Q9NR71 (ASAH2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Neutral ceramidase
Short name=N-CDase
Short name=NCDase
EC=3.5.1.23

Alternative name(s):
Acylsphingosine deacylase 2
BCDase
LCDase
Short name=hCD
N-acylsphingosine amidohydrolase 2
Non-lysosomal ceramidase

Cleaved into the following chain:

1. Neutral ceramidase soluble form

Gene names

Name:	ASAH2
Synonyms:	HNAC1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	780 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid at an optimal pH of 6.5-8.5. Acts as a key regulator of sphingolipid signaling metabolites by generating sphingosine at the cell surface. Acts as a repressor of apoptosis both by reducing C16-ceramide, thereby preventing ceramide-induced apoptosis, and generating sphingosine, a precursor of the antiapoptotic factor sphingosine 1-phosphate. Probably involved in the digestion of dietary sphingolipids in intestine by acting as a key enzyme for the catabolism of dietary sphingolipids and regulating the levels of bioactive sphingolipid metabolites in the intestinal tract. Ref.2 Ref.7
Catalytic activity	N-acylsphingosine + H2O = a carboxylate + sphingosine. Ref.4 Ref.8
Enzyme regulation	Inhibited by dithiothreitol (DTT), 2-mercaptoethanol, Zn2+, Cu2+ and Fe2+. Enhanced by Na+ and Ca2+, and at lower level Mg2+ and Mn2+.
Subcellular location	Cell membrane; Single-pass type II membrane protein. Note: The neutral ceramidase soluble form is a secreted protein. According to Ref.4, it is mitochondrial. However, they used a shorter form in its N-terminus, which may explain this localization which probably does not exist in vivo. Ref.4 Ref.6
Tissue specificity	Primarily expressed in the intestine (Ref.9). Ubiquitously expressed with higher levels in kidney, skeletal muscle and heart (Ref.4). According to Ref.9, ubiquitous expression attributed to ASAH2 may be actually that of the paralog ASAH2B. Ref.4 Ref.9
Post-translational modification	N-glycosylated. Required for enzyme activity By similarity. Ref.6 O-glycosylated. Required to retain it as a type II membrane protein at the cell surface. Ref.6 Phosphorylated. May prevent ubiquitination and subsequent degradation By similarity. Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is triggered by nitric oxid By similarity.
Sequence similarities	Belongs to the neutral ceramidase family.
Biophysicochemical properties	Kinetic parameters: KM=71.4 µM for octanoyl-sphingosine Ref.4 Ref.8 KM=66 µM for palmitoyl-sphingosine KM=60.1 µM for D-erythro-C12-NBD-ceramide Vmax=160 µmol/min/mg enzyme with octanoyl-sphingosine as substrate Vmax=16 µmol/min/mg enzyme with palmitoyl-sphingosine as substrate Vmax=0.68 nmol/min/mg enzyme with D-erythro-C12-NBD-ceramide as substrate pH dependence: Optimum pH is 7.5-9.5.
Sequence caution	The sequence AAL06061.1 differs from that shown. Reason: Erroneous initiation. The sequence CAI15870.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Apoptosis Lipid metabolism Sphingolipid metabolism
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Hydrolase
PTM	Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW ceramide metabolic process Traceable author statement Ref.4. Source: ProtInc glycosphingolipid metabolic process Traceable author statement. Source: Reactome phospholipid metabolic process Traceable author statement. Source: Reactome signal transduction Traceable author statement Ref.4. Source: ProtInc small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrion Traceable author statement Ref.4. Source: ProtInc plasma membrane Traceable author statement. Source: Reactome
Molecular_function	ceramidase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9NR71-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9NR71-2)

