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SDHC
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Pogledaj/uredi – čovjek

Podjedinica C kompleksa sukcinat-dehidrogenaze, znana i kao mitohondrijska podjedinica sukcinat-dehidrogenaze citohroma b560, jest protein/enzim koji je kod ljudi kodiran genom SDHC sa hromosoma 1.^[1] Ovaj gen kodira jednu od četiri jedarno kodirane podjedinice, koje sadrže sukcinat-dehidrogenazu, također poznatu kao mitohondrijski kompleks II, ključni enzimski kompleks ciklusa trikarboksilnih kiselina i aerobni respiratorni lanci mitohondrija. Kodirani protein je jedan od dva integralna membranska proteina koji učvršćuju druge podjedinice kompleksa, sauzčesnike u formiranju katalitskog jezgra, za unutrašnju mitohondrijalnu membranu. Postoji nekoliko srodnih pseudogena za ovaj gen na različitim hromosomima. Mutacije ovog gena povezane su sa feohromocitomima i paragangliomima. Opisane su alternativno prerađene varijante transkripta.^[2]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 169 aminokiselina, a molekulska težina 18.610 Da.^[3]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MAALLLRHVG	RHCLRAHFSP	QLCIRNAVPL	GTTAKEEMER	FWNKNIGSNR
PLSPHITIYS	WSLPMAMSIC	HRGTGIALSA	GVSLFGMSAL	LLPGNFESYL
ELVKSLCLGP	ALIHTAKFAL	VFPLMYHTWN	GIRHLMWDLG	KGLKIPQLYQ
SGVVVLVLTV	LSSMGLAAM

Struktura

Gen koji kodira SDHC protein je jedarni, iako se protein nalazi u unutrašnjoj membrani mitohondrija. Lokacija gena kod ljudi je na hromosomu 1 na poziciji q21. Gen je podijeljen u šest egzona. SDHC gen proizvodi protein od 18,6 kDa, sastavljen od 169 aminokiselina.^[4]^[5]

SDHC protein je jedna od dvije transmembranske podjedinice proteinskog kompleksa sa četiri podjedinice sukcinat-dehidrogenaze (kompleks II) koji se nalazi u unutrašnjoj mitohondrijskoj membrani. Druga transmembranska podjedinica je SDHD. Proteinski dimer SDHC/SDHD povezan je sa podjedinicom SDHB za transport elektrona, koja je zauzvrat povezana sa podjedinicom SDHA.^[6]

Funkcija

Protein SDHC je jedna od četiri jedarno kodirane podjedinice koje sadrže sukcinat-dehidrogenazu, poznatu i kao kompleks II lanca transporta elektrona, ključni enzimski kompleks ciklusa limunske kiseline i aerobnih respiratornih mitohondrijskih lanaca. Kodirani protein je jedan od dva integralna membranska proteina koji pričvršćuju druge podjedinice kompleksa, formirajući katalitsko jezgro, za unutrašnju mitohondrijsku membranu.^[2]

SDHC čini dio transmembranskog dimernog proteina sa SDHD koji sidri kompleks II za unutrašnju mitohondrijsku membranu. Dimer SDHC/SDHD obezbjeđuje mjesta vezanja za ubikinon i vodu, tokom transporta elektrona u kompleks II. U početku, SDHA oksidira sukcinat putem deprotonacija na FAD mjestu vezivanja, formirajući FADH₂ i ostavljajući fumarat, labavo vezan za aktivno mjesto, slobodan za izlazak iz proteina. Elektroni izvedeni iz sukcinatnog tunela duž [Fe-S] releja u SDHB podjedinici, dok ne stignu u [3Fe-4S] klaster gvožđe-sumpor. Elektroni se zatim prenose na molekulu ubikinona koji čeka na aktivnom mjestu Q pula u dimeru SDHC/SDHD. O1 karbonil kisik ubikinona je orijentiran na aktivnom mestu (slika 4) interakcijom vodikovih veza sa Tyr83 u SDHD. Prisustvo elektrona u klasteru gvožđe-sumpor [3Fe-4S] izaziva kretanje ubikinona u drugu orijentaciju. Ovo olakšava drugu interakciju vikove veze između O4 karbonilne grupe ubikinona i Ser27 SDHC-a. Nakon prvog koraka redukcije jednog elektrona, formira se radikalna vrsta semikinon. Drugi elektron stiže iz [3Fe-4S] klastera kako bi osigurao potpunu redukciju ubikinona u ubikinol.^[7]

