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171  structures 18654  species 13  interactions 63581  sequences 184  architectures

Family: FAD_binding_2 (PF00890)

Summary: FAD binding domain

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This is the Wikipedia entry entitled "Succinate dehydrogenase". More...

Succinate dehydrogenase Edit Wikipedia article

succinate dehydrogenase (succinate-ubiquinone oxidoreductase)
Succinate Dehydrogenase 1YQ3 and Membrane.png
The structure of SQR in a phospholipid membrane. SdhA, SdhB, SdhC and SdhD
EC number
CAS number 9028-11-9
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Succinate dehydrogenase or succinate-coenzyme Q reductase (SQR) or respiratory Complex II is an enzyme complex, bound to the inner mitochondrial membrane of mammalian mitochondria and many bacterial cells. It is the only enzyme that participates in both the citric acid cycle and the electron transport chain.[2]

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.


Subunits of succinate dehydrogenase


Mammalian, mitochondrial, and many bacterial monomer SQRs are composed of four subunits: two hydrophilic and two hydrophobic. The first two subunits, a flavoprotein (SdhA) and an iron-sulfur protein (SdhB), are hydrophilic. 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, which can be seen in Image 4. 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 image 3. 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[1]

No. Subunit name Human protein Protein description from UniProt Pfam family with Human protein
1 SdhA SDHA_HUMAN Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Pfam PF00890, Pfam PF02910
2 SdhB SDHB_HUMAN Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial Pfam PF13085, Pfam PF13183
3 SdhC C560_HUMAN Succinate dehydrogenase cytochrome b560 subunit, mitochondrial Pfam PF01127
4 SdhD DHSD_HUMAN Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial Pfam PF05328

Ubiquinone binding site

Ubiquinone’s binding site, image 4, 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 (not shown in the image).[5]

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].[6] 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 Ã… through the enzyme monomer. All edge-to-edge distances between the centers are less than the suggested 14 Ã… limit for physiological electron transfer.[4] This electron transfer is demonstrated in image 8.


Image 6: E2 Succinate oxidation mechanism.
Image 7: E1cb Succinate oxidation mechanism.

Succinate oxidation

Little is known about the exact succinate oxidation mechanism. However, the crystal structure shows that FAD, Glu255, Arg286, and His242 of subunit A (not shown) are good candidates for the initial deprotonation 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.
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 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.[7]

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.


There are two distinct classes of inhibitors 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.[8]

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. More recently, other compounds with a broader spectrum against a range of plant pathogens have been developed including boscalid, penthiopyrad and fluopyram.[9] Some agriculturally important fungi are not sensitive towards members of the new generation of ubiquinone type inhibitors [10]

Role in disease

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.

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.

See also


  1. ^ a b Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D et al. (2005). "Crystal structure of mitochondrial respiratory membrane protein complex II.". Cell 121 (7): 1043–57. doi:10.1016/j.cell.2005.05.025. PMID 15989954. 
  2. ^ Oyedotun KS, Lemire BD (March 2004). "The quaternary structure of the Saccharomyces cerevisiae succinate dehydrogenase. Homology modeling, cofactor docking, and molecular dynamics simulation studies". J. Biol. Chem. 279 (10): 9424–31. doi:10.1074/jbc.M311876200. PMID 14672929. 
  3. ^ Tomitsuka E, Hirawake H, Goto Y, Taiwaki M, Harada S, Kita K (2003). "Direct evidence for two distinct forms of the flavoprotein subunit of human mitochondrial complex II (succinate-ubiquinone reductase)". J. Biochem 134 (2): 191–5. doi:10.1093/jb/mvg144. PMID 12966066. 
  4. ^ a b Yankovskaya V, Horsefield R, Törnroth S et al. (January 2003). "Architecture of succinate dehydrogenase and reactive oxygen species generation". Science 299 (5607): 700–4. doi:10.1126/science.1079605. PMID 12560550. 
  5. ^ Horsefield R, Yankovskaya V, Sexton G et al. (March 2006). "Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction". J. Biol. Chem. 281 (11): 7309–16. doi:10.1074/jbc.M508173200. PMID 16407191. 
  6. ^ Kenney WC (April 1975). "The reaction of N-ethylmaleimide at the active site of succinate dehydrogenase". J. Biol. Chem. 250 (8): 3089–94. PMID 235539. 
  7. ^ Tran QM, Rothery RA, Maklashina E, Cecchini G, Weiner JH (October 2006). "The quinone binding site in Escherichia coli succinate dehydrogenase is required for electron transfer to the heme b". J. Biol. Chem. 281 (43): 32310–7. doi:10.1074/jbc.M607476200. PMID 16950775. 
  8. ^ Muller FL, Liu Y, Abdul-Ghani MA et al. (January 2008). "High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates". Biochem. J. 409 (2): 491–9. doi:10.1042/BJ20071162. PMID 17916065. 
  9. ^ Avenot, H. F.; Michailides, T. J. (2010). "Progress in understanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungi". Crop Protection 29 (7): 643. doi:10.1016/j.cropro.2010.02.019.  edit
  10. ^ Dubos, T.; Pasquali, M.; Pogoda, F.; Casanova, A. L.; Hoffmann, L.; Beyer, M. (2013). "Differences between the succinate dehydrogenase sequences of isopyrazam sensitive Zymoseptoria tritici and insensitive Fusarium graminearum strains". Pesticide Biochemistry and Physiology 105: 28. doi:10.1016/j.pestbp.2012.11.004.  edit

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

FAD binding domain Provide feedback

This family includes members that bind FAD. This family includes the flavoprotein subunits from succinate and fumarate dehydrogenase, aspartate oxidase and the alpha subunit of adenylylsulphate reductase.

