Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHBgene.[5][6][7]
The succinate dehydrogenase (also called SDH or Complex II) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA, SDHC and SDHD. The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein with three iron-sulfur clusters. It weighs 30 kDa.
Structure
The gene that codes for the SDHB protein is nuclear, not mitochondrial DNA. However, the expressed protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome at locus p36.1-p35. The gene is coded in 1,162 base pairs, partitioned in 8 exons.[5] The expressed protein weighs 31.6 kDa and is composed of 280 amino acids.[8][9] SDHB contains the iron-sulphur clusters necessary for tunneling electrons through the complex. It is located between SDHA and the two transmembrane subunits SDHC and SDHD.[10]
Function
Figure 1: Function of the SDHB protein. Electrons are transferred from the Citric Acid Cycle to the Respiratory Chain. Electron path is shown by red arrows.
The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain. SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1:
Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S].
Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. This function is part of the Respiratory chain.
Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. Electrons from FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S] and tunnel along the [Fe-S] relay until they reach the [3Fe-4S] iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. 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 SDHC. 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.[11]
Clinical significance
Germline mutations in the gene can cause familial paraganglioma (in old nomenclature, Paraganglioma Type PGL4). The same condition is often called familial pheochromocytoma. Less frequently, renal cell carcinoma can be caused by this mutation.
Paragangliomas related to SDHB mutations have a high rate of malignancy. When malignant, treatment is currently the same as for any malignant paraganglioma/pheochromocytoma.
Cancer
Paragangliomas caused by SDHB mutations have several distinguishing characteristics:
Malignancy is common, ranging from 38%-83%[12][13] in carriers with disease. In contrast, tumors caused by SDHD mutations are almost always benign. Sporadic paragangliomas are malignant in less than 10% of cases.
Malignant paragangliomas caused by SDHB are usually (perhaps 92%[13]) extra-adrenal. Sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases.
The penetrance of the gene is often reported as 77% by age 50[12] (i.e. 77% of carriers will have at least one tumour by the age of 50). This is likely an overestimate. Currently (2011), families with silent SDHB mutations are being screened[14] to determine the frequency of silent carriers.
The average age of onset is approximately the same for SDHB vs non-SDHB related disease (approximately 36 years).
Mutations causing disease have been seen in exons 1 through 7, but not 8. As with the SDHC and SDHD genes, SDHB is a tumor suppressor gene.
Tumor formation generally follows the Knudson "two hit" hypothesis. The first copy of the gene is mutated in all cells, however the second copy functions normally. When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH) occurs and the SDHB protein is no longer produced. Tumor formation then becomes possible.
Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected. However, the sensitivity of these cells to oxygen levels may play a role.
Disease pathways
The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms.[15]
Generation of reactive oxygen species
Figure 2: Disease Pathways for SDHB mutations. Electron path during normal function is shown by solid red arrows. Red dashed arrow shows superoxide generation (Pathway 1). Purple dashed arrow shows diffusion of succinate to block PHD (Pathway 2). Black crosses indicate the non-mutated process is blocked.
When succinate-ubiquinone activity is inhibited, electrons that would normally transfer through the SDHB subunit to the Ubiquinone pool are instead transferred to O2 to create Reactive Oxygen Species (ROS) such as superoxide. The dashed red arrow in Figure 2 shows this. ROS accumulate and stabilize the production of HIF1-α. HIF1-α combines with HIF1-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic genes in the cell nucleus.
Succinate accumulation in the cytosol
SDH inactivation can block the oxidation of succinate, starting a cascade of reactions:
The succinate accumulated in the mitochondrial matrix diffuses through the inner and outer mitochondrial membranes to the cytosol (purple dashed arrows in Figure 2).
Under normal cellular function, HIF1-α in the cytosol is quickly hydroxylated by prolyl hydroxylase (PHD), shown with the light blue arrow. This process is blocked by the accumulated succinate.
