorhabditis elegans. [3] The subunits form a membrane-bound cytochrome b complex with six transmembrane helices containing one heme b group and a ubiquinone-binding site. Two phospholipid molecules, one cardiolipin and one phosphatidylethanolamine, are also found in the SDHC and SDHD subunits (not shown in the image). They serve to occupy the hydrophobic space below the heme b. These subunits are displayed in the attached image. SDHA is green, SDHB is teal, SDHC is fuchsia, and SDHD is yellow. Around SDHC and SDHD is a phospholipid membrane with the intermembrane space at the top of the image. [4]

Table of subunit composition [5]

No.Subunit name Human proteinProtein description from UniProt Pfam family with Human protein
1SDHA SDHA_HUMANSuccinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Pfam PF00890, Pfam PF02910
2SDHB SDHB_HUMANSuccinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial Pfam PF13085, Pfam PF13183
3SDHC C560_HUMAN Succinate dehydrogenase cytochrome b560 subunit, mitochondrial Pfam PF01127
4SDHD DHSD_HUMAN Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial Pfam PF05328

Ubiquinone binding site

Two distinctive ubiquinone binding sites can be recognized on mammalian SDH – matrix-proximal QP and matrix-distal QD. Ubiquinone binding site Qp, which shows higher affinity to ubiquinone, is located in a gap composed of SDHB, SDHC, and SDHD. Ubiquinone is stabilized by the side chains of His207 of subunit B, Ser27 and Arg31 of subunit C, and Tyr83 of subunit D. The quinone ring is surrounded by Ile28 of subunit C and Pro160 of subunit B. These residues, along with Il209, Trp163, and Trp164 of subunit B, and Ser27 (C atom) of subunit C, form the hydrophobic environment of the quinone-binding pocket Qp. [6] In contrast, ubiquinone binding site QD, which lies closer to inter-membrane space, is composed of SDHD only and has lower affinity to ubiquinone. [7]

Succinate binding site

SDHA provides the binding site for the oxidation of succinate. The side chains Thr254, His354, and Arg399 of subunit A stabilize the molecule while FAD oxidizes and carries the electrons to the first of the iron-sulfur clusters, [2Fe-2S]. [8] This can be seen in image 5.

Redox centers

The succinate-binding site and ubiquinone-binding site are connected by a chain of redox centers including FAD and the iron-sulfur clusters. This chain extends over 40 Å through the enzyme monomer. All edge-to-edge distances between the centers are less than the suggested 14 Å limit for physiological electron transfer. [4] This electron transfer is demonstrated in image 8.

Assembly and maturation

All subunits of human mitochondrial SDH are nuclear encoded. After translation, SDHA subunit is translocated as apoprotein into the mitochondrial matrix. Subsequently, one of the first steps is covalent attachment of the FAD cofactor (covalent flavinylation). This process is enhanced by succinate dehydrogenase assembly factor 2 (SDHAF2; [9] also called SDH5 in yeast and SDHE in bacteria) and by some of the Krebs cycle intermediates. Fumarate most strongly stimulates covalent flavinylation of SDHA. [10] Through studies of the bacterial system, the mechanism of FAD attachment has been shown to involve a quinone:methide intermediate. [11] In mitochondrial, but not bacterial, assembly, SDHA interacts with a second assembly factor called succinate dehydrogenase assembly factor 4 (SDHAF4; called SDH8 in yeast) before it is inserted into the final complex. [7]

Fe-S prosthetic groups of the subunit SDHB are being preformed in the mitochondrial matrix by protein complex ISU. The complex is also thought to be capable of inserting the iron-sulphur clusters in SDHB during its maturation. The studies suggest that Fe-S cluster insertion precedes SDHA-SDHB dimer forming. Such incorporation requires reduction of cysteine residues within active site of SDHB. Both reduced cysteine residues and already incorporated Fe-S clusters are highly susceptible to ROS damage. Two more SDH assembly factors, SDHAF1 (SDH6) and SDHAF3 (SDH7 in yeast), seem to be involved in SDHB maturation in way of protecting the subunit or dimer SDHA-SDHB from Fe-S cluster damage caused by ROS. [7]

Assembly of the hydrophobic anchor consisting of subunits SDHC and SDHD remains unclear. Especially in case of heme b insertion and even its function. Heme b prosthetic group does not appear to be part of electron transporting pathway within the complex II. [5] The cofactor rather maintains the anchor stability.