The sequence of this isoform differs from the canonical sequence as follows:
     410-444: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 780	780	Neutral ceramidase		PRO_0000247099
	Chain	99 – 780	682	Neutral ceramidase soluble form By similarity		PRO_0000247100
Regions
	Topological domain	1 – 12	12	Cytoplasmic Potential
	Transmembrane	13 – 33	21	Helical; Signal-anchor for type II membrane protein; Potential
	Topological domain	34 – 780	747	Lumenal Potential
	Region	770 – 780	11	Required for correct folding and localization By similarity
Sites
	Active site	354	1	Nucleophile Ref.8
Amino acid modifications
	Glycosylation	62	1	O-linked (GalNAc...) Potential
	Glycosylation	67	1	O-linked (GalNAc...) Potential
	Glycosylation	68	1	O-linked (GalNAc...) Potential
	Glycosylation	70	1	O-linked (GalNAc...) Potential
	Glycosylation	73	1	O-linked (GalNAc...) Potential
	Glycosylation	74	1	O-linked (GalNAc...) Potential
	Glycosylation	76	1	O-linked (GalNAc...) Potential
	Glycosylation	78	1	O-linked (GalNAc...) Potential
	Glycosylation	79	1	O-linked (GalNAc...) Potential
	Glycosylation	80	1	O-linked (GalNAc...) Potential
	Glycosylation	82	1	O-linked (GalNAc...) Potential
	Glycosylation	84	1	O-linked (GalNAc...) Potential
	Glycosylation	98	1	N-linked (GlcNAc...) Potential
	Glycosylation	151	1	N-linked (GlcNAc...) Potential
	Glycosylation	217	1	N-linked (GlcNAc...) Potential
	Glycosylation	468	1	N-linked (GlcNAc...) Potential
	Glycosylation	564	1	N-linked (GlcNAc...) Potential
	Glycosylation	730	1	N-linked (GlcNAc...) Potential
	Glycosylation	779	1	O-linked (GalNAc...) Potential
Natural variations
	Alternative sequence	410 – 444	35	Missing in isoform 2.		VSP_019928
	Natural variant	51	1	T → A. Corresponds to variant rs7067625 [ dbSNP | Ensembl ].		VAR_027064
	Natural variant	346	1	A → S. Corresponds to variant rs993869 [ dbSNP | Ensembl ].		VAR_027065
Experimental info
	Mutagenesis	258	1	S → A: Impairs enzyme activity. Ref.8
	Mutagenesis	352	1	D → A: Abolishes enzyme activity. Ref.8
	Mutagenesis	354	1	S → A: Abolishes enzyme activity. Ref.8
	Mutagenesis	362	1	C → A: Abolishes enzyme activity. Ref.8
	Mutagenesis	374	1	S → A: Impairs enzyme activity. Ref.8
	Mutagenesis	396	1	S → A: No effect. Ref.8
	Mutagenesis	595	1	S → A: Impairs enzyme activity. Ref.8
	Mutagenesis	729	1	S → A: Impairs enzyme activity. Ref.8
	Sequence conflict	274	1	S → P in AAL06061. Ref.1
	Sequence conflict	274	1	S → P in AAF86240. Ref.4
	Sequence conflict	602	1	T → A in AAL06061. Ref.1
	Sequence conflict	602	1	T → A in AAF86240. Ref.4
	Sequence conflict	689	1	T → N in CAI17190. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 25, 2006. Version 2. Checksum: D2BD7947B022A619	FASTA	780	85,516
