HADHA

Mitohondrijska podjednica alfa trifunkcijskog enzima znana i kao podjedinica alfa hidroksiacil-CoA dehidrogenaze/3-ketoacil-CoA tiolaze/enoil-CoA hidrataze alfa (trifunkcijski protein) jest enzim koji je kod ljudi kodiran genom HADHA sa hromosoma 2. Mutacije u HADHA su povezane sa nedostatkom trifunkcijskog proteina ili nedostatkom dugolančane 3-hidroksacil-koenzim A dehidrogenaze.^[5]

HADHA
Identifikatori
Aliasi	HADHA
Vanjski ID-jevi	OMIM: 600890 MGI: 2135593 HomoloGene: 152 GeneCards: HADHA
Lokacija gena (čovjek) Hrom. Hromosom 2 (čovjek)[1] Bend 2p23.3 Početak 26,190,635 bp[1] Kraj 26,244,672 bp[1]
Lokacija gena (miš) Hrom. Hromosom 5 (miš)[2] Bend 5|5 B1 Početak 30,323,302 bp[2] Kraj 30,360,160 bp[2]
Ontologija gena Molekularna funkcija • fatty-acyl-CoA binding • acetyl-CoA C-acyltransferase activity • GO:0032403 protein-containing complex binding • NAD binding • enoyl-CoA hydratase activity • acetyl-CoA C-acetyltransferase activity • long-chain-3-hydroxyacyl-CoA dehydrogenase activity • GO:0001948, GO:0016582 vezivanje za proteine • catalytic activity • lyase activity • oxidoreductase activity • long-chain-enoyl-CoA hydratase activity • 3-hydroxyacyl-CoA dehydrogenase activity Ćelijska komponenta • mitohondrija • mitochondrial inner membrane • mitochondrial nucleoid • Mitohondrijski trofunkcijski protein • GO:0005578 Vanćelijski matriks Biološki proces • lipid metabolism • fatty acid metabolic process • response to insulin • fatty acid beta-oxidation • metabolizam • cardiolipin acyl-chain remodeling Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	3030	97212
Ensembl	ENSG00000084754	ENSMUSG00000025745
UniProt	P40939	Q8BMS1
RefSeq (mRNK)	NM_000182	NM_178878
RefSeq (bjelančevina)	NP_000173	NP_849209
Lokacija (UCSC)	Chr 2: 26.19 – 26.24 Mb	Chr 5: 30.32 – 30.36 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Amiokiselininska sekvenca

Dužina polipeptidnog lanca je 763 aminokiseline, a molkekulska iežina 83.000 Da.^[6]

• 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
MVACRAIGIL		SRFSAFRILR		SRGYICRNFT		GSSALLTRTH		INYGVKGDVA
VVRINSPNSK		VNTLSKELHS		EFSEVMNEIW		ASDQIRSAVL		ISSKPGCFIA
GADINMLAAC		KTLQEVTQLS		QEAQRIVEKL		EKSTKPIVAA		INGSCLGGGL
EVAISCQYRI		ATKDRKTVLG		TPEVLLGALP		GAGGTQRLPK		MVGVPAALDM
MLTGRSIRAD		RAKKMGLVDQ		LVEPLGPGLK		PPEERTIEYL		EEVAITFAKG
LADKKISPKR		DKGLVEKLTA		YAMTIPFVRQ		QVYKKVEEKV		RKQTKGLYPA
PLKIIDVVKT		GIEQGSDAGY		LCESQKFGEL		VMTKESKALM		GLYHGQVLCK
KNKFGAPQKD		VKHLAILGAG		LMGAGIAQVS		VDKGLKTILK		DATLTALDRG
QQQVFKGLND		KVKKKALTSF		ERDSIFSNLT		GQLDYQGFEK		ADMVIEAVFE
DLSLKHRVLK		EVEAVIPDHC		IFASNTSALP		ISEIAAVSKR		PEKVIGMHYF
SPVDKMQLLE		IITTEKTSKD		TSASAVAVGL		KQGKVIIVVK		DGPGFYTTRC
LAPMMSEVIR		ILQEGVDPKK		LDSLTTSFGF		PVGAATLVDE		VGVDVAKHVA
EDLGKVFGER		FGGGNPELLT		QMVSKGFLGR		KSGKGFYIYQ		EGVKRKDLNS
DMDSILASLK		LPPKSEVSSD		EDIQFRLVTR		FVNEAVMCLQ		EGILATPAEG
DIGAVFGLGF		PPCLGGPFRF		VDLYGAQKIV		DRLKKYEAAY		GKQFTPCQLL
ADHANSPNKK		FYQ