HIF1-α stabilizes and passes to the cell nucleus (orange arrow) where it combines with HIF1-β to form an active HIF complex that induces the expression of tumor causing genes.[16]
This pathway raises the possibility of a therapeutic treatment. The build-up of succinate inhibits PHD activity. PHD action normally requires oxygen and alpha-ketoglutarate as cosubstrates and ferrous iron and ascorbate as cofactors. Succinate competes with α-ketoglutarate in binding to the PHD enzyme. Therefore, increasing α-ketoglutarate levels can offset the effect of succinate accumulation.
Normal α-ketoglutarate does not permeate cell walls efficiently, and it is necessary to create a cell permeating derivative (e.g. α-ketoglutarate esters). In-vitro trials show this supplementation approach can reduce HIF1-α levels, and may result in a therapeutic approach to tumours resulting from SDH deficiency.[17]
Impaired developmental apoptosis
Paraganglionic tissue is derived from the neural crest cells present in an embryo. Abdominal extra-adrenal paraganglionic cells secrete catecholamines that play an important role in fetal development. After birth these cells usually die, a process that is triggered by a decline in nerve growth factor (NGF)which initiates apoptosis (cell death).
This cell death process is mediated by an enzyme called prolyl hydroxylase EglN3. Succinate accumulation caused by SDH inactivation inhibits the prolyl hydroxylase EglN3.[18] The net result is that paranglionic tissue that would normally die after birth remains, and this tissue may be able to trigger paraganglioma/pheochromocytoma later.
Glycolysis upregulation
Inhibition of the Citric Acid Cycle forces the cell to create ATP glycolytically in order to generate its required energy. The induced glycolytic enzymes could potentially block cell apoptosis.
RNA editing
The mRNA transcripts of the SDHB gene in human are edited through an unknown mechanism at ORF nucleotide position 136 causing the conversion of C to U and thus generating a stop codon resulting in the translation of the edited transcripts to a truncated SDHB protein with an R46X amino acid change. This editing has been shown in monocytes and some human lymphoid cell-lines,[19] and is enhanced by hypoxia.[20]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
^ abNeumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C (August 2004). "Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations". JAMA. 292 (8): 943–51. doi:10.1001/jama.292.8.943. PMID15328326. S2CID21673619.
^Conference: National Institute of Health (U.S.A.), "SDHB-related Pheochromocytoma: Recent Discoveries & Current Diagnostic and Therapeutic Approaches", September 29, 2006
^Gottlieb E, Tomlinson IP (November 2005). "Mitochondrial tumour suppressors: a genetic and biochemical update". Nat. Rev. Cancer. 5 (11): 857–66. doi:10.1038/nrc1737. PMID16327764. S2CID20851047.
Alrashdi I, Bano G, Maher ER, Hodgson SV (2010). "Carney triad versus Carney Stratakis syndrome: two cases which illustrate the difficulty in distinguishing between these conditions in individual patients". Fam. Cancer. 9 (3): 443–7. doi:10.1007/s10689-010-9323-z. PMID20119652. S2CID21792188.
Gill AJ, Benn DE, Chou A, et al. (2010). "Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes". Hum. Pathol. 41 (6): 805–14. doi:10.1016/j.humpath.2009.12.005. PMID20236688.
Eng C, Kiuru M, Fernandez MJ, Aaltonen LA (2003). "A role for mitochondrial enzymes in inherited neoplasia and beyond". Nat. Rev. Cancer. 3 (3): 193–202. doi:10.1038/nrc1013. PMID12612654. S2CID20549458.
Lee J, Wang J, Torbenson M, et al. (2010). "Loss of SDHB and NF1 genes in a malignant phyllodes tumor of the breast as detected by oligo-array comparative genomic hybridization". Cancer Genet. Cytogenet. 196 (2): 179–83. doi:10.1016/j.cancergencyto.2009.09.005. PMID20082856.
