ACADVL

ACADVL
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2UXW, 3B96
Identifikatori
Aliasi	ACADVL
Vanjski ID-jevi	OMIM: 609575 MGI: 895149 HomoloGene: 5 GeneCards: ACADVL
Lokacija gena (čovjek)
Hrom.	Hromosom 17 (čovjek)
Kraj	7,225,266 bp
Lokacija gena (miš)
Hrom.	Hromosom 11 (miš)
Kraj	69,906,237 bp
Ontologija gena
Molekularna funkcija	• oxidoreductase activity, acting on the CH-CH group of donors; • acyl-CoA dehydrogenase activity; • oxidoreductase activity; • flavin adenine dinucleotide binding; • long-chain-acyl-CoA dehydrogenase activity; • fatty-acyl-CoA binding; • very-long-chain-acyl-CoA dehydrogenase activity;
Ćelijska komponenta	• membrana; • mitochondrial matrix; • Jedarce; • mitohondrija; • mitochondrial inner membrane; • mitochondrial nucleoid; • jedro; • citosol; • mitochondrial membranes;
Biološki proces	• epithelial cell differentiation; • negative regulation of fatty acid biosynthetic process; • lipid metabolism; • negative regulation of fatty acid oxidation; • energy derivation by oxidation of organic compounds; • fatty acid metabolic process; • regulation of cholesterol metabolic process; • IRE1-mediated unfolded protein response; • fatty acid beta-oxidation; • temperature homeostasis; • fatty acid catabolic process; • response to cold; • fatty acid beta-oxidation using acyl-CoA dehydrogenase;
	Izvori:Amigo / QuickGO
Ortolozi
	37
	11370
	ENSG00000072778
	ENSMUSG00000018574
	P49748
	P50544
	NM_000018; NM_001033859; NM_001270447; NM_001270448
	NM_017366
	NP_000009; NP_001029031; NP_001257376; NP_001257377
	NP_059062
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Mitohondrijska specifična acil-CoA dehidrogenaza vrlo dugog lanca (VLCAD) je enzim koji kod ljudi kodira genom ACADV.

Mutacije u ACADVL povezane su sa nedostatkom acil-koenzima A dehidrogenaze vrlo dugog lanca. Protein koji kodira ovaj gen usmjeren je na unutrašnju mitohondrijsku membranu, gdje katalizira prvi korak beta-oksidacijskog puta mitohondrijske masne kiseline. Ova acil-koenzim A dehidrogenaza specifična je za dugolančane i vrlo dugolančane masne kiseline. Nedostatak ovog genskog proizvoda smanjuje beta-oksidaciju masnih kiselina miokarda i povezan je sa kardiomiopatijom. Alternativna prerada rezultira u više varijanti transkripta koji kodiraju različite izoforme.^[5]

Struktura[uredi | uredi izvor]

Dužina polipeptidnog lanca je 655 aminokiselina, a molekulska težina 70.390 Da.^[6]

Aminokiselinska sekvenca

10	20	30	40	50
MQAARMAASL	GRQLLRLGGG	SSRLTALLGQ	PRPGPARRPY	AGGAAQLALD
KSDSHPSDAL	TRKKPAKAES	KSFAVGMFKG	QLTTDQVFPY	PSVLNEEQTQ
FLKELVEPVS	RFFEEVNDPA	KNDALEMVEE	TTWQGLKELG	AFGLQVPSEL
GGVGLCNTQY	ARLVEIVGMH	DLGVGITLGA	HQSIGFKGIL	LFGTKAQKEK
YLPKLASGET	VAAFCLTEPS	SGSDAASIRT	SAVPSPCGKY	YTLNGSKLWI
SNGGLADIFT	VFAKTPVTDP	ATGAVKEKIT	AFVVERGFGG	ITHGPPEKKM
GIKASNTAEV	FFDGVRVPSE	NVLGEVGSGF	KVAMHILNNG	RFGMAAALAG
TMRGIIAKAV	DHATNRTQFG	EKIHNFGLIQ	EKLARMVMLQ	YVTESMAYMV
SANMDQGATD	FQIEAAISKI	FGSEAAWKVT	DECIQIMGGM	GFMKEPGVER
VLRDLRIFRI	FEGTNDILRL	FVALQGCMDK	GKELSGLGSA	LKNPFGNAGL
LLGEAGKQLR	RRAGLGSGLS	LSGLVHPELS	RSGELAVRAL	EQFATVVEAK
LIKHKKGIVN	EQFLLQRLAD	GAIDLYAMVV	VLSRASRSLS	EGHPTAQHEK
MLCDTWCIEA	AARIREGMAA	LQSDPWQQEL	YRNFKSISKA	LVERGGVVTS
NPLGF