Struktura

HADHA je protein od 82,9 kDa koji se sastoji od 763 aminokiseline.^[7][8]

Mitohondrijski membranski vezani heterokompleks sastoji se od početiri alfa i beta podjedinice, pri čemu alfa podjedinica katalizira aktivnosti 3-hidroksiacil-CoA dehidrogenaze i enoil-CoA hidrataze. Geni alfa i beta podjedinica mitohondrijskog trifunkcijskog proteina nalaze se jedni uz druge u ljudskom genomu u orijentaciji glava-glava.^[5]

Funkcija

Ovaj gen kodira alfa podjedinicu mitohondrijskog trifunkcijskog proteina, koji katalizira posljednja tri koraka mitohondrijske beta-oksidacije dugolančanih masnih kiselina.^[5] Enzim pretvara srednje- i dugolančane spojeve 2-enoil-CoA u sljedeće 3-ketoacil-CoA kada je prisutan isključivo NAD i acetil-CoA , kada su prisutni NAD i CoASH .^[9] Alfa podjedinica katalizira ovu reakciju i vezana je za HADHB, koji katalizira posljednji korak reakcije.^[10]

Klinički značaj

Mutacije ovog gena rezultiraju nedostatkom trifunkcijskog proteina ili nedostatkom dugolančane 3-hidroksiacil-koenzim A dehidrogenaze.^[5]

Najčešći oblik mutacije je G1528C, u kojem se guanin na 1528. poziciji mijenja u citozin. Mutacija gena stvara nedostatak proteina koji je povezan sa poremećenom oksidacijom dugolančanih masnih kiselina, što može dovesti do iznenadne smrti novorođenčeta.^[11] Kliničke manifestacije ovog nedostatka mogu biti miopatija, kardiomiopatija, epizode koma i hipoglikemija.^[12] Nedostatak dugolančane L-3-hidroksiacil-koenzim dehidrogenaze povezan je s nekim poremećajima specifičnim za trudnoću, uključujući preeklampsiju, HELLP sindrom (hemoliza, povišeni enzimi jetre, niske razine trombocita), hyperemesis gravidarum, akutno masnu jetru u trudnoći i infarkt placente na njenom majčinskom dnu.^[13][14] Pored toga, to je povezano sa bolešću akutno masna jetra u trudnoći (AFLP).^[15]

Iz kliničke perspektive, HADHA bi takođe mogao biti koristan marker za predviđanje otpornosti na određene tipove hemoterapije kod pacijenata sa rakom pluća.^[16]

Interakcije

Pokazalo se da HADHA ima 142 binarne interakcije protein-protein uključujući 117 kokompleksnih interakcija. Čini se da je HADHA u interakciji sa GABARAP, MAP1LC3B, TRAF6, GABARAPL2, GABARAPL1, GAST, BCAR3, EPB41, TNFRSF1A, HLA-B, NFKB2, MAP3K1, IKBKE, PRKAB1, RIPK3, CD74, NR4A1, cdsA, mtaD, ATXN2L, ABCF2 i MAPK3.^[17]