Musil Z; Puchmajerová A; Krepelová A; et al. (2010). "Paraganglioma in a 13-year-old girl: a novel SDHB gene mutation in the family?". Cancer Genet. Cytogenet. 197 (2): 189–92. doi:10.1016/j.cancergencyto.2009.11.010. PMID20193854.
Shimada M, Miyagawa T, Kawashima M, et al. (2010). "An approach based on a genome-wide association study reveals candidate loci for narcolepsy". Hum. Genet. 128 (4): 433–41. doi:10.1007/s00439-010-0862-z. PMID20677014. S2CID24207887.
Schimke RN, Collins DL, Stolle CA (2010). "Paraganglioma, neuroblastoma, and a SDHB mutation: Resolution of a 30-year-old mystery". Am. J. Med. Genet. A. 152A (6): 1531–5. doi:10.1002/ajmg.a.33384. PMID20503330. S2CID22768946.
Gill AJ, Chou A, Vilain R, et al. (2010). "Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types". Am. J. Surg. Pathol. 34 (5): 636–44. doi:10.1097/PAS.0b013e3181d6150d. PMID20305538. S2CID2314622.
Cerecer-Gil NY, Figuera LE, Llamas FJ, et al. (2010). "Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma". Clin. Cancer Res. 16 (16): 4148–54. doi:10.1158/1078-0432.CCR-10-0637. PMID20592014. S2CID12502978.
Krawczyk A, Hasse-Lazar K, Pawlaczek A, et al. (2010). "Germinal mutations of RET, SDHB, SDHD, and VHL genes in patients with apparently sporadic pheochromocytomas and paragangliomas". Endokrynol Pol. 61 (1): 43–8. PMID20205103.
2005 children's novel by Ian Ogilvy Measle and the Mallockee First editionAuthorIan OgilvyCover artistChris MouldCountryUnited KingdomLanguageEnglishSeriesMeasle StubbsGenreChildren's fantasyPublisherOxford University PressPublication date6 Oct 2005Media typePrintPages384 pagesISBN978-0060586928OCLC59512793Preceded byMeasle and the Wrathmonk Followed byMeasle and the Slitherghoul Measle and the Mallockee is a children's novel written by Ian Ogilvy and illustrate...
Mgr.Carlos Filipe Ximenes BeloS.D.B.Administrator Apostolik Emeritus DiliGerejaGereja Katolik RomaTakhtaKeuskupan DiliAwal masa jabatan21 Maret 1988PendahuluMartinho da Costa LopesPenerusBasílio do NascimentoImamatTahbisan imam26 Juni 1980(43 tahun, 278 hari)oleh José Policarpo[2]Tahbisan uskup19 Juni 1988oleh Francesco Canalini, FX Hadisumarta, O.Carm, dan Donatus Djagom, S.V.D.[1]Informasi pribadiLahir3 Februari 1948 (umur 76) Vemasse, Baucau, Timo...
Surveyor 1Sonde spatiale ( Lune ) Une maquette de la sonde lunaire Surveyor 1Données générales Organisation NASA Constructeur Hughes Aircraft Programme Surveyor Domaine Exploration de la Lune Type de mission Atterrisseur Statut Mission terminée Autres noms Surveyor-A Base de lancement Cape Kennedy, LC-36A Lancement 30 mai 1966 à 14 h 41 TU Lanceur Atlas-Centaur (AC-10)(Atlas-D # 290 - Centaur D) Fin de mission 7 janvier 1967 Durée 63,6 heures Durée de vie 45 jours (mission primaire) I...
Questa voce o sezione sull'argomento Vietnam non cita le fonti necessarie o quelle presenti sono insufficienti. Puoi migliorare questa voce aggiungendo citazioni da fonti attendibili secondo le linee guida sull'uso delle fonti. Viet MinhLega per l'indipendenza del VietnamCombattenti viet minh durante la battaglia di Dien Bien PhuAttiva1941 - 1954 Nazione Indocina francese ContestoSeconda guerra mondiale e Guerra fredda IdeologiaComunismo Marxismo-leninismo Indipendentismo Nazionalismo d...
