HADHB
Podjedinica beta mitohondrijskog trifunkcijskog enzima (TP-beta) znana i kao 3-ketoacil-CoA tiolaza, acetil-CoA aciltransferaza ili beta-ketotiolaza jest enzim koji je kod ljudi kodiran genom HADHB sa hromosoma 2.[5]
Amiokiselininska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 474 [[aminokiselina e]], a molkekulska iežina 51.294 Da.[6]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MTILTYPFKN | LPTASKWALR | FSIRPLSCSS | QLRAAPAVQT | KTKKTLAKPN | ||||
| IRNVVVVDGV | RTPFLLSGTS | YKDLMPHDLA | RAALTGLLHR | TSVPKEVVDY | ||||
| IIFGTVIQEV | KTSNVAREAA | LGAGFSDKTP | AHTVTMACIS | ANQAMTTGVG | ||||
| LIASGQCDVI | VAGGVELMSD | VPIRHSRKMR | KLMLDLNKAK | SMGQRLSLIS | ||||
| KFRFNFLAPE | LPAVSEFSTS | ETMGHSADRL | AAAFAVSRLE | QDEYALRSHS | ||||
| LAKKAQDEGL | LSDVVPFKVP | GKDTVTKDNG | IRPSSLEQMA | KLKPAFIKPY | ||||
| GTVTAANSSF | LTDGASAMLI | MAEEKALAMG | YKPKAYLRDF | MYVSQDPKDQ | ||||
| LLLGPTYATP | KVLEKAGLTM | NDIDAFEFHE | AFSGQILANF | KAMDSDWFAE | ||||
| NYMGRKTKVG | LPPLEKFNNW | GGSLSLGHPF | GATGCRLVMA | AANRLRKEGG | ||||
| QYGLVAACAA | GGQGHAMIVE | AYPK |
Struktura
[uredi | uredi izvor]HADHB gen se nalazi na hromsomu 2, a njegova specifična lokacija je 2p23.[5] Gen sadrži 17 egzona. HADHB kodira protein od 51,2 kDa koji se sastoji od 474 aminokiseline; 124 peptida uočeno je putem masene spektrometrije.[7][8]
Funkcija
[uredi | uredi izvor]
Ovaj gen kodira beta podjedinicu mitohondrijskog trifunkcijskog proteina, katalizatora mitohondrijske beta-oksidacije dugolančanih masnih kiselina. HADHB protein katalizira završni korak beta-oksidacije, u kojem 3-ketoacil CoA cijepa tiolnu grupu druge molekule koenzima A. Tiol je umetnut između C-2 i C-3, što daje molekulu acetil CoA i molekulu acil CoA, koji je dva ugljika kraći.
Kodirani protein također može vezati RNK i smanjiti stabilnost nekih iRNK. Geni alfa i beta podjedinica mitohondrijskog trifunkcijaskog proteina nalaze se jedni uz druge u ljudskom genomu u orijentaciji glava-glava.[5]
Klinički značaj
[uredi | uredi izvor]Mutacije u ovom genu, zajedno s mutacijama u HADHA, rezultiraju nedostatkom trifunkcijskog proteina.[5] Mutacije u oba gena imaju slične kliničke slike.[9] Nedostatak rrifunkcijskog proteina karakterizira smanjena aktivnost dugolančane 3-hidroksiacil-CoA dehidrogenaze (LCHAD), dugolančane enoil-CoA hidrataze i dugolančane tiolaze. Ovaj nedostatak se može klasificirati u tri glavna klinička fenotipa: neonatusni početak teškog, smrtonosnog stanja koje rezultira sindromom iznenadne smrti dojenčadi (SIDS)),[10] dojenački početak jetrenog Reyeovog sindroma i kasni adolescentni početak primarno skeletne miopatije.[11] Osim toga, neki nalazi pokazali su simptome povezane s miopatijom, ponavljajuću i epizodnu rabdomiolizu i senzomotornu aksonsku neuropatiju.[12] U nekim slučajevima, simptomi nedostatka mogu se manifestovati kao proširena kardiomiopatija, kongestivna srčana insuficijencija i respiratorna insuficijencija. Nedostatak se manifestirao kao hidrops fetalis i fetusni HELLP sindrom.[13] Složena heterozigotna mutacija HADHB gena može uzrokovati aksonskuu Charcot-Marie-Toothovu bolest, neurološki poremećaj, koji pokazuje da mutacije ovog gena mogu rezultirati nedostacima koji su prisutni u novim oblicima koji ranije nisu opisani.[14]
Interakcije
[uredi | uredi izvor]HADHB je funkcionalna molekulska meta ERα u mitohondrijama, a interakcija može imati važnu ulogu u estrogeno posredovanom metabolizmu lipida kod životinja i ljudi.[15] Dodatno, pokazalo se da se HADHB vezuje za distalnu neprevedenu regiju reninske iRNK, čime se regulira ekspresija proteina renina.[16]
Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000138029 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000086347 - Ensembl, maj 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d "Entrez Gene: hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein)".
