ACADM

ACADM
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1EGC, 1EGD, 1EGE, 1T9G, 2A1T, 4P13
Identifikatori
Aliasi	ACADM
Vanjski ID-jevi	OMIM: 607008 MGI: 87867 HomoloGene: 3 GeneCards: ACADM
Lokacija gena (čovjek)
Hrom.	Hromosom 1 (čovjek)
Kraj	75,787,575 bp
Lokacija gena (miš)
Hrom.	Hromosom 3 (miš)
Kraj	153,650,269 bp
Ontologija gena
Molekularna funkcija	• oxidoreductase activity, acting on the CH-CH group of donors; • acyl-CoA dehydrogenase activity; • vezivanje identičnih proteina; • oxidoreductase activity; • medium-chain-acyl-CoA dehydrogenase activity; • flavin adenine dinucleotide binding;
Ćelijska komponenta	• Akson; • mitohondrija; • Egzosom; • jedro; • nuclear speck; • mitochondrial matrix; • mitochondrial membranes;
Biološki proces	• medium-chain fatty acid metabolic process; • lipid metabolism; • fatty acid beta-oxidation using acyl-CoA dehydrogenase; • fatty acid metabolic process; • metabolizam; • carnitine biosynthetic process; • medium-chain fatty acid catabolic process; • carnitine metabolic process, CoA-linked; • fatty acid beta-oxidation; • regulation of lipid metabolic process;
	Izvori:Amigo / QuickGO
Ortolozi
	34
	11364
	ENSG00000117054
	ENSMUSG00000062908
	P11310
	P45952
	NM_000016; NM_001127328; NM_001286042; NM_001286043; NM_001286044
	NM_007382
	NP_000007; NP_001120800; NP_001272971; NP_001272972; NP_001272973
	NP_031408
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

ACADM (C-4 to C-12 ravnolančana acil-koenzim A dehidrogenaza) jest gen koji se kod ljudi nalazi na hromosomu 1. Daje uputstva za stvaranje enzima acil-koenzim A dehidrogenaza koji je važan za razgradnju (razlaganje) određene grupe masti koje se nazivaju srednjelančane masne kiseline.

Ove masne kiseline nalaze se u hrani kao što su mlijeko i određena ulja, a također se skladište u masnom tkivu tijela. Također nastaju kada se veće masne kiseline razgrađuju.

Enzim acil-koenzim A dehidrogenaza za srednjelančane masne kiseline (ACADM) je neophodan za pretvaranje ovih posebnih masnih kiselina u energiju, posebno tokom perioda bez hrane (post). ACADM enzim funkcionira u mitohondrijama, centrima za proizvodnju energije unutar ćelija. Nalazi se u mitohondrijma nekoliko tipova tkiva, posebno u jetri.

ACADM gen se nalazi na kratkom (p) kraku hromosoma 1 na poziciji 31, od baznog para 75,902.302 do baznog para 75,941.203.

Amiokiselininska sekvenca

Dužina polipeptidnog lanca je 421 aminokiselina, a molekulska težina 46.588 Da.^[5]

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
MAAGFGRCCR	VLRSISRFHW	RSQHTKANRQ	REPGLGFSFE	FTEQQKEFQA
TARKFAREEI	IPVAAEYDKT	GEYPVPLIRR	AWELGLMNTH	IPENCGGLGL
GTFDACLISE	ELAYGCTGVQ	TAIEGNSLGQ	MPIIIAGNDQ	QKKKYLGRMT
EEPLMCAYCV	TEPGAGSDVA	GIKTKAEKKG	DEYIINGQKM	WITNGGKANW
YFLLARSDPD	PKAPANKAFT	GFIVEADTPG	IQIGRKELNM	GQRCSDTRGI
VFEDVKVPKE	NVLIGDGAGF	KVAMGAFDKT	RPVVAAGAVG	LAQRALDEAT
KYALERKTFG	KLLVEHQAIS	FMLAEMAMKV	ELARMSYQRA	AWEVDSGRRN
TYYASIAKAF	AGDIANQLAT	DAVQILGGNG	FNTEYPVEKL	MRDAKIYQIY
EGTSQIQRLI	VAREHIDKYK	N

