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25  structures 445  species 0  interactions 900  sequences 15  architectures

Family: NAAA-beta (PF15508)

Summary: beta subunit of N-acylethanolamine-hydrolyzing acid amidase

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "ASAH1". More...

ASAH1 Edit Wikipedia article

ASAH1
Identifiers
AliasesASAH1, AC, ACDase, ASAH, PHP, PHP32, SMAPME, N-acylsphingosine amidohydrolase (acid ceramidase) 1, N-acylsphingosine amidohydrolase 1
External IDsOMIM: 613468 MGI: 1277124 HomoloGene: 10504 GeneCards: ASAH1
Gene location (Human)
Chromosome 8 (human)
Chr.Chromosome 8 (human)[1]
Chromosome 8 (human)
Genomic location for ASAH1
Genomic location for ASAH1
Band8p22Start18,055,992 bp[1]
End18,084,998 bp[1]
RNA expression pattern
PBB GE ASAH1 210980 s at fs.png

PBB GE ASAH1 213702 x at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001127505
NM_004315
NM_177924
NM_001363743

NM_019734

RefSeq (protein)

NP_001120977
NP_004306
NP_808592
NP_001350672

NP_062708

Location (UCSC)Chr 8: 18.06 – 18.08 MbChr 8: 41.34 – 41.37 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The ASAH1 gene encodes in humans the acid ceramidase enzyme.[5][6][7]

Function

This gene encodes a heterodimeric protein consisting of a nonglycosylated alpha subunit and a glycosylated beta subunit that is cleaved to the mature enzyme posttranslationally. The encoded protein catalyzes the synthesis and degradation of ceramide into sphingosine and fatty acid. Mutations in this gene have been associated with a lysosomal storage disorder known as Farber disease and, recently, with a rare neurodegenerative condition known as spinal muscular atrophy with progressive myoclonic epilepsy.[8] Two transcript variants encoding distinct isoforms have been identified for this gene.[7] In melanocytic cells ASAH1 gene expression may be regulated by MITF.[9]

As a glioblastoma drug target

ASAH1 expression is upregulated following radiation, suggesting it plays a role in conferring radioresistance to glioblastoma and in the development of recurrent glioblastoma.[10] Inhibiting the activity of ASAH1 with carmofur, a drug that has been approved for clinical treatment of colorectal cancers in several countries, leads to substantial cell deaths and as a result has been proposed as a drug target in the treatment of glioblastoma.[11] It has also been suggested to be a novel drug target against pediatric brain tumors as well.[12]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104763 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031591 - Ensembl, May 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. ^ Koch J, Gärtner S, Li CM, Quintern LE, Bernardo K, Levran O, Schnabel D, Desnick RJ, Schuchman EH, Sandhoff K (December 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.
  6. ^ Li CM, Park JH, He X, Levy B, Chen F, Arai K, Adler DA, Disteche CM, Koch J, Sandhoff K, Schuchman EH (December 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.
  7. ^ a b "Entrez Gene: ASAH1 N-acylsphingosine amidohydrolase (acid ceramidase) 1".
  8. ^ 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 (July 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.
  9. ^ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 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.
  10. ^ Doan NB, Nguyen HS, Al-Gizawiy MM, Mueller WM, Sabbadini RA, Rand SD, Connelly JM, Chitambar CR, Schmainda KM, Mirza SP (October 2017). "Acid ceramidase confers radioresistance to glioblastoma cells". Oncology Reports. 38 (4): 1932–40. doi:10.3892/or.2017.5855. PMC 5652937. PMID 28765947.
  11. ^ 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 (December 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.
  12. ^ 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.

External links

Further reading

  • Perry DK, Hannun YA (December 1998). "The role of ceramide in cell signaling". Biochimica et Biophysica Acta. 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 (May 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 (January 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 (October 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 (October 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 (September 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 (March 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.
  • Ferlinz K, Kopal G, Bernardo K, Linke T, Bar J, Breiden B, Neumann U, Lang F, Schuchman EH, Sandhoff K (September 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 (November 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.
  • Zhang H, Li XJ, Martin DB, Aebersold R (June 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.
  • 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 (February 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.


This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

beta subunit of N-acylethanolamine-hydrolyzing acid amidase Provide feedback

NAAA-beta is a family of vertebral sequences that form the beta subunit of vertebral N-acylethanolamine-hydrolyzing acid amidase, a member of the choloylglycine hydrolase acid ceramidase family. The alpha subunit is represented by family CBAH, PF02275.

Literature references

  1. Li CM, Park JH, He X, Levy B, Chen F, Arai K, Adler DA, Disteche CM, Koch J, Sandhoff K, Schuchman EH;, Genomics. 1999;62:223-231.: The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression. PUBMED:10610716 EPMC:10610716

  2. Tsuboi K, Sun YX, Okamoto Y, Araki N, Tonai T, Ueda N;, J Biol Chem. 2005;280:11082-11092.: Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. PUBMED:15655246 EPMC:15655246

  3. West JM, Zvonok N, Whitten KM, Vadivel SK, Bowman AL, Makriyannis A;, PLoS One. 2012;7:e43877.: Biochemical and mass spectrometric characterization of human N-acylethanolamine-hydrolyzing Acid amidase inhibition. PUBMED:22952796 EPMC:22952796

  4. Lodola A, Branduardi D, De Vivo M, Capoferri L, Mor M, Piomelli D, Cavalli A;, PLoS One. 2012;7:e32397.: A catalytic mechanism for cysteine N-terminal nucleophile hydrolases, as revealed by free energy simulations. PUBMED:22389698 EPMC:22389698


This tab holds annotation information from the InterPro database.

InterPro entry IPR029130

This entry represents the N-terminal domain of acid ceramidase (AC), which degrades ceramide into sphingosine and fatty acid [PUBMED:10610716], and N-acylethanolamine-hydrolysing acid amidase (NAAA). NAAA is an N-acylethanolamine-hydrolysing enzyme that shows structural and functional similarity to acid ceramidase [PUBMED:15655246]. AC and NAAA can be cleaved into two chains: alpha and beta [PUBMED:18281275, PUBMED:17980170]. This entry represent the beta subunit (chain).

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(68)
Full
(900)
Representative proteomes UniProt
(1423)
NCBI
(1622)
Meta
(7)
RP15
(147)
RP35
(286)
RP55
(529)
RP75
(869)
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PP/heatmap 1 View               

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(68)
Full
(900)
Representative proteomes UniProt
(1423)
NCBI
(1622)
Meta
(7)
RP15
(147)
RP35
(286)
RP55
(529)
RP75
(869)
Alignment:
Format:
Order:
Sequence:
Gaps:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(68)
Full
(900)
Representative proteomes UniProt
(1423)
NCBI
(1622)
Meta
(7)
RP15
(147)
RP35
(286)
RP55
(529)
RP75
(869)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Jackhmmer:Q13510
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: De Vivo M , Coggill P
Number in seed: 68
Number in full: 900
Average length of the domain: 61.20 aa
Average identity of full alignment: 28 %
Average coverage of the sequence by the domain: 16.23 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.0 27.0
Noise cut-off 26.7 26.9
Model length: 63
Family (HMM) version: 7
Download: download the raw HMM for this family

Species distribution

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the NAAA-beta domain has been found. There are 25 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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