- ^ "UniProt, P55084" (jezik: engleski). Pristupljeno 12. 11. 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.
- ^ "Trifunctional enzyme subunit beta, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Arhivirano s originala, 4. 3. 2016. Pristupljeno 23. 3. 2015.
- ^ Spiekerkoetter, U; Khuchua, Z; Yue, Z; Bennett, MJ; Strauss, AW (februar 2004). "General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover". Pediatric Research. 55 (2): 190–6. doi:10.1203/01.pdr.0000103931.80055.06. PMID 14630990.
- ^ Sonta, SI; Sandberg, AA (1977). "Chromosomes and causation of human cancer and leukemia: XXVIII. Value of detailed chromosome studies on large numbers of cells in CML". American Journal of Hematology. 3 (2): 121–6. doi:10.1002/ajh.2830030202. PMID 272120. S2CID 13141165.
- ^ Spiekerkoetter, U; Sun, B; Khuchua, Z; Bennett, MJ; Strauss, AW (juni 2003). "Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations". Human Mutation. 21 (6): 598–607. doi:10.1002/humu.10211. PMID 12754706. S2CID 85671653.
- ^ den Boer, ME; Dionisi-Vici, C; Chakrapani, A; van Thuijl, AO; Wanders, RJ; Wijburg, FA (juni 2003). "Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement". The Journal of Pediatrics. 142 (6): 684–9. doi:10.1067/mpd.2003.231. PMID 12838198.
- ^ Jackson, S; Kler, RS; Bartlett, K; Briggs, H; Bindoff, LA; Pourfarzam, M; Gardner-Medwin, D; Turnbull, DM (oktobar 1992). "Combined enzyme defect of mitochondrial fatty acid oxidation". The Journal of Clinical Investigation. 90 (4): 1219–25. doi:10.1172/jci115983. PMC 443162. PMID 1401059.
- ^ Hong, YB; Lee, JH; Park, JM; Choi, YR; Hyun, YS; Yoon, BR; Yoo, JH; Koo, H; Jung, SC; Chung, KW; Choi, BO (5. 12. 2013). "A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease". BMC Medical Genetics. 14: 125. doi:10.1186/1471-2350-14-125. PMC 4029087. PMID 24314034.
- ^ Zhou, Z; Zhou, J; Du, Y (juli 2012). "Estrogen receptor alpha interacts with mitochondrial protein HADHB and affects beta-oxidation activity". Molecular & Cellular Proteomics. 11 (7): M111.011056. doi:10.1074/mcp.m111.011056. PMC 3394935. PMID 22375075.
- ^ Adams, DJ; Beveridge, DJ; van der Weyden, L; Mangs, H; Leedman, PJ; Morris, BJ (7. 11. 2003). "HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression". The Journal of Biological Chemistry. 278 (45): 44894–903. doi:10.1074/jbc.m307782200. PMID 12933794.