Struktura

Protein kodiran genom ACADM veličine je ~47 kDa i sastoji se od 421 aminokiseline.^[6]

Funkcija

Enzim LCAD katalizuje većinu beta-oksidacije masnih kiselina formiranjem C2-C3 trans-dvostruke veze u masnoj kiselini. MCAD djelije na dugolančane masne kiseline, obično između C4 i C12-acylCoA.^[7] Dokazano je da oksidacija masnih kiselina štedi glukozu u uvjetima natašte, a potrebna je i za metabolizam aminokiselina, što je neophodno za održavanje adekvatne proizvodnje glukoze.^[8] Nadalje, MCAD učestvuje u metabolizmu masnih kiselina i PPAR signalnom putu.^[9]

Klinički značaj

Nedostatak srednjelančane acil-koenzim A dehidrogenaze može biti uzrokovan mutacijom u ACADM genu. Identificirano je više od 54 ACADM genske mutacije koje uzrokuju nedostatak srednjelančane acil-koenzima A dehidrogenaze.^[10] Mnoge od ovih mutacija mijenjaju gradivni blok aminokiselina u ACADM enzimu. Najčešća aminokiselinskih supstitucija zamjenjuje lizin sa glutaminskom kiselinom na poziciji 329 u lancu aminokiselina enzima (također napisano i kao Lys329Glu ili K329E) .^[11] Ova mutacija i druge zamjene aminokiselina mijenjaju strukturu enzima, smanjujući ili ukidajući njegovu aktivnost. Druge mutacije deletiraju ili dupliciraju dio ACADM gena, što dovodi do nestabilnog enzima koji ne može funkcionirati.

Uz nedostatak funkcionalnog ACADM enzima, srednjelančane masne kiseline se ne mogu razgraditi i preraditi. Kao rezultat toga, ove masti se ne pretvaraju u energiju, što može dovesti do karakterističnih simptoma ovog poremećaja, kao što su nedostatak energije (letargija) i nizak šećer u krvi. Nivoi srednjelančanih masnih kiselina ili djelomično razgrađenih masnih kiselina mogu se nakupiti u tkivima i oštetiti jetru i mozak, uzrokujući ozbiljnije komplikacije.^[12]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000117054 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000062908 - 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.
^ "UniProt, P11310" (jezik: engleski). Pristupljeno 21. 11. 2021.
^ "ACADM – Medium-chain specific acyl-CoA dehydrogenase, mitochondrial precursor – Homo sapiens (Human) – ACADM gene & protein". www.uniprot.org.
^ Matsubara Y, Kraus JP, Yang-Feng TL, Francke U, Rosenberg LE, Tanaka K (Sep 1986). "Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1". Proceedings of the National Academy of Sciences of the United States of America. 83 (17): 6543–7. Bibcode:1986PNAS...83.6543M. doi:10.1073/pnas.83.17.6543. PMC 386540. PMID 3462713.
^ Goetzman ES, Alcorn JF, Bharathi SS, Uppala R, McHugh KJ, Kosmider B, Chen R, Zuo YY, Beck ME, McKinney RW, Skilling H, Suhrie KR, Karunanidhi A, Yeasted R, Otsubo C, Ellis B, Tyurina YY, Kagan VE, Mallampalli RK, Vockley J (Apr 2014). "Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction". The Journal of Biological Chemistry. 289 (15): 10668–79. doi:10.1074/jbc.M113.540260. PMC 4036448. PMID 24591516.
^ Ezzeddini R, Taghikhani M, Salek Farrokhi A, Somi MH, Samadi N, Esfahani A, Rasaee, MJ (maj 2021). "Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and its related clinical significance". Journal of Physiology and Biochemistry. 77 (2): 249–260. doi:10.1007/s13105-021-00791-3. PMID 33730333.
^ Pagon RA, Bird TD, Dolan CR, et al. (1993). "Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency". PMID 20301597. journal zahtijeva |journal= (pomoć)
^ Gregersen N, Andresen BS, Bross P, Winter V, Rüdiger N, Engst S, Christensen E, Kelly D, Strauss AW, Kølvraa S (Apr 1991). "Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329 to glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli" (PDF). Human Genetics. 86 (6): 545–51. doi:10.1007/bf00201539. PMID 1902818. S2CID 9687627.
^ Sturm M, Herebian D, Mueller M, Laryea MD, Spiekerkoetter U (2012). "Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants". PLOS ONE. 7 (9): e45110. Bibcode:2012PLoSO...745110S. doi:10.1371/journal.pone.0045110. PMC 3444485. PMID 23028790.

