Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

complex, found in many

bacterial Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among the ...

cells and in the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

eukaryotes The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of ...

. It is the only enzyme that participates in both the

citric acid cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...

and

oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...

. Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential. In step 6 of the

, SQR

catalyzes Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

the

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

succinate 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 Fuma ...

fumarate Fumaric acid or ''trans''-butenedioic acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The sa ...

with the reduction of

ubiquinone Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring Cofactor (biochemistry), biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, ...

ubiquinol A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans. The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...

. This occurs in the inner mitochondrial

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

coupling A coupling is a device used to connect two shafts together at their ends for the purpose of transmitting power. The primary purpose of couplings is to join two pieces of rotating equipment while permitting some degree of misalignment or end mo ...

the two reactions together.

Structure

Subunits

Mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

and many

SQRs are composed of four structurally different subunits: two

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

and two

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

. The first two subunits, a

flavoprotein Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin. These proteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repair. ...

(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 In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which ma ...

(FAD) cofactor and the

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

and SDHB contains three iron-sulfur clusters: Fe-2S Fe-4S and Fe-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 Cytochrome b is a protein found in the membranes of aerobic cells. In eukaryotic mitochondria (inner membrane) and in aerobic prokaryotes, cytochrome b is a component of respiratory chain complex III () — also known as the bc1 complex or ubiq ...

complex with six

transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...

helices A helix (; ) is a shape like a cylindrical coil spring or the thread of a machine screw. It is a type of smoothness (mathematics), smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as ...

containing one heme b group and a

-binding site. Two

phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

molecules, one

cardiolipin Cardiolipin (IUPAC name 1,3-bis(''sn''-3’-phosphatidyl)-''sn''-glycerol, "''sn''" designating stereospecific numbering) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. ...

and one

phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...

, 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 The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cells. The cell membranes of almost all organisms and many viruses are made of a l ...

with the intermembrane space at the top of the image.

Table of subunit composition

Ubiquinone binding site

Two distinctive

s can be recognized on mammalian SDH – matrix-proximal Q_P and matrix-distal Q_D. Ubiquinone binding site Qp, which shows higher affinity to ubiquinone, is located in a gap composed of SDHB, SDHC, and SDHD.

Ubiquinone Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring Cofactor (biochemistry), biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, ...

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

environment of the

quinone The quinones are a class of organic compounds that are formally "derived from aromatic compounds benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= groups into –C(=O)– groups with ...

-binding pocket Qp. In contrast, ubiquinone binding site Q_D, which lies closer to inter-membrane space, is composed of SDHD only and has lower affinity to ubiquinone.

Succinate binding site

SDHA provides the

for the

. The side chains Thr254, His354, and Arg399 of subunit A stabilize the

molecule A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

while

FAD A fad, trend, or craze is any form of collective behavior that develops within a culture, a generation, or social group in which a group of people enthusiastically follow an impulse for a short time period. Fads are objects or behaviors tha ...

oxidizes and carries the

electrons The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...

to the first of the iron-sulfur clusters, Fe-2S This can be seen in image 5.

Redox centers

The

-binding site and

-binding site are connected by a chain of redox centers including

and the

iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...

sulfur Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...

clusters. This chain extends over 40 Å through the

monomer A monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called polymerization. Classification Chemis ...

. All edge-to-edge distances between the centers are less than the suggested 14 Å limit for

physiological Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...

electron transfer Electron transfer (ET) occurs when an electron relocates from an atom, ion, or molecule, to another such chemical entity. ET describes the mechanism by which electrons are transferred in redox reactions. Electrochemical processes are ET reactio ...

. This

is demonstrated in image 8.

Assembly and maturation

All subunits of human mitochondrial SDH are nuclear encoded. After translation,

SDHA Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the ''SDHA'' gene. This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial resp ...

subunit is translocated as apoprotein into the mitochondrial matrix. Subsequently, one of the first steps is covalent attachment of the

cofactor (covalent flavinylation). This process is enhanced by succinate dehydrogenase assembly factor 2 (

SDHAF2 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 flavina ...

