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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 the electron transport chain. Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential. 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.

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. 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.

No. Subunit nameHuman proteinProtein description from UniProtPfam family with Human protein 1 SdhA SDHA HUMAN Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial , 2 SdhB SDHB HUMAN Succinate dehydrogenase [ubiquinone] iron sulfur subunit, mitochondrial , 3 SdhC C560 HUMAN Succinate dehydrogenase cytochrome b560 subunit, mitochondrial 4 SdhD DHSD HUMAN Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial

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. In contrast, ubiquinone binding site QD, which lies closer to inter membrane space, is composed of SdhD only and has lower affinity to ubiquinone.

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]. This can be seen in image 5.

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. 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. Through studies of the bacterial system, the mechanism of FAD attachment has been shown to involve a quinone:methide intermediate. 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.

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.

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. 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. More recently, other compounds with a broader spectrum against a range of plant pathogens have been developed including boscalid, fluopyram, fluxapyroxad, pydiflumetofen and sedaxane. FRAC has a working group for SDHIs and recommends resistance management practices.

The fundamental role of succinate coenzyme Q reductase in the electron transfer chain of mitochondria makes it vital in most multicellular organisms, removal of this enzyme from the genome has also been shown to be lethal at the embryonic stage in mice. SdhA mutations can lead to Leigh syndrome, mitochondrial encephalopathy, and optic atrophy. SdhB mutations can lead to tumorogenesis in chromaffin cells, causing a class of tumors known as succinate dehydrogenase deficient including hereditary paraganglioma and hereditary pheochromocytoma, succinate dehydrogenase deficient renal carcinoma and succinate dehydrogenase deficient gastrointestinal stromal tumor (GIST). Tumors tend to be malignant. It can also lead to decreased life span and increased production of superoxide ions. SdhC mutations can lead to decreased life span, increased production of superoxide ions, hereditary paraganglioma and hereditary pheochromocytoma. Tumors tend to be benign. These mutations are uncommon. SdhD mutations can lead to hereditary paraganglioma and hereditary pheochromocytoma. Tumors tend to be benign, and occur often in the head and neck regions. These mutations can also decrease life span and increase production of superoxide ions. Mammalian succinate dehydrogenase functions not only in mitochondrial energy generation, but also has a role in oxygen sensing and tumor suppression; and, therefore, is the object of ongoing research. Reduced levels of the mitochondrial enzyme succinate dehydrogenase (SDH), the main element of complex II, 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.