Klinički značaj

Mutacije ovog gena su povezane sa paragangliomima.^[2]^[8] Utvrđeno je da više od 30 mutacija u SDHC genu povećavaju rizik od nasljednog paraganglioma-feohromocitoma tipa 3. Ljudi sa ovim stanjem imaju paragangliome, feohromocitome ili oba. Naslijeđena mutacija SDHC gena predisponira za to stanje, a da izazove nasljedni paragangliom-feokromocitom tipa 3 potrebna je somatska mutacija koja deletira normalnu kopiju SDHC gena. Većina naslijeđenih mutacija SDHC gena mijenja po jednu aminokiselinu u sekvenci SDHC proteina ili rezultiraju skraćenim proteinom. Kao rezultat, postoji mala ili nikakva aktivnost enzima SDH. Budući da mutirani enzim SDH ne može pretvoriti sukcinat u fumarat, sukcinat se akumulira u ćeliji. Višak sukcinata abnormalno stabilizuje hipoksijski inducirani faktor (HIF), koji se također nakuplja u ćelijama. Višak HIF-a stimuliše ćelije da se dijele i pokreće proizvodnju krvnih sudova kada nisu potrebni. Brza i nekontrolirana ćelijska dioba, uz stvaranje novih krvnih žila, može dovesti do razvoja tumora kod osoba s nasljednim paragangliomom-feohromocitomom.^[9]

Interaktivna mapa puta

Šablon:TCACycle WP78

Reference

^ Hirawake H, Taniwaki M, Tamura A, Kojima S, Kita K (1997). "Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23". Cytogenetics and Cell Genetics. 79 (1–2): 132–8. doi:10.1159/000134700. PMID 9533030.
^ ^a ^b ^c "Entrez Gene: succinate dehydrogenase complex".
^ "UniProt, Q99643" (jezik: engleski). Pristupljeno 18. 12. 2021.
^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (oktobar 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
^ "SDHC - Succinate dehydrogenase cytochrome b560 subunit, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Arhivirano s originala, 19. 7. 2018. Pristupljeno 18. 12. 2021.
^ Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (juli 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. S2CID 16697879.
^ Horsefield R, Yankovskaya V, Sexton G, Whittingham W, Shiomi K, Omura S, Byrne B, Cecchini G, Iwata S (mart 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". The Journal of Biological Chemistry. 281 (11): 7309–16. doi:10.1074/jbc.m508173200. PMID 16407191.
^ Niemann S, Müller U, Engelhardt D, Lohse P (juli 2003). "Autosomal dominant malignant and catecholamine-producing paraganglioma caused by a splice donor site mutation in SDHC". Human Genetics. 113 (1): 92–4. doi:10.1007/s00439-003-0938-0. PMID 12658451. S2CID 32412131.
^ "SDHC". Genetics Home Reference. U.S. National Library of Medicine. Pristupljeno 26. 3. 2015.