; 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. Fe-S prosthetic groups of the subunit

SDHB Succinate dehydrogenase biquinoneiron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the ''SDHB'' gene. The succinate dehydrogenase (also called SDH or Compl ...

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 Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

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. Assembly of the hydrophobic anchor consisting of subunits

SDHC Secure Digital (SD) is a proprietary, non-volatile, flash memory card format developed by the SD Association (SDA). Owing to their compact size, SD cards have been widely adopted in a variety of portable consumer electronics, including digi ...

and

SDHD Succinate dehydrogenase biquinonecytochrome b small subunit, mitochondrial (CybS), also known as succinate dehydrogenase complex subunit D (SDHD), is a protein that in humans is encoded by the ''SDHD'' gene. Names previously used for SDHD were ...

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. The cofactor rather maintains the anchor stability.

Mechanism

Succinate oxidation

Much is known about the

mechanism Mechanism may refer to: *Mechanism (economics), a set of rules for a game designed to achieve a certain outcome **Mechanism design, the study of such mechanisms *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a ...

, 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 structure In crystallography, crystal structure is a description of ordered arrangement of atoms, ions, or molecules in a crystalline material. Ordered structures occur from intrinsic nature of constituent particles to form symmetric patterns that repeat ...

s 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 In the nomenclature of organic chemistry, a locant is a term to indicate the position of a functional group or substituent within a molecule. Numeric locants The International Union of Pure and Applied Chemistry (IUPAC) recommends the use of n ...

, and FAD accepts the

hydride In chemistry, a hydride is formally the anion of hydrogen (H−), a hydrogen ion with two electrons. In modern usage, this is typically only used for ionic bonds, but it is sometimes (and has been more frequently in the past) applied to all che ...

from the beta carbon,

oxidizing Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

the bound

—refer to image 6. In E1cb, an

enolate In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the Organic synthesis, synthesis of organic compounds. Bonding and structure Enolate ...

intermediate is formed, shown in image 7, before

accepts the

. Further research is required to determine which elimination mechanism succinate undergoes in Succinate Dehydrogenase.

Oxidized Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

, now loosely bound to the

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

, is free to exit the

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

Electron tunneling

After the

are derived from

via

, they tunnel along the e-Srelay until they reach the Fe-4Scluster. These

are subsequently transferred to an awaiting

within the

. The

Iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...

Sulfur Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...

electron The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...

tunneling system is shown in image 9.

Ubiquinone reduction

Succinate Dehydrogenase 1YQ3 Electron Carriers Labeled

The O1

carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

is oriented at the active site (image 4) by

hydrogen bond In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

interactions with Tyr83 of subunit D. The presence of

in the Fe-4Siron sulphur cluster induces the movement of

into a second orientation. This facilitates a second

interaction between the O4

carbonyl group In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such as aldehydes ...

and Ser27 of subunit C. Following the first single

reduction step, a

semiquinone Semiquinones (or ubisemiquinones, if their origin is ubiquinone) are free radicals resulting from the removal of one hydrogen atom with its electron during the process of dehydrogenation of a hydroquinone, such as hydroquinone itself or catechol, t ...

radical species is formed. The second

arrives from the Fe-4Scluster to provide full reduction of the

. This mechanism of the

reduction is shown in image 8.

Heme prosthetic group

Although the functionality of the

heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...

in succinate dehydrogenase is still being researched, some studies have asserted that the first

delivered to

via Fe-4Smay tunnel back and forth between the

and the

intermediate. In this way, the

cofactor acts as an

sink. Its role is to prevent the interaction of the intermediate with molecular oxygen to produce

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(ROS). The

group, relative to

, is shown in image 4. It has also been proposed that a gating

may be in place to prevent the

from tunneling directly to the

from the Fe-4Scluster. A potential candidate is residue His207, which lies directly between the cluster and the

. His207 of subunit B is in direct proximity to the Fe-4Scluster, the bound

, and the

; and could modulate

flow between these redox centers.