Robert Mitchum pada tahun 1949 Robert Charles Durman Mitchum (6 Agustus 1917-1 Juli 1997) merupakan seorang penyanyi dan aktor berkebangsaan Amerika Serikat yang menjadi terkenal pada era 1950-an dan 1960-an. Dia dilahirkan di Bridgeport, Connecticut. Dia berkarier di dunia film sejak tahun 1942 hingga 1996. Filmografi Utama: Saboteur (1942) The Human Comedy (1943) Hoppy Serves a Writ (1943) Aerial Gunner (1943) Border Patrol (1943) Follow the Band (1943) Leather Burners (1943) Colt Comrades ...
Keuskupan PadovaDioecesis PatavinaDiocesi di PadovaKatedral PadovaLokasiNegaraItaliaStatistikLuas3.297 km2 (1.273 sq mi)Populasi- Total- Katolik(per 2004)1.039.1171,027,662 (98.9%)Paroki459InformasiRitusRomaPendirianAbad ke-3KatedralBasilica Cattedrale di S. MariaKepemimpinan kiniPausFransiskusUskupClaudio Cipolla[1]EmeritusAntonio MattiazzoPetaSitus webwww.diocesipadova.it Keuskupan Padova (bahasa Italia: Diocesi di Padova; bahasa Latin: Dio...
French composer and pianist (1866–1925) Satie in 1920 by Henri Manuel Eric Alfred Leslie Satie[n 1] (17 May 1866 – 1 July 1925), who signed his name Erik Satie after 1884, was a French composer and pianist. He was the son of a French father and a British mother. He studied at the Paris Conservatoire, but was an undistinguished student and obtained no diploma. In the 1880s he worked as a pianist in café-cabaret in Montmartre, Paris, and began composing works, mostly f...
Ancient Roman term for a rural village or neighborhood For the early Peruvian culture, see Vicus (Peru). Politics of ancient Rome Periods Roman Kingdom753–509 BC Roman Republic509–27 BC Roman Empire27 BC – AD 395 Principate27 BC – AD 284 DominateAD 284–641 WesternAD 395–476 EasternAD 395–1453 Timeline Constitution Kingdom Republic Sullan republic Empire Augustan reforms Late Empire Political institutions Imperium Collegiality Auctoritas Roman citizenship Cursus honorum Assemblie...
U.S. Highway in New Hampshire, United States This article is about the section of U.S. Route 2 in New Hampshire. For the entire route, see U.S. Route 2. U.S. Route 2US 2 highlighted in redRoute informationMaintained by NHDOTLength35.437 mi[1] (57.030 km)Existed1926[2]–presentMajor junctionsWest end US 2 at the Vermont state line in LancasterMajor intersections US 3 in Lancaster NH 16 in Gorham East end US 2 at the Maine state...
40°11′38″N 47°45′14″E / 40.19389°N 47.75389°E / 40.19389; 47.75389 Place in Zardab, AzerbaijanBöyük DəkkəBöyük DəkkəCoordinates: 40°11′38″N 47°45′14″E / 40.19389°N 47.75389°E / 40.19389; 47.75389Country AzerbaijanRayonZardabTime zoneUTC+4 (AZT) • Summer (DST)UTC+5 (AZT) Böyük Dəkkə (also, Bëyuk Dekkya) is a village in the Zardab Rayon of Azerbaijan. The village forms part of the municipality ...
2018 book by Thomas Page McBee Amateur: A True Story About What Makes a Man AuthorThomas Page McBeeCountryUnited StatesLanguageEnglishGenreMemoirPublisherScribnerPublication dateAugust 14, 2018Media typePrintISBN9781501168741 Amateur: A True Story About What Makes a Man is a nonfiction book by Thomas Page McBee, published August 14, 2018, by Scribner. The book was a finalist a Lambda Literary Award for Transgender Nonfiction[1] and was shortlisted for The Baillie Gifford Prize fo...