Mechanism

Image 6: E2 Succinate oxidation mechanism. S.D.Oxidation of Succinate E2.gif
Image 6: E2 Succinate oxidation mechanism.
Image 7: E1cb Succinate oxidation mechanism. S.D.Oxidation of Succinate E1cb.gif
Image 7: E1cb Succinate oxidation mechanism.

Succinate oxidation

Much is known about the succinate oxidation mechanism, which involves the transfer of a proton and a hydride. A combination of mutagenesis and structural analysis identifies Arg-286 of the SDHA subunit (E. coli numbering) as the proton shuttle. Crystal structures of the enzymes from multiple organisms shows that this is well poised for the proton transfer step. Thereafter, there are two possible elimination mechanisms: E2 or E1cb. In the E2 elimination, the mechanism is concerted. The basic residue or cofactor deprotonates the alpha carbon, and FAD accepts the hydride from the beta carbon, oxidizing the bound succinate to fumarate—refer to image 6. In E1cb, an enolate intermediate is formed, shown in image 7, before FAD accepts the hydride. Further research is required to determine which elimination mechanism succinate undergoes in Succinate Dehydrogenase. Oxidized fumarate, now loosely bound to the active site, is free to exit the protein.

Electron tunneling

After the electrons are derived from succinate oxidation via FAD, they tunnel along the [Fe-S] relay until they reach the [3Fe-4S] cluster. These electrons are subsequently transferred to an awaiting ubiquinone molecule within the active site. The Iron-Sulfur electron tunneling system is shown in image 9.

Ubiquinone reduction

Image 8: Ubiquinone reduction mechanism. QuinoneMechanism.gif
Image 8: Ubiquinone reduction mechanism.
Image 9: Electron carriers of the SQR complex. FADH2, iron-sulfur centers, heme b, and ubiquinone. Succinate Dehydrogenase 1YQ3 Electron Carriers Labeled.png
Image 9: Electron carriers of the SQR complex. FADH2, iron-sulfur centers, heme b, and ubiquinone.

The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of subunit D. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of subunit C. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to ubiquinol. This mechanism of the ubiquinone reduction is shown in image 8.

Heme prosthetic group

Although the functionality of the heme in succinate dehydrogenase is still being researched, some studies[ by whom? ] have asserted that the first electron delivered to ubiquinone via [3Fe-4S] may tunnel back and forth between the heme and the ubiquinone intermediate. In this way, the heme cofactor acts as an electron sink. Its role is to prevent the interaction of the intermediate with molecular oxygen to produce reactive oxygen species (ROS). The heme group, relative to ubiquinone, is shown in image 4.

It has also been proposed that a gating mechanism may be in place to prevent the electrons from tunneling directly to the heme from the [3Fe-4S] cluster. A potential candidate is residue His207, which lies directly between the cluster and the heme. His207 of subunit B is in direct proximity to the [3Fe-4S] cluster, the bound ubiquinone, and the heme; and could modulate electron flow between these redox centers. [12]

Proton transfer

To fully reduce the quinone in SQR, two electrons as well as two protons are needed. It has been argued that a water molecule (HOH39) arrives at the active site and is coordinated by His207 of subunit B, Arg31 of subunit C, and Asp82 of subunit D. The semiquinone species is protonated by protons delivered from HOH39, completing the ubiquinone reduction to ubiquinol. His207 and Asp82 most likely facilitate this process. Other studies claim that Tyr83 of subunit D is coordinated to a nearby histidine as well as the O1 carbonyl oxygen of ubiquinone. The histidine residue decreases the pKa of tyrosine, making it more suitable to donate its proton to the reduced ubiquinone intermediate.

