ASAH1

ASAH1
Identifikatori
Aliasi	ASAH1
Vanjski ID-jevi	OMIM: 613468 MGI: 1277124 HomoloGene: 10504 GeneCards: ASAH1
Lokacija gena (čovjek)
Hrom.	Hromosom 8 (čovjek)
Kraj	18,084,998 bp
Lokacija gena (miš)
Hrom.	Hromosom 8 (miš)
Kraj	41,827,810 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• N-acylsphingosine amidohydrolase activity; • catalytic activity; • hydrolase activity; • hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds; • ceramidase activity; • hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides;
Ćelijska komponenta	• Lizozom; • lysosomal lumen; • Egzosom; • extracellular region; • Vanćelijsko; • tertiary granule lumen; • ficolin-1-rich granule lumen; • early endosome; • Endoplazmatski retikulum; • jedro; • citoplazma;
Biološki proces	• glycosphingolipid metabolic process; • ceramide metabolic process; • lipid metabolism; • neutrophil degranulation; • sphingosine biosynthetic process; • ceramide biosynthetic process; • ceramide catabolic process; • keratinocyte differentiation; • regulation of steroid biosynthetic process; • regulation of programmed necrotic cell death; • cellular response to tumor necrosis factor; • sphingolipid metabolic process;
	Izvori:Amigo / QuickGO
Ortolozi
	427
	11886
	ENSG00000104763
	ENSMUSG00000031591
	Q13510
	Q9WV54
	NM_001127505; NM_004315; NM_177924; NM_001363743
	NM_019734
	NP_001120977; NP_004306; NP_808592; NP_001350672
	NP_062708
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Gen ASAH1 kod ljudi kodira enzim kiselu keramidazu.^[5]^[6]^[7]

Aminokiselinska sekvenca[uredi | uredi izvor]

Dužina polipeptidnog lanca je 395 aminokiselina, а molekulska težina 44.660 Da.^[8]

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
MPGRSCVALV	LLAAAVSCAV	AQHAPPWTED	CRKSTYPPSG	PTYRGAVPWY
TINLDLPPYK	RWHELMLDKA	PVLKVIVNSL	KNMINTFVPS	GKIMQVVDEK
LPGLLGNFPG	PFEEEMKGIA	AVTDIPLGEI	ISFNIFYELF	TICTSIVAED
KKGHLIHGRN	MDFGVFLGWN	INNDTWVITE	QLKPLTVNLD	FQRNNKTVFK
ASSFAGYVGM	LTGFKPGLFS	LTLNERFSIN	GGYLGILEWI	LGKKDVMWIG
FLTRTVLENS	TSYEEAKNLL	TKTKILAPAY	FILGGNQSGE	GCVITRDRKE
SLDVYELDAK	QGRWYVVQTN	YDRWKHPFFL	DDRRTPAKMC	LNRTSQENIS
FETMYDVLST	KPVLNKLTVY	TTLIDVTKGQ	FETYLRDCPD	PCIGW

Funkcija[uredi | uredi izvor]

Ovaj gen kodira protein heterodimerni protein koji se sastoji od neglikozilirane podjedinice alfa i glikozilirane podjedinice beta koja se posttranslacijski cijepa na zreli enzim. Kodirani protein katalizira sintezu i razgradnju keramida u sfingozin i masnu kiselinu. Mutacije u ovom genu povezane su s poremećajem lizosomnog skladištenja, poznatim kao Farberova bolest, a odnedavno i s rijetkim neurodegenerativnim stanjem poznatim kao spinalna mišićna atrofija s progresivnom mioklonskom epilepsijom.^[9] Two transcript variants encoding distinct isoforms have been identified for this gene.^[7] U melanocitnim ćelijama ekspresija ASAH1 gena može se regulirati MITF-om.^[10]

Kao cilj lijeka za glioblastom[uredi | uredi izvor]

Ekspresija ASAH1 je pojačano regulirana nakon zračenja, što sugerira da ima ulogu u davanju radiootpornosti na glioblastom i u razvoju rekurentnog glioblastoma.^[11] Inhibicija aktivnosti ASAH1 s carmofurom, lijekom koji je odobren za kliničko liječenje kolorektumskog karcinoma u nekoliko zemalja, dovodi do značajne smrti ćelija i kao rezultat toga je predložena kao meta lijeka u liječenje glioblastoma.^[12] Također je predloženo da bude nova meta lijekova i za dječje tumore mozga.^[13]

Reference[uredi | uredi izvor]