Simboli

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

Gen ACADVL sadrži 20 egzona,^[7] i dug je oko 5,4 kb.^[8] VLCAD ima zanimljivu gensku strukturu kod ljudi, koja se nalazi u strukturi glave do glave sa genom DLG4 na hromosomu 17, i da se transkribirani regioni ovih gena preklapaju. Pokazano je da tretman sa DEHP rezultira regulacijom minimalnim promotorom.^[9] While DLG4 and VLCAD share common regulatory elements, they each have separate and distinct tissue-specific elements that confer their function. In mice, these two genes are in a head-to-head orientation, but they do not overlap.^[8]

Funkcija[uredi | uredi izvor]

VLCAD enzim katalizira većinu beta-oksidacije masnih kiselina, stvarajući C2-C3 trans-dvostruku vezu u masnoj kiselini. Specifičan je za masne kiseline vrlo dugog lanca, obično C16-acylCoA i duže.^[10] Miševi koji imaju nedostatak VLCAD, imaju malo ili nimalo hiperacetilacije proteina u jetri; to implicira da je protein VLCAD također neophodan za acetilaciju proteina u ovom biološkom sistemu.^[11]

Klinički značaj[uredi | uredi izvor]

ACADVL je povezan sa nedostatakom acil-koenzima dugolančane A dehidrogenaze (VLCADD), koji ima mnogo simptoma, i obično se ispoljava kao jedan od tri fenotipa. Prvi je težak, sa ranim djetinjstvenom i visokom stopom smrtnosti; najčešći simptom ovog oblika je kardiomiopatija. Drugi je sa kasnim početkom dječjeg oblika, s blažim simptomima koji se najčešće javljaju kao hipoketonska hipoglikemija. Konačni oblik se pojavljuje u odrasloj dobi i uljučuje izolirano zahvatanje skeletnih mišića, rabdomiolizu i mioglobinuriju, što je izazvano vježbanjem ili postom.^[12] Bolest se obično dijagnosticira tako što se prvo izvrši tandemska masena spektrometrija na uzorku krvi pacijenta tokom perioda stresa, a zatim se izvrši molekulskoo genetičko testiranje na prisustvo gena ACADVL. Nedostatak se sistematski liječi, ali se izbjegavaju određena stanja kao što su post, iritacija miokarda, dehidracija i dijeta s visokim udjelom masti, u pokušaju sprječavanja sekundarnih komplikacija.^[13]

Interakcije[uredi | uredi izvor]

Pokazalo se da ACADVL ima 75 binarnih interakcije protein-protein, uključujući 73 kompleksne interakcije. Čini se da ACADVL komunicira sa RPSA i GPHN.^[14]

Također pogledajte[uredi | uredi izvor]

Acil CoA dehidrogenaza

Reference[uredi | uredi izvor]

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000072778 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000018574 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "acyl-CoA dehydrogenase, very long chain".
^ "UniProt, P49748". Pristupljeno 16. 6. 2021.
^ Strauss AW, Powell CK, Hale DE, Anderson MM, Ahuja A, Brackett JC, Sims HF (Nov 1995). "Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood". Proceedings of the National Academy of Sciences of the United States of America. 92 (23): 10496–500. doi:10.1073/pnas.92.23.10496. PMC 40638. PMID 7479827.
^ ^a ^b Zhou C, Blumberg B (Feb 2003). "Overlapping gene structure of human VLCAD and DLG4". Gene. 305 (2): 161–6. doi:10.1016/s0378-1119(02)01235-0. PMID 12609736.
^ Zhang LF, Ding JH, Yang BZ, He GC, Roe C (Dec 2003). "Characterization of the bidirectional promoter region between the human genes encoding VLCAD and PSD-95". Genomics. 82 (6): 660–8. doi:10.1016/s0888-7543(03)00211-8. PMID 14611808.
^ Aoyama T, Souri M, Ushikubo S, Kamijo T, Yamaguchi S, Kelley RI, Rhead WJ, Uetake K, Tanaka K, Hashimoto T (Jun 1995). "Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients". The Journal of Clinical Investigation. 95 (6): 2465–73. doi:10.1172/JCI117947. PMC 295925. PMID 7769092.
^ Pougovkina O, te Brinke H, Ofman R, van Cruchten AG, Kulik W, Wanders RJ, Houten SM, de Boer VC (Jul 2014). "Mitochondrial protein acetylation is driven by acetyl-CoA from fatty acid oxidation". Human Molecular Genetics. 23 (13): 3513–22. doi:10.1093/hmg/ddu059. PMID 24516071.
^ Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N (Feb 1999). "Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency". American Journal of Human Genetics. 64 (2): 479–94. doi:10.1086/302261. PMC 1377757. PMID 9973285.
^ Leslie, N. D.; Valencia, C. A.; Strauss, A. W.; Zhang, K.; Adam, M. P.; Ardinger, H. H.; Pagon, R. A.; Wallace, S. E.; Bean LJH; Stephens, K.; Amemiya, A. (1993). "Very Long-Chain Acyl-Coenzyme a Dehydrogenase Deficiency". PMID 20301763. journal zahtijeva |journal= (pomoć)
^ "75 binary interactions found for search term ACADVL". IntAct Molecular Interaction Database. EMBL-EBI. Pristupljeno 24. 8. 2018.