Inhibitors

There are two distinct classes of inhibitors (SDHIs) of complex II: those that bind in the succinate pocket and those that bind in the ubiquinone pocket. Ubiquinone type inhibitors include carboxin and thenoyltrifluoroacetone. Succinate-analogue inhibitors include the synthetic compound malonate as well as the TCA cycle intermediates, malate and oxaloacetate. Indeed, oxaloacetate is one of the most potent inhibitors of Complex II. Why a common TCA cycle intermediate would inhibit Complex II is not entirely understood, though it may exert a protective role in minimizing reverse-electron transfer mediated production of superoxide by Complex I. [13] Atpenin 5a are highly potent Complex II inhibitors mimicking ubiquinone binding.

Ubiquinone type inhibitors have been used as fungicides in agriculture since the 1960s. Carboxin was mainly used to control disease caused by basidiomycetes such as stem rusts and Rhizoctonia diseases. In the 1980s simple benzanilides were found to have comparable activity to carboxin and a number of these were marketed, including benodanil, flutolanil and mepronil. [14] More recently, other compounds with a broader spectrum against a range of plant pathogens have been developed including boscalid, fluopyram, fluxapyroxad, pydiflumetofen and sedaxane. [15] [14] Some agriculturally important fungi are not sensitive towards members of the new generation of ubiquinone type inhibitors. [16] FRAC has a working group [17] for SDHIs and recommends resistance management practices. [18]

Complex II inhibitors are also used as insecticides and acaricides, in IRAC group 25. [19]

Role in disease

The fundamental role of succinate-coenzyme Q reductase in both oxidative phosphorylation and the citric acid cycle makes it vital in all eukaryotic organisms. Loss of function of SDH via mutations or through toxins can cause a wide range of disease.

When SDH is dysfunctional in the citric acid cycle, it can lead to a buildup of the oncometabolite succinate, which can lead to tumorogenesis. This is well-known to occur in chromaffin cells, causing neuroendocrine tumors such as paraganglioma, renal carcinoma, and Gastrointestinal stromal tumor (GISTs). [20] The penetrance data for SDH mutations causing tumorigenesis is lacking, and international guidelines suggest thorough screening for any carriers. [21] The penetrance of paraganglioma in loss of function mutations of SDH is incomplete and varies by subunit. SDHB mutations have a penetrance between 8% and 37%, SDHD mutations have a penetrance between 38% and 64% with some maternal imprinting effects, and the penetrance for both SDHA and SDHC mutations are poorly studied, but likely between 1% and 30%. [22] [23] Mammalian SDH functions not only in energy generation, but also has a role in oxygen sensing. Buildup of succinate due to defective SDH can cause a pseudo-hypoxia and angiogenesis, both of which contribute to the distinctly vascular and characteristic "salt and pepper" appearance of paraganglioma on imaging. [24]

Bi-Allelic loss of function mutations of SDHA, SDHB, SDHD, and SDHAF1 or monoallelic loss of function mutations of SDHA can cause Mitochondrial complex II deficiency. This disruption in oxidative phosphorylation can lead to Leigh syndrome, mitochondrial encephalopathy, optic atrophy, myopathy, and a spectrum of disease. These presentations can range from death within the first year of life or in utero to mild symptoms beginning as an adult. [25]

Reduced levels SDH are observed post mortem in the brains of patients with Huntington's disease, and energy metabolism defects have been identified in both presymptomatic and symptomatic HD patients. [26]

See also

Related Research Articles

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<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">Coenzyme Q – cytochrome c reductase</span> Class of enzymes