Reference

1. GRCh38: Ensembl release 89: ENSG00000084754 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025745 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit".
6. "UniProt, P40939" (jezik: engleski). Pristupljeno 12. 11. 2021.
7. 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 (Oct 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.
8. "hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Arhivirano s originala, 5. 3. 2016. Pristupljeno 13. 11. 2021.
9. Carpenter K, Pollitt RJ, Middleton B (Mar 1992). "Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria". Biochemical and Biophysical Research Communications. 183 (2): 443–8. doi:10.1016/0006-291x(92)90501-b. PMID 1550553.
10. Voet DJ, Voet JG, Pratt CW (2010). "Chapter 18, Mitochondrial ATP synthesis". Principles of Biochemistry (4th izd.). Wiley. str. 669. ISBN 978-0-470-23396-2.
11. IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ (august 1996). "Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene". The Journal of Clinical Investigation. 98 (4): 1028–33. doi:10.1172/jci118863. PMC 507519. PMID 8770876.
12. Rocchiccioli F, Wanders RJ, Aubourg P, Vianey-Liaud C, Ijlst L, Fabre M, Cartier N, Bougneres PF (decembar 1990). "Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood". Pediatric Research. 28 (6): 657–62. doi:10.1203/00006450-199012000-00023. PMID 2284166.
13. Rakheja D, Bennett MJ, Rogers BB (juli 2002). "Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review". Laboratory Investigation; A Journal of Technical Methods and Pathology. 82 (7): 815–24. doi:10.1097/01.lab.0000021175.50201.46. PMID 12118083.
14. Griffin AC, Strauss AW, Bennett MJ, Ernst LM (September–October 2012). "Mutations in long-chain 3-hydroxyacyl coenzyme a dehydrogenase are associated with placental maternal floor infarction/massive perivillous fibrin deposition". Pediatric and Developmental Pathology. 15 (5): 368–74. doi:10.2350/12-05-1198-oa.1. PMID 22746996. S2CID 38407420.
15. Ibdah JA, Yang Z, Bennett MJ (September–October 2000). "Liver disease in pregnancy and fetal fatty acid oxidation defects". Molecular Genetics and Metabolism. 71 (1–2): 182–9. doi:10.1006/mgme.2000.3065. PMID 11001809.
16. Kageyama T, Nagashio R, Ryuge S, Matsumoto T, Iyoda A, Satoh Y, Masuda N, Jiang SX, Saegusa M, Sato Y (2011). "HADHA is a potential predictor of response to platinum-based chemotherapy for lung cancer". Asian Pacific Journal of Cancer Prevention. 12 (12): 3457–63. PMID 22471497.
17. "142 binary interactions found for search term HADHA". IntAct Molecular Interaction Database. EMBL-EBI. Pristupljeno 25. 8. 2018.

Dopunska literatura

• Rakheja D, Bennett MJ, Rogers BB (Jul 2002). "Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review". Laboratory Investigation. 82 (7): 815–24. doi:10.1097/01.lab.0000021175.50201.46. PMID 12118083.
• Isaacs JD, Sims HF, Powell CK, Bennett MJ, Hale DE, Treem WR, Strauss AW (Sep 1996). "Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele". Pediatric Research. 40 (3): 393–8. doi:10.1203/00006450-199609000-00005. PMID 8865274.
• Gillingham MB, Matern D, Harding CO (Oct 2009). "Effect of feeding, exercise and genotype on plasma 3-hydroxyacylcarnitines in children with lchad deficiency". Topics in Clinical Nutrition. 24 (4): 359–365. doi:10.1097/TIN.0b013e3181c62182. PMC 2892921. PMID 20589231.
• Milewska M, McRedmond J, Byrne PC (Nov 2009). "Identification of novel spartin-interactors shows spartin is a multifunctional protein". Journal of Neurochemistry. 111 (4): 1022–30. doi:10.1111/j.1471-4159.2009.06382.x. PMID 19765186. S2CID 205621232.
• Weekes J, Morrison K, Mullen A, Wait R, Barton P, Dunn MJ (Feb 2003). "Hyperubiquitination of proteins in dilated cardiomyopathy". Proteomics. 3 (2): 208–16. doi:10.1002/pmic.200390029. PMID 12601813. S2CID 19874662.
• Bogenhagen DF, Rousseau D, Burke S (Feb 2008). "The layered structure of human mitochondrial DNA nucleoids". Journal of Biological Chemistry. 283 (6): 3665–75. doi:10.1074/jbc.M708444200. PMID 18063578.
• Zhang QX, Baldwin GS (Oct 1994). "Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1219 (2): 567–75. doi:10.1016/0167-4781(94)90091-4. PMID 7918661.
• IJlst L, Oostheim W, Ruiter JP, Wanders RJ (Jul 1997). "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations". Journal of Inherited Metabolic Disease. 20 (3): 420–2. doi:10.1023/A:1005310903004. PMID 9266371. S2CID 23046057.
• Yagi M, Lee T, Awano H, Tsuji M, Tajima G, Kobayashi H, Hasegawa Y, Yamaguchi S, Takeshima Y, Matsuo M (Dec 2011). "A patient with mitochondrial trifunctional protein deficiency due to the mutations in the HADHB gene showed recurrent myalgia since early childhood and was diagnosed in adolescence". Molecular Genetics and Metabolism. 104 (4): 556–9. doi:10.1016/j.ymgme.2011.09.025. PMID 22000755.

Vanjski linkovi

• PDBe-KB provides an overview of all the structure information available in the PDB for Human Trifunctional enzyme subunit alpha, mitochondrial (HADHA)

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

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