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000104763 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000031591 - 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.
^ Koch J, Gärtner S, Li CM, Quintern LE, Bernardo K, Levran O, Schnabel D, Desnick RJ, Schuchman EH, Sandhoff K (decembar 1996). "Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. Identification Of the first molecular lesion causing Farber disease". The Journal of Biological Chemistry. 271 (51): 33110–5. doi:10.1074/jbc.271.51.33110. PMID 8955159.
^ Li CM, Park JH, He X, Levy B, Chen F, Arai K, Adler DA, Disteche CM, Koch J, Sandhoff K, Schuchman EH (decembar 1999). "The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression". Genomics. 62 (2): 223–31. doi:10.1006/geno.1999.5940. PMID 10610716.
^ ^a ^b "Entrez Gene: ASAH1 N-acylsphingosine amidohydrolase (acid ceramidase) 1".
^ "UniProt, Q13510". Pristupljeno 13. 9. 2021.
^ Zhou J, Tawk M, Tiziano FD, Veillet J, Bayes M, Nolent F, Garcia V, Servidei S, Bertini E, Castro-Giner F, Renda Y, Carpentier S, Andrieu-Abadie N, Gut I, Levade T, Topaloglu H, Melki J (juli 2012). "Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1". American Journal of Human Genetics. 91 (1): 5–14. doi:10.1016/j.ajhg.2012.05.001. PMC 3397266. PMID 22703880.
^ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (decembar 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. S2CID 24698373.
^ Doan NB, Nguyen HS, Al-Gizawiy MM, Mueller WM, Sabbadini RA, Rand SD, Connelly JM, Chitambar CR, Schmainda KM, Mirza SP (oktobar 2017). "Acid ceramidase confers radioresistance to glioblastoma cells". Oncology Reports. 38 (4): 1932–40. doi:10.3892/or.2017.5855. PMC 5652937. PMID 28765947.
^ Doan NB, Alhajala H, Al-Gizawiy MM, Mueller WM, Rand SD, Connelly JM, Cochran EJ, Chitambar CR, Clark P, Kuo J, Schmainda KM, Mirza SP (decembar 2017). "Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency". Oncotarget. 8 (68): 112662–74. doi:10.18632/oncotarget.22637. PMC 5762539. PMID 29348854.
^ Doan NB, Nguyen HS, Montoure A, Al-Gizawiy MM, Mueller WM, Kurpad S, Rand SD, Connelly JM, Chitambar CR, Schmainda KM, Mirza SP (april 2017). "Acid ceramidase is a novel drug target for pediatric brain tumors". Oncotarget. 8 (15): 24753–61. doi:10.18632/oncotarget.15800. PMC 5421885. PMID 28445970.

Dopunska literatura[uredi | uredi izvor]

Perry DK, Hannun YA (decembar 1998). "The role of ceramide in cell signaling". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1436 (1–2): 233–43. doi:10.1016/S0005-2760(98)00145-3. PMID 9838138.
Bernardo K, Hurwitz R, Zenk T, Desnick RJ, Ferlinz K, Schuchman EH, Sandhoff K (maj 1995). "Purification, characterization, and biosynthesis of human acid ceramidase". The Journal of Biological Chemistry. 270 (19): 11098–102. doi:10.1074/jbc.270.19.11098. PMID 7744740.
Maruyama K, Sugano S (januar 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (oktobar 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
Seelan RS, Qian C, Yokomizo A, Bostwick DG, Smith DI, Liu W (oktobar 2000). "Human acid ceramidase is overexpressed but not mutated in prostate cancer". Genes, Chromosomes & Cancer. 29 (2): 137–46. doi:10.1002/1098-2264(2000)9999:9999<::AID-GCC1018>3.0.CO;2-E. PMID 10959093.
Strelow A, Bernardo K, Adam-Klages S, Linke T, Sandhoff K, Krönke M, Adam D (septembar 2000). "Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death". The Journal of Experimental Medicine. 192 (5): 601–12. doi:10.1084/jem.192.5.601. PMC 2193270. PMID 10974027.
Bär J, Linke T, Ferlinz K, Neumann U, Schuchman EH, Sandhoff K (mart 2001). "Molecular analysis of acid ceramidase deficiency in patients with Farber disease". Human Mutation. 17 (3): 199–209. doi:10.1002/humu.5. PMID 11241842. S2CID 39656479.
Ferlinz K, Kopal G, Bernardo K, Linke T, Bar J, Breiden B, Neumann U, Lang F, Schuchman EH, Sandhoff K (septembar 2001). "Human acid ceramidase: processing, glycosylation, and lysosomal targeting". The Journal of Biological Chemistry. 276 (38): 35352–60. doi:10.1074/jbc.M103066200. PMID 11451951.
Muramatsu T, Sakai N, Yanagihara I, Yamada M, Nishigaki T, Kokubu C, Tsukamoto H, Ito M, Inui K (novembar 2002). "Mutation analysis of the acid ceramidase gene in Japanese patients with Farber disease". Journal of Inherited Metabolic Disease. 25 (7): 585–92. doi:10.1023/A:1022047408477. PMID 12638942. S2CID 26208268.
Zhang H, Li XJ, Martin DB, Aebersold R (juni 2003). "Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry". Nature Biotechnology. 21 (6): 660–6. doi:10.1038/nbt827. PMID 12754519. S2CID 581283.
Okino N, He X, Gatt S, Sandhoff K, Ito M, Schuchman EH (august 2003). "The reverse activity of human acid ceramidase". The Journal of Biological Chemistry. 278 (32): 29948–53. doi:10.1074/jbc.M303310200. PMID 12764132.
He X, Okino N, Dhami R, Dagan A, Gatt S, Schulze H, Sandhoff K, Schuchman EH (august 2003). "Purification and characterization of recombinant, human acid ceramidase. Catalytic reactions and interactions with acid sphingomyelinase". The Journal of Biological Chemistry. 278 (35): 32978–86. doi:10.1074/jbc.M301936200. PMID 12815059.
Hara S, Nakashima S, Kiyono T, Sawada M, Yoshimura S, Iwama T, Banno Y, Shinoda J, Sakai N (august 2004). "p53-Independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis". Cell Death and Differentiation. 11 (8): 853–61. doi:10.1038/sj.cdd.4401428. PMID 15088070.
Lewandrowski U, Moebius J, Walter U, Sickmann A (februar 2006). "Elucidation of N-glycosylation sites on human platelet proteins: a glycoproteomic approach". Molecular & Cellular Proteomics. 5 (2): 226–33. doi:10.1074/mcp.M500324-MCP200. PMID 16263699.