Proton transfer

To fully reduce the

in SQR, two

as well as two

protons A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' ( elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an electron (the pro ...

are needed. It has been argued that a water molecule (HOH39) arrives at the

and is coordinated by His207 of subunit B, Arg31 of subunit C, and Asp82 of subunit D. The

species is protonated by

delivered from HOH39, completing the

reduction to

. His207 and Asp82 most likely facilitate this process. Other studies claim that Tyr83 of subunit D is coordinated to a nearby

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

as well as the O1

. The

residue decreases the

pKa In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction :H ...

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

, making it more suitable to donate its

proton A proton is a stable subatomic particle, symbol , Hydron (chemistry), H+, or 1H+ with a positive electric charge of +1 ''e'' (elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an e ...

to the reduced

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 The conjugate acids are in :Carboxylic acids. {{Commons category, Carboxylate ions, Carboxylate anions Carbon compounds Anions ...

as well as the TCA cycle intermediates,

malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ( ...

and

oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...

. 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

fungicide Fungicides are pesticides used to kill parasitic fungi or their spores. Fungi can cause serious damage in agriculture, resulting in losses of yield and quality. Fungicides are used both in agriculture and to fight fungal infections in animals, ...

s in agriculture since the 1960s. Carboxin was mainly used to control disease caused by

basidiomycete Basidiomycota () is one of two large divisions that, together with the Ascomycota, constitute the subkingdom Dikarya (often referred to as the "higher fungi") within the kingdom Fungi. Members are known as basidiomycetes. More specifically, Basid ...

s such as

stem rust Stem rust, also known as cereal rust, black rust, red rust or red dust, is caused by the fungus ''Puccinia graminis'', which causes significant disease in cereal crops. Crop species that are affected by the disease include bread wheat, durum wh ...

s 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. Some agriculturally important fungi are not sensitive towards members of the new generation of ubiquinone type inhibitors. FRAC has a working group for SDHIs and recommends resistance management practices. Complex II inhibitors are also used as

insecticides Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. The major use of insecticides is in agriculture, but they are also used in home and garden settings, in ...

and

acaricides Acaricides are pesticides that kill members of the arachnid subclass ''Acari'', which includes ticks and mites. Acaricides are used both in medicine and agriculture, although the desired selective toxicity differs between the two fields. Termino ...

, in IRAC group 25.

Role in disease

The fundamental role of succinate-coenzyme Q reductase in both

and the

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 Chromaffin cells, also called pheochromocytes (or phaeochromocytes), are neuroendocrine cells found mostly in the medulla of the adrenal glands in mammals. These cells serve a variety of functions such as serving as a response to stress, monito ...

, causing neuroendocrine tumors such as

paraganglioma A paraganglioma is a rare neuroendocrine tumour, neuroendocrine neoplasm that may develop at various body sites (including the head, neck, thorax and abdomen). When the same type of tumor is found in the adrenal gland, they are referred to as a p ...

, renal carcinoma, and Gastrointestinal stromal tumor (GISTs). The penetrance data for SDH mutations causing tumorigenesis is lacking, and international guidelines suggest thorough screening for any carriers. 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%. Mammalian SDH functions not only in energy generation, but also has a role in

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. https://radiopaedia.org/articles/salt-and-pepper-sign-paraganglioma-1?lang=us 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 Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...

mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

, optic atrophy,

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...

, 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. Reduced levels SDH are observed post mortem in the brains of patients with

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

, and energy metabolism defects have been identified in both presymptomatic and symptomatic HD patients.

References

{{Portal bar, Biology, border=no EC 1.3.5

Structure

Subunits

Table of subunit composition

Ubiquinone binding site

Succinate binding site

Redox centers

Assembly and maturation

Mechanism

Succinate oxidation

Electron tunneling

Ubiquinone reduction

Heme prosthetic group

Proton transfer

Inhibitors

Role in disease

See also

References