Dopunska literatura[uredi | uredi izvor]

Costa CG, Dorland L, de Almeida IT, Jakobs C, Duran M, Poll-The BT (juni 1998). "The effect of fasting, long-chain triglyceride load and carnitine load on plasma long-chain acylcarnitine levels in mitochondrial very long-chain acyl-CoA dehydrogenase deficiency". Journal of Inherited Metabolic Disease. 21 (4): 391–9. doi:10.1023/A:1005354624735. PMID 9700596. S2CID 2198523.

Vanjski linkovi[uredi | uredi izvor]

GeneReviews/NCBI/NIH/UW entry on Very long-chain acyl-coenzyme A dehydrogenase deficiency
Lokacija ljudskog genoma ACADVL i stranica sa detaljima o genu ACADVL u UCSC Genome Browseru.

Šablon:Enzimi lipidnog metabolizma

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000072778 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000018574 - 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.

[entrez-5] "acyl-CoA dehydrogenase, very long chain".

[UniProt-6] "UniProt, P49748". Pristupljeno 16. 6. 2021.

[7] Strauss AW, Powell CK, Hale DE, Anderson MM, Ahuja A, Brackett JC, Sims HF (Nov 1995). "Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood". Proceedings of the National Academy of Sciences of the United States of America. 92 (23): 10496–500. doi:10.1073/pnas.92.23.10496. PMC 40638. PMID 7479827.

[Zhou_2003-8] Zhou C, Blumberg B (Feb 2003). "Overlapping gene structure of human VLCAD and DLG4". Gene. 305 (2): 161–6. doi:10.1016/s0378-1119(02)01235-0. PMID 12609736.

[9] Zhang LF, Ding JH, Yang BZ, He GC, Roe C (Dec 2003). "Characterization of the bidirectional promoter region between the human genes encoding VLCAD and PSD-95". Genomics. 82 (6): 660–8. doi:10.1016/s0888-7543(03)00211-8. PMID 14611808.

[10] Aoyama T, Souri M, Ushikubo S, Kamijo T, Yamaguchi S, Kelley RI, Rhead WJ, Uetake K, Tanaka K, Hashimoto T (Jun 1995). "Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients". The Journal of Clinical Investigation. 95 (6): 2465–73. doi:10.1172/JCI117947. PMC 295925. PMID 7769092.

[11] Pougovkina O, te Brinke H, Ofman R, van Cruchten AG, Kulik W, Wanders RJ, Houten SM, de Boer VC (Jul 2014). "Mitochondrial protein acetylation is driven by acetyl-CoA from fatty acid oxidation". Human Molecular Genetics. 23 (13): 3513–22. doi:10.1093/hmg/ddu059. PMID 24516071.

[12] Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N (Feb 1999). "Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency". American Journal of Human Genetics. 64 (2): 479–94. doi:10.1086/302261. PMC 1377757. PMID 9973285.

[13] Leslie, N. D.; Valencia, C. A.; Strauss, A. W.; Zhang, K.; Adam, M. P.; Ardinger, H. H.; Pagon, R. A.; Wallace, S. E.; Bean LJH; Stephens, K.; Amemiya, A. (1993). "Very Long-Chain Acyl-Coenzyme a Dehydrogenase Deficiency". PMID 20301763. journal zahtijeva |journal= (pomoć)

[14] "75 binary interactions found for search term ACADVL". IntAct Molecular Interaction Database. EMBL-EBI. Pristupljeno 24. 8. 2018.

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