The coenzyme Q : cytochrome c – oxidoreductase, sometimes called the cytochrome bc1 complex, and at other times complex III, is the third complex in the electron transport chain, playing a critical role in biochemical generation of ATP. Complex III is a multisubunit transmembrane protein encoded by both the mitochondrial and the nuclear genomes. Complex III is present in the mitochondria of all animals and all aerobic eukaryotes and the inner membranes of most bacteria. Mutations in Complex III cause exercise intolerance as well as multisystem disorders. The bc1 complex contains 11 subunits, 3 respiratory subunits, 2 core proteins and 6 low-molecular weight proteins.

<span class="mw-page-title-main">Succinic acid</span> Dicarboxylic acid

Succinic acid is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into fumarate by the enzyme succinate dehydrogenase in complex 2 of the electron transport chain which is involved in making ATP, and as a signaling molecule reflecting the cellular metabolic state.

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

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<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">SDHB</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Electron-transferring flavoprotein</span>

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

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

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<span class="mw-page-title-main">NDUFS1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Carney triad</span> Multiple neoplasia syndrome

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<span class="mw-page-title-main">Fumarate reductase (quinol)</span>

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:

<span class="mw-page-title-main">SDHAF2</span> Protein-coding gene in humans

Succinate dehydrogenase complex assembly factor 2, formerly known as SDH5 and also known as SDH assembly factor 2 or SDHAF2 is a protein that in humans is encoded by the SDHAF2 gene. This gene encodes a mitochondrial protein needed for the flavination of a succinate dehydrogenase complex subunit required for activity of the complex. Mutations in this gene are associated with pheochromocytoma and paraganglioma.

<span class="mw-page-title-main">SDHAF1</span> Protein-coding gene in the species Homo sapiens

Succinate dehydrogenase complex assembly factor 1 (SDHAF1), also known as LYR motif-containing protein 8 (LYRM8), is a protein that, in humans, is encoded by the SDHAF1, or LYRM8, gene. SDHAF1 is a chaperone protein involved in the assembly of the succinate dehydrogenase (SDH) complex. Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy and mitochondrial complex II deficiency.

<span class="mw-page-title-main">Mitochondrial complex II deficiency</span> Medical condition

Mitochondrial complex II deficiency, also called CII deficiency, is a rare mitochondrial disease caused by deficiency of mitochondrial complex II, also known as Succinate dehydrogenase (SDH). SDH plays a key role in metabolism; the catalytic end, made up of SDHA and SDHB oxidizes succinate to fumarate in the tricarboxylic acid (TCA) cycle. The electrons from this reaction then reduce FAD to FADH2, which ultimately reduces ubiquinone to ubiquinol in the mitochondrial electron transport chain. As of 2020, about 61 cases have been reported with genetic studies, but there are also documented cases of CII deficiencies as determined by biochemical and histological analysis without genetic studies.

References

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  16. ↑
  17. ↑ "SDHI Fungicides Working Group". FRAC (Fungicide Resistance Action Committee). 2020-01-31. Retrieved 2022-07-05.
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  24. ↑ https://radiopaedia.org/articles/salt-and-pepper-sign-paraganglioma-1?lang=us
  25. ↑ Fullerton M, McFarland R, Taylor RW, Alston CL (September 2020). "The genetic basis of isolated mitochondrial complex II deficiency". Molecular Genetics and Metabolism. 131 (1–2): 53–65. doi:10.1016/j.ymgme.2020.09.009. PMC   7758838 . PMID   33162331.
  26. ↑ Skillings EA, Morton AJ (2016). "Delayed Onset and Reduced Cognitive Deficits through Pre-Conditioning with 3-Nitropropionic Acid is Dependent on Sex and CAG Repeat Length in the R6/2 Mouse Model of Huntington's Disease". Journal of Huntington's Disease. 5 (1): 19–32. doi:10.3233/JHD-160189. PMID   27031731.
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