Municipality and city in Oaxaca, MexicoSan Juan Bautista TuxtepecMunicipality and cityFormer Tuxtepec Cathedral SealSan Juan Bautista Tuxtepec in OaxacaSan Juan Bautista TuxtepecCoordinates: 18°06′N 96°07′W / 18.100°N 96.117°W / 18.100; -96.117Country MexicoStateOaxacaMunicipalitySan Juan Bautista TuxtepecFoundedC. 14th (?)Municipality created1811Area • Total877 km2 (339 sq mi) • Municipal Seat41.92 km2 (16.19...
Not to be confused with Crockett County, Texas. City in Texas, United StatesCrockett, TexasCityDowntown Crockett, Texas SealNickname: Paradise in the PinesLocation of Crockett, TexasCoordinates: 31°19′1″N 95°27′30″W / 31.31694°N 95.45833°W / 31.31694; -95.45833CountryUnited StatesStateTexasCountyHoustonGovernment • TypeCouncil-Manager • MayorDr. Ianthia Fisher • City ManagerJohn Angerstein • City Council ...
В Википедии есть статьи о других людях с фамилией Хиллер. Артур Хиллерангл. Arthur Hiller Артур Хиллер в 2011 году Дата рождения 22 ноября 1923(1923-11-22) Место рождения Эдмонтон, Альберта, Канада Дата смерти 17 августа 2016(2016-08-17) (92 года) Место смерти Лос-Анджелес. США Гражданс...
Chimpanzee who learned how to draw and paint CongoA painting by CongoSpeciesChimpanzee (Pan troglodytes)SexMaleBornc. 1954Died1964 (aged 9–10)London Zoo, London, EnglandCause of deathTuberculosisYears active1956-1959Known forLearning to draw and paint Congo (1954–1964) was a chimpanzee artist and painter. Zoologist, author and surrealist painter Desmond Morris first observed his abilities when the chimpanzee was offered a pencil and paper at two years of age. By t...
HanDati amministrativiPoliticaTerritorio e popolazioneLo stato di Han e gli altri Regni combattenti Evoluzione storicaOra parte di Cina Modifica dati su Wikidata · ManualeStato di Han(220 a.C.) Lo stato di Han (韓國, Hánguó) (403 a.C.-230 a.C.) fu un regno cinese del Periodo dei regni combattenti. Il territorio dello Stato di Han si collocava fra lo stato di Qin e le pianure del nord, e per questo motivo divenne bersaglio di frequenti operazioni militari. Nonostante i tentativi...
Voce principale: Società Sportiva Juve Stabia. Società Sportiva Juventus StabiaStagione 1987-1988Sport calcio Squadra Juventus Stabia Allenatore Angelo Carrano Presidente Vincenzo Zurolo Serie C212º Coppa Italia Serie CSedicesimi di finale 1986-1987 1988-1989 Si invita a seguire il modello di voce Questa voce raccoglie le informazioni riguardanti la Società Sportiva Juve Stabia nelle competizioni ufficiali della stagione 1987-1988. Indice 1 Stagione 2 Rosa 3 Risultati 3.1 Campionato...
Hiéroglyphe symbole du Nome. Le nome d'Andjety (ˁnḏtj) est l'un des 42 nomes (division administrative) de l'Égypte antique. C'est l'un des vingt nomes de la Basse-Égypte et il porte le numéro neuf. Ville principale Bousiris Culte Andjéty Les nomes de Basse-Égypte v · mNomes et villes d'Égypte antique Nomes Basse-Égypte 1er : Nome de la Muraille blanche 2e : Nome de la Cuisse 3e : Nome de l'Occident 4e : Nome inférieur de Neith 5e : Nome supérieur de...