Dopunska literatura

Gregersen N, Andresen BS, Corydon MJ, Corydon TJ, Olsen RK, Bolund L, Bross P (Sep 2001). "Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship". Human Mutation. 18 (3): 169–89. doi:10.1002/humu.1174. PMID 11524729. S2CID 22616789.
Wang SS, Fernhoff PM, Hannon WH, Khoury MJ (1999). "Medium chain acyl-CoA dehydrogenase deficiency human genome epidemiology review". Genetics in Medicine. 1 (7): 332–9. doi:10.1097/00125817-199911000-00004. PMID 11263545.

Vanjski linkovi

GeneReviews/NIH/NCBI/UW entry on Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency
GeneCard
ACADM at The GDB Human Genome Database
Lokacija ljudskog genoma ACADM i stranica sa detaljima o genu ACADM u UCSC Genome Browseru.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000117054 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000062908 - 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.

[UniProt-5] "UniProt, P11310" (jezik: engleski). Pristupljeno 21. 11. 2021.

[6] "ACADM – Medium-chain specific acyl-CoA dehydrogenase, mitochondrial precursor – Homo sapiens (Human) – ACADM gene & protein". www.uniprot.org.

[7] Matsubara Y, Kraus JP, Yang-Feng TL, Francke U, Rosenberg LE, Tanaka K (Sep 1986). "Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1". Proceedings of the National Academy of Sciences of the United States of America. 83 (17): 6543–7. Bibcode:1986PNAS...83.6543M. doi:10.1073/pnas.83.17.6543. PMC 386540. PMID 3462713.

[8] Goetzman ES, Alcorn JF, Bharathi SS, Uppala R, McHugh KJ, Kosmider B, Chen R, Zuo YY, Beck ME, McKinney RW, Skilling H, Suhrie KR, Karunanidhi A, Yeasted R, Otsubo C, Ellis B, Tyurina YY, Kagan VE, Mallampalli RK, Vockley J (Apr 2014). "Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction". The Journal of Biological Chemistry. 289 (15): 10668–79. doi:10.1074/jbc.M113.540260. PMC 4036448. PMID 24591516.

[9] Ezzeddini R, Taghikhani M, Salek Farrokhi A, Somi MH, Samadi N, Esfahani A, Rasaee, MJ (maj 2021). "Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and its related clinical significance". Journal of Physiology and Biochemistry. 77 (2): 249–260. doi:10.1007/s13105-021-00791-3. PMID 33730333.

[10] Pagon RA, Bird TD, Dolan CR, et al. (1993). "Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency". PMID 20301597. journal zahtijeva |journal= (pomoć)

[11] Gregersen N, Andresen BS, Bross P, Winter V, Rüdiger N, Engst S, Christensen E, Kelly D, Strauss AW, Kølvraa S (Apr 1991). "Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329 to glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli" (PDF). Human Genetics. 86 (6): 545–51. doi:10.1007/bf00201539. PMID 1902818. S2CID 9687627.

[12] Sturm M, Herebian D, Mueller M, Laryea MD, Spiekerkoetter U (2012). "Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants". PLOS ONE. 7 (9): e45110. Bibcode:2012PLoSO...745110S. doi:10.1371/journal.pone.0045110. PMC 3444485. PMID 23028790.

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