Literature references

  1. Mittl PR, Schulz GE , Protein Sci 1994;3:799-809.: Structure of glutathione reductase from Escherichia coli at 1.86 A resolution: comparison with the enzyme from human erythrocytes. PUBMED:8061609 EPMC:8061609

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003953

This domain is found in proteins that bind FAD, such as the flavoprotein subunits from succinate and fumarate dehydrogenase, aspartate oxidase and the alpha subunit of adenylylsulphate reductase [PUBMED:8061609].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan NADP_Rossmann (CL0063), which has the following description:

A class of redox enzymes are two domain proteins. One domain, termed the catalytic domain, confers substrate specificity and the precise reaction of the enzyme. The other domain, which is common to this class of redox enzymes, is a Rossmann-fold domain. The Rossmann domain binds nicotinamide adenine dinucleotide (NAD+) and it is this cofactor that reversibly accepts a hydride ion, which is lost or gained by the substrate in the redox reaction. Rossmann domains have an alpha/beta fold, which has a central beta sheet, with approximately five alpha helices found surrounding the beta sheet.The strands forming the beta sheet are found in the following characteristic order 654123. The inter sheet crossover of the stands in the sheet form the NAD+ binding site [1]. In some more distantly relate Rossmann domains the NAD+ cofactor is replaced by the functionally similar cofactor FAD.

The clan contains the following 181 members:

2-Hacid_dh_C 3Beta_HSD 3HCDH_N adh_short adh_short_C2 ADH_zinc_N ADH_zinc_N_2 AdoHcyase_NAD AdoMet_MTase AlaDh_PNT_C Amino_oxidase ApbA AviRa B12-binding Bac_GDH Bin3 CheR CMAS CmcI CoA_binding CoA_binding_2 CoA_binding_3 Cons_hypoth95 DAO DapB_N DFP DNA_methylase DOT1 DREV DUF1442 DUF166 DUF1776 DUF2431 DUF268 DUF3321 DUF364 DUF43 DUF938 DXP_redisom_C DXP_reductoisom Eco57I ELFV_dehydrog Eno-Rase_FAD_bd Eno-Rase_NADH_b Enoyl_reductase Epimerase F420_oxidored FAD_binding_2 FAD_binding_3 FAD_oxidored Fibrillarin FMO-like FmrO FtsJ G6PD_N GCD14 GDI GDP_Man_Dehyd GFO_IDH_MocA GIDA GidB GLF Glu_dehyd_C Glyco_hydro_4 GMC_oxred_N Gp_dh_N GRAS GRDA HI0933_like HIM1 IlvN K_oxygenase KR LCM Ldh_1_N Lycopene_cycl Malic_M Mannitol_dh MCRA Met_10 Methyltrans_Mon Methyltrans_SAM Methyltransf_10 Methyltransf_11 Methyltransf_12 Methyltransf_15 Methyltransf_16 Methyltransf_17 Methyltransf_18 Methyltransf_19 Methyltransf_2 Methyltransf_20 Methyltransf_21 Methyltransf_22 Methyltransf_23 Methyltransf_24 Methyltransf_25 Methyltransf_26 Methyltransf_28 Methyltransf_29 Methyltransf_3 Methyltransf_30 Methyltransf_31 Methyltransf_32 Methyltransf_34 Methyltransf_4 Methyltransf_5 Methyltransf_7 Methyltransf_8 Methyltransf_9 Methyltransf_PK MethyltransfD12 MetW Mg-por_mtran_C Mqo MT-A70 MTS Mur_ligase N2227 N6-adenineMlase N6_Mtase N6_N4_Mtase NAD_binding_10 NAD_binding_2 NAD_binding_3 NAD_binding_4 NAD_binding_5 NAD_binding_7 NAD_binding_8 NAD_binding_9 NAD_Gly3P_dh_N NAS NmrA NNMT_PNMT_TEMT NodS Nol1_Nop2_Fmu NSP13 OCD_Mu_crystall PARP_regulatory PCMT PDH Polysacc_synt_2 Pox_MCEL Prenylcys_lyase PrmA PRMT5 Pyr_redox Pyr_redox_2 Pyr_redox_3 RmlD_sub_bind Rossmann-like rRNA_methylase RrnaAD Rsm22 RsmJ Sacchrp_dh_NADP SAM_MT SAMBD SE Semialdhyde_dh Shikimate_DH Spermine_synth TehB THF_DHG_CYH_C Thi4 ThiF TPMT TrkA_N TRM TRM13 TrmK tRNA_U5-meth_tr Trp_halogenase TylF Ubie_methyltran UDPG_MGDP_dh_N UPF0020 UPF0146 V_cholerae_RfbT XdhC_C YjeF_N


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Curation and family details

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Curation View help on the curation process

Seed source: Pfam-B_255 (release 3.0)
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 62
Number in full: 63581
Average length of the domain: 378.10 aa
Average identity of full alignment: 26 %
Average coverage of the sequence by the domain: 71.10 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.4 20.4
Trusted cut-off 20.4 20.4
Noise cut-off 20.3 20.3
Model length: 417
Family (HMM) version: 20
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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There are 13 interactions for this family. More...

FAD_binding_2 Fer4 Fer4_8 Fer2_3 Succ_DH_flav_C Fumarate_red_C Fer4_9 Fer4_17 Cytochrom_c3_2 APS-reductase_C Succ_DH_flav_C Cytochrom_c3_2 Sdh_cyt


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FAD_binding_2 domain has been found. There are 171 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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