Dopunska literatura

Bayley JP, Weiss MM, Grimbergen A, van Brussel BT, Hes FJ, Jansen JC, Verhoef S, Devilee P, Corssmit EP, Vriends AH (septembar 2009). "Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients". Endocrine-Related Cancer. 16 (3): 929–37. doi:10.1677/ERC-09-0084. PMID 19546167.
Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA (januar 2008). "Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD". European Journal of Human Genetics. 16 (1): 79–88. doi:10.1038/sj.ejhg.5201904. PMID 17667967.
Gaal J, Burnichon N, Korpershoek E, Roncelin I, Bertherat J, Plouin PF, de Krijger RR, Gimenez-Roqueplo AP, Dinjens WN (mart 2010). "Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas". The Journal of Clinical Endocrinology and Metabolism. 95 (3): 1274–8. doi:10.1210/jc.2009-2170. PMID 19915015.
Milosevic D, Lundquist P, Cradic K, Vidal-Folch N, Huynh T, Pacak K, Grebe SK (maj 2010). "Development and validation of a comprehensive mutation and deletion detection assay for SDHB, SDHC, and SDHD". Clinical Biochemistry. 43 (7–8): 700–4. doi:10.1016/j.clinbiochem.2010.01.016. PMC 3419008. PMID 20153743.
Bonache S, Martínez J, Fernández M, Bassas L, Larriba S (juni 2007). "Single nucleotide polymorphisms in succinate dehydrogenase subunits and citrate synthase genes: association results for impaired spermatogenesis". International Journal of Andrology. 30 (3): 144–52. doi:10.1111/j.1365-2605.2006.00730.x. PMID 17298551.
Cascón A, López-Jiménez E, Landa I, Leskelä S, Leandro-García LJ, Maliszewska A, Letón R, de la Vega L, García-Barcina MJ, Sanabria C, Alvarez-Escolá C, Rodríguez-Antona C, Robledo M (septembar 2009). "Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma". Hormone and Metabolic Research. 41 (9): 672–5. doi:10.1055/s-0029-1202814. PMID 19343621.
Goto Y, Ando T, Naito M, Goto H, Hamajima N (2006). "No association of an SDHC gene polymorphism with gastric cancer". Asian Pacific Journal of Cancer Prevention. 7 (4): 525–8. PMID 17250422.
Cascón A, Pita G, Burnichon N, Landa I, López-Jiménez E, Montero-Conde C, Leskelä S, Leandro-García LJ, Letón R, Rodríguez-Antona C, Díaz JA, López-Vidriero E, González-Neira A, Velasco A, Matias-Guiu X, Gimenez-Roqueplo AP, Robledo M (maj 2009). "Genetics of pheochromocytoma and paraganglioma in Spanish patients". The Journal of Clinical Endocrinology and Metabolism. 94 (5): 1701–5. doi:10.1210/jc.2008-2756. PMID 19258401.
Boedeker CC, Neumann HP, Maier W, Bausch B, Schipper J, Ridder GJ (juli 2007). "Malignant head and neck paragangliomas in SDHB mutation carriers". Otolaryngology–Head and Neck Surgery. 137 (1): 126–9. doi:10.1016/j.otohns.2007.01.015. PMID 17599579. S2CID 13650583.
Gill AJ, Benn DE, Chou A, Clarkson A, Muljono A, Meyer-Rochow GY, Richardson AL, Sidhu SB, Robinson BG, Clifton-Bligh RJ (juni 2010). "Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes". Human Pathology. 41 (6): 805–14. doi:10.1016/j.humpath.2009.12.005. PMID 20236688.
Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER (septembar 2008). "Germline SDHB mutations and familial renal cell carcinoma". Journal of the National Cancer Institute. 100 (17): 1260–2. doi:10.1093/jnci/djn254. PMID 18728283.
McWhinney SR, Pasini B, Stratakis CA (septembar 2007). "Familial gastrointestinal stromal tumors and germ-line mutations". The New England Journal of Medicine. 357 (10): 1054–6. doi:10.1056/NEJMc071191. PMID 17804857.
Eng C, Kiuru M, Fernandez MJ, Aaltonen LA (mart 2003). "A role for mitochondrial enzymes in inherited neoplasia and beyond". Nature Reviews. Cancer. 3 (3): 193–202. doi:10.1038/nrc1013. PMID 12612654. S2CID 20549458.
Hermsen MA, Sevilla MA, Llorente JL, Weiss MM, Grimbergen A, Allonca E, Garcia-Inclán C, Balbín M, Suárez C (januar 2010). "Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management". Cellular Oncology. 32 (4): 275–83. doi:10.3233/CLO-2009-0498. PMC 4619289. PMID 20208144.
Brière JJ, Favier J, El Ghouzzi V, Djouadi F, Bénit P, Gimenez AP, Rustin P (oktobar 2005). "Succinate dehydrogenase deficiency in human". Cellular and Molecular Life Sciences. 62 (19–20): 2317–24. doi:10.1007/s00018-005-5237-6. PMID 16143825. S2CID 23793565.
Mannelli M, Castellano M, Schiavi F, Filetti S, Giacchè M, Mori L, Pignataro V, Bernini G, Giachè V, Bacca A, Biondi B, Corona G, Di Trapani G, Grossrubatscher E, Reimondo G, Arnaldi G, Giacchetti G, Veglio F, Loli P, Colao A, Ambrosio MR, Terzolo M, Letizia C, Ercolino T, Opocher G (maj 2009). "Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas" (PDF). The Journal of Clinical Endocrinology and Metabolism. 94 (5): 1541–7. doi:10.1210/jc.2008-2419. PMID 19223516.
Richalet JP, Gimenez-Roqueplo AP, Peyrard S, Vénisse A, Marelle L, Burnichon N, Bouzamondo A, Jeunemaitre X, Azizi M, Elghozi JL (decembar 2009). "A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?". Clinical Autonomic Research. 19 (6): 335–42. doi:10.1007/s10286-009-0028-z. PMID 19768395. S2CID 2265162.
Pigny P, Cardot-Bauters C, Do Cao C, Vantyghem MC, Carnaille B, Pattou F, Caron P, Wemeau JL, Porchet N (februar 2009). "Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?". European Journal of Endocrinology. 160 (2): 227–31. doi:10.1530/EJE-08-0574. PMID 19029228.
Korpershoek E, Van Nederveen FH, Dannenberg H, Petri BJ, Komminoth P, Perren A, Lenders JW, Verhofstad AA, De Herder WW, De Krijger RR, Dinjens WN (august 2006). "Genetic analyses of apparently sporadic pheochromocytomas: the Rotterdam experience". Annals of the New York Academy of Sciences. 1073 (1): 138–48. Bibcode:2006NYASA1073..138K. doi:10.1196/annals.1353.014. PMID 17102080. S2CID 8418586.
Wang L, McDonnell SK, Hebbring SJ, Cunningham JM, St Sauver J, Cerhan JR, Isaya G, Schaid DJ, Thibodeau SN (decembar 2008). "Polymorphisms in mitochondrial genes and prostate cancer risk". Cancer Epidemiology, Biomarkers & Prevention. 17 (12): 3558–66. doi:10.1158/1055-9965.EPI-08-0434. PMC 2750891. PMID 19064571.