Dopunska literatura
[uredi | uredi izvor]- Wang R, Yang Z, Zhu JM, et al. (2006). "[Screening for G1528C mutation in mitochondrial trifunctional protein gene in pregnant women with severe preeclampsia and new born infant]". Zhonghua Fu Chan Ke Za Zhi. 41 (10): 672–5. PMID 17199921.
- Aboulaich N; Vainonen JP; Strålfors P; Vener AV (2004). "Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes". Biochem. J. 383 (Pt 2): 237–48. doi:10.1042/BJ20040647. PMC 1134064. PMID 15242332.
- Adams DJ, Beveridge DJ, van der Weyden L, et al. (2003). "HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression". J. Biol. Chem. 278 (45): 44894–903. doi:10.1074/jbc.M307782200. PMID 12933794.
- Spiekerkoetter U, Khuchua Z, Yue Z, et al. (2004). "General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover". Pediatr. Res. 55 (2): 190–6. doi:10.1203/01.PDR.0000103931.80055.06. PMID 14630990.
- Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
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- Middleton B (1994). "The mitochondrial long-chain trifunctional enzyme: 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-oxoacyl-CoA thiolase". Biochem. Soc. Trans. 22 (2): 427–31. doi:10.1042/bst0220427. PMID 7958339.
- Zhao Y, Meng XM, Wei YJ, et al. (2003). "Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I.". J. Mol. Med. 81 (5): 297–304. doi:10.1007/s00109-003-0427-x. PMID 12721663. S2CID 13468188.
- Behrends C, Sowa ME, Gygi SP, Harper JW (2010). "Network organization of the human autophagy system". Nature. 466 (7302): 68–76. Bibcode:2010Natur.466...68B. doi:10.1038/nature09204. PMC 2901998. PMID 20562859.
- Purevsuren J, Fukao T, Hasegawa Y, et al. (2009). "Clinical and molecular aspects of Japanese patients with mitochondrial trifunctional protein deficiency". Mol. Genet. Metab. 98 (4): 372–7. doi:10.1016/j.ymgme.2009.07.011. PMID 19699128.
- Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature. 434 (7034): 724–31. Bibcode:2005Natur.434..724H. doi:10.1038/nature03466. PMID 15815621.
- Spiekerkoetter U, Sun B, Khuchua Z, et al. (2003). "Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations". Hum. Mutat. 21 (6): 598–607. doi:10.1002/humu.10211. PMID 12754706. S2CID 85671653.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Fould B, Garlatti V, Neumann E, et al. (2010). "Structural and functional characterization of the recombinant human mitochondrial trifunctional protein". Biochemistry. 49 (39): 8608–17. doi:10.1021/bi100742w. PMID 20825197.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Ibdah JA, Tein I, Dionisi-Vici C, et al. (1998). "Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation". J. Clin. Invest. 102 (6): 1193–9. doi:10.1172/JCI2091. PMC 509102. PMID 9739053.
- Gevaert K, Goethals M, Martens L, et al. (2003). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nat. Biotechnol. 21 (5): 566–9. doi:10.1038/nbt810. PMID 12665801. S2CID 23783563.
- Hendrickson SL, Lautenberger JA, Chinn LW, et al. (2010). "Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression". PLOS ONE. 5 (9): e12862. Bibcode:2010PLoSO...512862H. doi:10.1371/journal.pone.0012862. PMC 2943476. PMID 20877624.
- Frackowiak J, Mazur-Kolecka B, Kaczmarski W, Dickson D (2001). "Deposition of Alzheimer's vascular amyloid-beta is associated with decreased expression of brain L-3-hydroxyacyl-coenzyme A dehydrogenase (ERAB)". Brain Res. 907 (1–2): 44–53. doi:10.1016/S0006-8993(01)02497-0. PMID 11430884. S2CID 22800813.
Vanjski linkovi
[uredi | uredi izvor]
- HADHB protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.
