5u7z

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Human acid ceramidase (ASAH1, aCDase) self-activatedHuman acid ceramidase (ASAH1, aCDase) self-activated

Structural highlights

5u7z is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ASAH1_HUMAN Farber disease;Spinal muscular atrophy-progressive myoclonic epilepsy syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

ASAH1_HUMAN Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH (PubMed:10610716, PubMed:7744740, PubMed:15655246, PubMed:11451951). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:10610716). Has a higher catalytic efficiency towards C12-ceramides versus other ceramides (PubMed:7744740, PubMed:15655246). Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine (PubMed:12764132, PubMed:12815059). For the reverse synthetic reaction, the natural sphingosine D-erythro isomer is more efficiently utilized as a substrate compared to D-erythro-dihydrosphingosine and D-erythro-phytosphingosine, while the fatty acids with chain lengths of 12 or 14 carbons are the most efficiently used (PubMed:12764132). Has also an N-acylethanolamine hydrolase activity (PubMed:15655246). By regulating the levels of ceramides, sphingosine and sphingosine-1-phosphate in the epidermis, mediates the calcium-induced differentiation of epidermal keratinocytes (PubMed:17713573). Also indirectly regulates tumor necrosis factor/TNF-induced apoptosis (By similarity). By regulating the intracellular balance between ceramides and sphingosine, in adrenocortical cells, probably also acts as a regulator of steroidogenesis (PubMed:22261821).[UniProtKB:Q9WV54][1] [2] [3] [4] [5] [6] [7] [8] [9] Isoform 2: May directly regulate steroidogenesis by binding the nuclear receptor NR5A1 and negatively regulating its transcriptional activity.[10]

Publication Abstract from PubMed

Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into sphingosine, the backbone of all sphingolipids, to regulate many cellular processes. Abnormal function of aCDase leads to Farber disease, spinal muscular atrophy with progressive myoclonic epilepsy, and is associated with Alzheimer's, diabetes, and cancer. Here, we present crystal structures of mammalian aCDases in both proenzyme and autocleaved forms. In the proenzyme, the catalytic center is buried and protected from solvent. Autocleavage triggers a conformational change exposing a hydrophobic channel leading to the active site. Substrate modeling suggests distinct catalytic mechanisms for substrate hydrolysis versus autocleavage. A hydrophobic surface surrounding the substrate binding channel appears to be a site of membrane attachment where the enzyme accepts substrates facilitated by the accessory protein, saposin-D. Structural mapping of disease mutations reveals that most would destabilize the protein fold. These results will inform the rational design of aCDase inhibitors and recombinant aCDase for disease therapeutics.

Structural basis for the activation of acid ceramidase.,Gebai A, Gorelik A, Li Z, Illes K, Nagar B Nat Commun. 2018 Apr 24;9(1):1621. doi: 10.1038/s41467-018-03844-2. PMID:29692406[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. Li CM, Park JH, He X, Levy B, Chen F, Arai K, Adler DA, Disteche CM, Koch J, Sandhoff K, Schuchman EH. The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression. Genomics. 1999 Dec 1;62(2):223-31. doi: 10.1006/geno.1999.5940. PMID:10610716 doi:http://dx.doi.org/10.1006/geno.1999.5940
  2. Ferlinz K, Kopal G, Bernardo K, Linke T, Bar J, Breiden B, Neumann U, Lang F, Schuchman EH, Sandhoff K. Human acid ceramidase: processing, glycosylation, and lysosomal targeting. J Biol Chem. 2001 Sep 21;276(38):35352-60. doi: 10.1074/jbc.M103066200. Epub 2001, Jul 12. PMID:11451951 doi:http://dx.doi.org/10.1074/jbc.M103066200
  3. Okino N, He X, Gatt S, Sandhoff K, Ito M, Schuchman EH. The reverse activity of human acid ceramidase. J Biol Chem. 2003 Aug 8;278(32):29948-53. doi: 10.1074/jbc.M303310200. Epub 2003 , May 22. PMID:12764132 doi:http://dx.doi.org/10.1074/jbc.M303310200
  4. He X, Okino N, Dhami R, Dagan A, Gatt S, Schulze H, Sandhoff K, Schuchman EH. Purification and characterization of recombinant, human acid ceramidase. Catalytic reactions and interactions with acid sphingomyelinase. J Biol Chem. 2003 Aug 29;278(35):32978-86. doi: 10.1074/jbc.M301936200. Epub 2003, Jun 18. PMID:12815059 doi:http://dx.doi.org/10.1074/jbc.M301936200
  5. Tsuboi K, Sun YX, Okamoto Y, Araki N, Tonai T, Ueda N. Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem. 2005 Mar 25;280(12):11082-92. Epub 2005 Jan 17. PMID:15655246 doi:http://dx.doi.org/M413473200
  6. Sun W, Xu R, Hu W, Jin J, Crellin HA, Bielawski J, Szulc ZM, Thiers BH, Obeid LM, Mao C. Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes. J Invest Dermatol. 2008 Feb;128(2):389-97. doi: 10.1038/sj.jid.5701025. Epub 2007, Aug 23. PMID:17713573 doi:http://dx.doi.org/10.1038/sj.jid.5701025
  7. Lucki NC, Bandyopadhyay S, Wang E, Merrill AH, Sewer MB. Acid ceramidase (ASAH1) is a global regulator of steroidogenic capacity and adrenocortical gene expression. Mol Endocrinol. 2012 Feb;26(2):228-43. doi: 10.1210/me.2011-1150. Epub 2012 Jan, 19. PMID:22261821 doi:http://dx.doi.org/10.1210/me.2011-1150
  8. Bernardo K, Hurwitz R, Zenk T, Desnick RJ, Ferlinz K, Schuchman EH, Sandhoff K. Purification, characterization, and biosynthesis of human acid ceramidase. J Biol Chem. 1995 May 12;270(19):11098-102. PMID:7744740
  9. Li CM, Park JH, He X, Levy B, Chen F, Arai K, Adler DA, Disteche CM, Koch J, Sandhoff K, Schuchman EH. The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression. Genomics. 1999 Dec 1;62(2):223-31. doi: 10.1006/geno.1999.5940. PMID:10610716 doi:http://dx.doi.org/10.1006/geno.1999.5940
  10. Lucki NC, Li D, Bandyopadhyay S, Wang E, Merrill AH, Sewer MB. Acid ceramidase (ASAH1) represses steroidogenic factor 1-dependent gene transcription in H295R human adrenocortical cells by binding to the receptor. Mol Cell Biol. 2012 Nov;32(21):4419-31. doi: 10.1128/MCB.00378-12. Epub 2012 Aug , 27. PMID:22927646 doi:http://dx.doi.org/10.1128/MCB.00378-12
  11. Gebai A, Gorelik A, Li Z, Illes K, Nagar B. Structural basis for the activation of acid ceramidase. Nat Commun. 2018 Apr 24;9(1):1621. doi: 10.1038/s41467-018-03844-2. PMID:29692406 doi:http://dx.doi.org/10.1038/s41467-018-03844-2

5u7z, resolution 2.50Å

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