Vanjski linkovi

GeneReviews/NCBI/NIH/UW entry on Hereditary Paraganglioma-Pheochromocytoma Syndromes

Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.

Šablon:CH-CH oksidoreductaze

[pmid9533030-1] Hirawake H, Taniwaki M, Tamura A, Kojima S, Kita K (1997). "Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23". Cytogenetics and Cell Genetics. 79 (1–2): 132–8. doi:10.1159/000134700. PMID 9533030.

[entrez-2] "Entrez Gene: succinate dehydrogenase complex".

[UniProt-3] "UniProt, Q99643" (jezik: engleski). Pristupljeno 18. 12. 2021.

[COPaKB-4] Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (oktobar 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.

[url_COPaKB-5] "SDHC - Succinate dehydrogenase cytochrome b560 subunit, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Arhivirano s originala, 19. 7. 2018. Pristupljeno 18. 12. 2021.

[6] Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (juli 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. S2CID 16697879.

[7] Horsefield R, Yankovskaya V, Sexton G, Whittingham W, Shiomi K, Omura S, Byrne B, Cecchini G, Iwata S (mart 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". The Journal of Biological Chemistry. 281 (11): 7309–16. doi:10.1074/jbc.m508173200. PMID 16407191.

[pmid12658451-8] Niemann S, Müller U, Engelhardt D, Lohse P (juli 2003). "Autosomal dominant malignant and catecholamine-producing paraganglioma caused by a splice donor site mutation in SDHC". Human Genetics. 113 (1): 92–4. doi:10.1007/s00439-003-0938-0. PMID 12658451. S2CID 32412131.

[9] "SDHC". Genetics Home Reference. U.S. National Library of Medicine. Pristupljeno 26. 3. 2015.

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p r u Enzimi
Teme	Aktivno mjesto Alosterna regulacija Difuzijski limitirani enzim EC broj Enzimska kataliza Inhibicija enzimskih reakcija Kinetika enzima Koenzim Kooperativnost Lineweaver–Burkov dijagram Michaelis–Mentenova kinetika Mjesto vezanja Spisak enzima
Tipovi	EC1 Oksidoreduktaze/spisak EC2 Transferaze/spisak EC3 Hidrolaze/spisak EC4 Lijaze/spisak EC5 Izomeraze/spisak EC6 Ligaze/spisak

SDHC