	10 20 30 40 50 60 MAKRTFSNLE TFLIFLLVMM SAITVALLSL LFITSGTIEN HKDLGGHFFS TTQSPPATQG 70 80 90 100 110 120 STAAQRSTAT QHSTATQSST ATQTSPVPLT PESPLFQNFS GYHIGVGRAD CTGQVADINL 130 140 150 160 170 180 MGYGKSGQNA QGILTRLYSR AFIMAEPDGS NRTVFVSIDI GMVSQRLRLE VLNRLQSKYG 190 200 210 220 230 240 SLYRRDNVIL SGTHTHSGPA GYFQYTVFVI ASEGFSNQTF QHMVTGILKS IDIAHTNMKP 250 260 270 280 290 300 GKIFINKGNV DGVQINRSPY SYLQNPQSER ARYSSNTDKE MIVLKMVDLN GDDLGLISWF 310 320 330 340 350 360 AIHPVSMNNS NHLVNSDNVG YASYLLEQEK NKGYLPGQGP FVAAFASSNL GDVSPNILGP 370 380 390 400 410 420 RCINTGESCD NANSTCPIGG PSMCIAKGPG QDMFDSTQII GRAMYQRAKE LYASASQEVT 430 440 450 460 470 480 GPLASAHQWV DMTDVTVWLN STHASKTCKP ALGYSFAAGT IDGVGGLNFT QGKTEGDPFW 490 500 510 520 530 540 DTIRDQILGK PSEEIKECHK PKPILLHTGE LSKPHPWHPD IVDVQIITLG SLAITAIPGE 550 560 570 580 590 600 FTTMSGRRLR EAVQAEFASH GMQNMTVVIS GLCNVYTHYI TTYEEYQAQR YEAASTIYGP 610 620 630 640 650 660 HTLSAYIQLF RNLAKAIATD TVANLSRGPE PPFFKQLIVP LIPSIVDRAP KGRTFGDVLQ 670 680 690 700 710 720 PAKPEYRVGE VAEVIFVGAN PKNSVQNQTH QTFLTVEKYE ATSTSWQIVC NDASWETRFY 730 740 750 760 770 780 WHKGLLGLSN ATVEWHIPDT AQPGIYRIRY FGHNRKQDIL KPAVILSFEG TSPAFEVVTI
	Isoform 2 [UniParc]. Checksum: B4577FFD1C6397EA	FASTA	745	81,718
	10 20 30 40 50 60 MAKRTFSNLE TFLIFLLVMM SAITVALLSL LFITSGTIEN HKDLGGHFFS TTQSPPATQG 70 80 90 100 110 120 STAAQRSTAT QHSTATQSST ATQTSPVPLT PESPLFQNFS GYHIGVGRAD CTGQVADINL 130 140 150 160 170 180 MGYGKSGQNA QGILTRLYSR AFIMAEPDGS NRTVFVSIDI GMVSQRLRLE VLNRLQSKYG 190 200 210 220 230 240 SLYRRDNVIL SGTHTHSGPA GYFQYTVFVI ASEGFSNQTF QHMVTGILKS IDIAHTNMKP 250 260 270 280 290 300 GKIFINKGNV DGVQINRSPY SYLQNPQSER ARYSSNTDKE MIVLKMVDLN GDDLGLISWF 310 320 330 340 350 360 AIHPVSMNNS NHLVNSDNVG YASYLLEQEK NKGYLPGQGP FVAAFASSNL GDVSPNILGP 370 380 390 400 410 420 RCINTGESCD NANSTCPIGG PSMCIAKGPG QDMFDSTQII GRAMYQRAKS KTCKPALGYS 430 440 450 460 470 480 FAAGTIDGVG GLNFTQGKTE GDPFWDTIRD QILGKPSEEI KECHKPKPIL LHTGELSKPH 490 500 510 520 530 540 PWHPDIVDVQ IITLGSLAIT AIPGEFTTMS GRRLREAVQA EFASHGMQNM TVVISGLCNV 550 560 570 580 590 600 YTHYITTYEE YQAQRYEAAS TIYGPHTLSA YIQLFRNLAK AIATDTVANL SRGPEPPFFK 610 620 630 640 650 660 QLIVPLIPSI VDRAPKGRTF GDVLQPAKPE YRVGEVAEVI FVGANPKNSV QNQTHQTFLT 670 680 690 700 710 720 VEKYEATSTS WQIVCNDASW ETRFYWHKGL LGLSNATVEW HIPDTAQPGI YRIRYFGHNR 730 740 KQDILKPAVI LSFEGTSPAF EVVTI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Neutral ceramidase gene: role in regulating ceramide-induced apoptosis." Choi M.S., Anderson M.A., Zhang Z., Zimonjic D.B., Popescu N., Mukherjee A.B. Gene 315:113-122(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha." Osawa Y., Uchinami H., Bielawski J., Schwabe R.F., Hannun Y.A., Brenner D.A. J. Biol. Chem. 280:27879-27887(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION.
[3]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"Molecular cloning and characterization of a human mitochondrial ceramidase." El Bawab S., Roddy P., Qian T., Bielawska A., Lemasters J.J., Hannun Y.A. J. Biol. Chem. 275:21508-21513(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 20-780 (ISOFORM 1), ENZYME ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, POSSIBLE SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 20-780 (ISOFORM 2).
[6]	"Subcellular localization of human neutral ceramidase expressed in HEK293 cells." Hwang Y.H., Tani M., Nakagawa T., Okino N., Ito M. Biochem. Biophys. Res. Commun. 331:37-42(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, GLYCOSYLATION.
