Succinate dehydrogenase

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succinate dehydrogenase (succinate-ubiquinone oxidoreductase)
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Succinate dehydrogenase
Identifiers
SymbolRespiratory complex II
OPM superfamily3
OPM protein1zoy
Membranome656

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

eukaryotes. It is the only enzyme that participates in both the citric acid cycle and the electron transport chain.[1] Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential.[2]

In step 6 of the

ubiquinone to ubiquinol. This occurs in the inner mitochondrial membrane by coupling
the two reactions together.

Structure

Image 5: Subunits of succinate dehydrogenase

Subunits

phospholipid membrane with the intermembrane space at the top of the image.[4]

Table of subunit composition[5]

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

Two distinctive

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

iron-sulfur clusters, [2Fe-2S].[8]
This can be seen in image 5.

Redox centers

The

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,

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.
Image 7: E1cb Succinate oxidation mechanism.

Succinate oxidation

Much is known about the

fumarate, now loosely bound to the active site, is free to exit the protein
.

Electron tunneling

After the

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

ubiquinone
reduction is shown in image 8.

Heme prosthetic group

Although the functionality of the

ubiquinone
, is shown in image 4.

It has also been proposed that a gating

ubiquinone, and the heme; and could modulate electron flow between these redox centers.[12]

Proton transfer

To fully reduce the

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

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

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]

resistance management practices.[18]

Role in disease

The fundamental role of succinate-coenzyme Q reductase in the

organisms, removal of this enzyme from the genome
has also been shown to be lethal at the embryonic stage in mice.

All SDHx mutations can lead to tumorogenesis in

optic atrophy. SDHB mutations are the most penetrant for paraganglioma and pheochromocytoms[20] and both SDHD and SDHAF2 mutations have some maternal imprinting effects.[21]

Mammalian succinate dehydrogenase functions not only in

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.[22]

See also

References

  1. PMID 14672929
    .
  2. ^ webmaster (2009-03-04). "Using Histochemistry to Determine Muscle Properties". Succinate Dehydrogenase: Identifying Oxidative Potential. University of California, San Diego. Archived from the original on 2018-10-10. Retrieved 2017-12-27.
  3. PMID 12966066
    .
  4. ^
    S2CID 29222766
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  5. ^
    PMID 15989954
    .
  6. PMID 16407191
    .
  7. ^
    PMID 25488574
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  8. PMID 235539
    .
  9. PMID 32887801
    .
  10. PMID 36089066
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  11. PMID 29348404
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  12. PMID 16950775
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  13. PMID 17916065
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  14. ^
    ISBN 978-3-527-33947-1
    .
  15. doi:10.1016/j.cropro.2010.02.019
    .
  16. ^
    • Lucas JA, Hawkins NJ, Fraaije BA (2015). The Evolution of Fungicide Resistance. Advances in Applied Microbiology. Vol. 90. pp. 29–92.
      PMID 24238287
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  17. Fungicide Resistance Action Committee
    ). 2020-01-31. Retrieved 2022-07-05.
  18. ^ "Recommendations for SDHI". FRAC. March 2020. Retrieved 2022-07-05.
  19. S2CID 32088940
    .
  20. PMID 28503760
    .
  21. PMID 23291190
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  22. PMID 27031731
    .
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