Vanjski linkovi[uredi | uredi izvor]

Lokacija ljudskog genoma ASAH1 i stranica sa detaljima o genu ASAH1 u UCSC Genome Browseru.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000104763 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000031591 - 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.

[pmid8955159-5] Koch J, Gärtner S, Li CM, Quintern LE, Bernardo K, Levran O, Schnabel D, Desnick RJ, Schuchman EH, Sandhoff K (decembar 1996). "Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. Identification Of the first molecular lesion causing Farber disease". The Journal of Biological Chemistry. 271 (51): 33110–5. doi:10.1074/jbc.271.51.33110. PMID 8955159.

[pmid10610716-6] Li CM, Park JH, He X, Levy B, Chen F, Arai K, Adler DA, Disteche CM, Koch J, Sandhoff K, Schuchman EH (decembar 1999). "The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression". Genomics. 62 (2): 223–31. doi:10.1006/geno.1999.5940. PMID 10610716.

[entrez-7] "Entrez Gene: ASAH1 N-acylsphingosine amidohydrolase (acid ceramidase) 1".

[UniProt-8] "UniProt, Q13510". Pristupljeno 13. 9. 2021.

[9] Zhou J, Tawk M, Tiziano FD, Veillet J, Bayes M, Nolent F, Garcia V, Servidei S, Bertini E, Castro-Giner F, Renda Y, Carpentier S, Andrieu-Abadie N, Gut I, Levade T, Topaloglu H, Melki J (juli 2012). "Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1". American Journal of Human Genetics. 91 (1): 5–14. doi:10.1016/j.ajhg.2012.05.001. PMC 3397266. PMID 22703880.

[pmid19067971-10] Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (decembar 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. S2CID 24698373.

[11] Doan NB, Nguyen HS, Al-Gizawiy MM, Mueller WM, Sabbadini RA, Rand SD, Connelly JM, Chitambar CR, Schmainda KM, Mirza SP (oktobar 2017). "Acid ceramidase confers radioresistance to glioblastoma cells". Oncology Reports. 38 (4): 1932–40. doi:10.3892/or.2017.5855. PMC 5652937. PMID 28765947.

[12] Doan NB, Alhajala H, Al-Gizawiy MM, Mueller WM, Rand SD, Connelly JM, Cochran EJ, Chitambar CR, Clark P, Kuo J, Schmainda KM, Mirza SP (decembar 2017). "Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency". Oncotarget. 8 (68): 112662–74. doi:10.18632/oncotarget.22637. PMC 5762539. PMID 29348854.

[13] Doan NB, Nguyen HS, Montoure A, Al-Gizawiy MM, Mueller WM, Kurpad S, Rand SD, Connelly JM, Chitambar CR, Schmainda KM, Mirza SP (april 2017). "Acid ceramidase is a novel drug target for pediatric brain tumors". Oncotarget. 8 (15): 24753–61. doi:10.18632/oncotarget.15800. PMC 5421885. PMID 28445970.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]