[7]	"Mechanisms of sphingosine and sphingosine 1-phosphate generation in human platelets." Tani M., Sano T., Ito M., Igarashi Y. J. Lipid Res. 46:2458-2467(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"Identification of a novel amidase motif in neutral ceramidase." Galadari S., Wu B.X., Mao C., Roddy P., El Bawab S., Hannun Y.A. Biochem. J. 393:687-695(2006) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVE SITE, MUTAGENESIS OF SER-258; ASP-352; SER-354; CYS-362; SER-374; SER-396; SER-595 AND SER-729.
[9]	"A novel gene derived from a segmental duplication shows perturbed expression in Alzheimer's disease." Avramopoulos D., Wang R., Valle D., Fallin M.D., Bassett S.S. Neurogenetics 8:111-120(2007) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY049008 Genomic DNA. Translation: AAL06061.1. Different initiation. AF449759 mRNA. Translation: AAQ04667.2. AL450382 Genomic DNA. Translation: CAI15870.1. Different initiation. AL589794 Genomic DNA. Translation: CAI15766.1. Sequence problems. AL589794 Genomic DNA. Translation: CAI15767.1. Sequence problems. AL954360 Genomic DNA. Translation: CAI17190.1. AF250847 mRNA. Translation: AAF86240.1. BC107105 mRNA. Translation: AAI07106.1.
IPI	IPI00419967. IPI00645992.
RefSeq	NP_001137446.1. NM_001143974.1. NP_063946.2. NM_019893.2.
UniGene	Hs.512645. Hs.710005.
3D structure databases
ProteinModelPortal	Q9NR71.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000378897.
Polymorphism databases
DMDM	110832757.
Proteomic databases
PaxDb	Q9NR71.
PRIDE	Q9NR71.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000329428; ENSP00000329886; ENSG00000188611. ENST00000395526; ENSP00000378897; ENSG00000188611. ENST00000447815; ENSP00000388206; ENSG00000188611.
GeneID	56624.
KEGG	hsa:56624. hsa:653308.
UCSC	uc001jjd.3. human. uc009xos.3. human.
Organism-specific databases
CTD	56624. 653308.
GeneCards	GC10M051944.
H-InvDB	HIX0058802.
HGNC	HGNC:18860. ASAH2.
MIM	611202. gene.
neXtProt	NX_Q9NR71.
PharmGKB	PA134977109.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG75118.
HOVERGEN	HBG080870.
InParanoid	Q9NR71.
KO	K12349.
OMA	SWFAVHP.
OrthoDB	EOG4G4GPW.
Enzyme and pathway databases
BRENDA	3.5.1.23. 2681.
Reactome	REACT_111217. Metabolism.
SABIO-RK	Q9NR71.
Gene expression databases
ArrayExpress	Q9NR71.
Bgee	Q9NR71.
CleanEx	HS_ASAH2.
Genevestigator	Q9NR71.
GermOnline	ENSG00000188611. Homo sapiens.
Family and domain databases
InterPro	IPR006823. Ceramidase_alk. [Graphical view]
PANTHER	PTHR12670. PTHR12670. 1 hit.
Pfam	PF04734. Ceramidase_alk. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	62071.
SOURCE	Search...

Entry information

Entry name

ASAH2_HUMAN

Accession

Primary (citable) accession number: Q9NR71
Secondary accession number(s): Q3KNU1 , Q5SNT7, Q5SZP6, Q5SZP7, Q5T1D5, Q71ME6

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 25, 2006
Last sequence update:	July 25, 2006
Last modified:	May 1, 2013
This is version 86 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.