Sfingomyeliini taas katabolisella tiellään muodostaa SMM, sfingomyeliinimetaboliitteja.
Niitä on perustavasti neljää:
(1). takaisinpäin lysosomissa muodostuvaa keramidia N-acyl-sfingosiiniä.
(2) siitä edelleen taaksepäin: sfingosiinia (So)
tai (3) Sfingosiinin fosforylaatiotuotetta Sfingosiini-1-fosfaattia( So-1-P)
tai lysosomin avulla SPL, sfingosyylifosfaryylikoliinia. (SphingosylPhospharyl Cholin) .
Sfingomyeliinin säästötie SALVAGE on uudestaan NAcyl-keramidin muodostamista ja siitä edellen glykolipidejä tai Sfingomyeliinejä.
Kataboliatie onkin sitten vaikeammin hahmotettavissa.
Sanotaan että sfingomyeliinin verkostosta pääsee pois (EXIT) ainoastaan siten, että So-1-P muuttuu fosfatidyletanolamidiksi ja rasvahappoaldehydiksi.
Sitten onkin paljon selvitelty, mitä kaikkea voi tällä reittiytyneellä alueella tapahtua.
On havaittu että So, sfingosiini voi suorittaa kolmea aineenvaihdunnallista jatkoreittiä:
Se voi uudestaan (1) N-asyloitua keramidiksi ( SALVAGE tie).
Se voi (2) fosforyloitua So-1-P- muotoon. On havaittu, että on SPP1 ja SPP2-entsyymit, jotka ovat sfingosiinifosfaattifosfataaseja ja voivat palauttaa takaisin tärkeään sfingosiinimuotoon (So).
Sitten on havaittu myös (3) N-metyloituminen ja tällä tiellä löytyy N-Me-So, N,N-2MeSo ja N,N,N-3MeSo ja nämä ovat vaikuttavia molekyylejä eikosanoidikaskadin alueella .
Sanotaan.että tumasäätö vaikuttuu myös - tästä joskus erikseen. En ole tästä nähnyt kovin montaa artikkelia.
https://www.ncbi.nlm.nih.gov/pubmed/8621258
https://www.ncbi.nlm.nih.gov/pubmed/1657377?dopt=Abstract&holding=npg
Tässä mainitsen yleensä kuvatun kataboliseen kohdan: jossa joko Sfinganiinifosfaatti (Sa-P) tai Sfingosiinifosfaatti (So-P) joutuvat lyaasin kohteeksi ja muuttuvat etanolamiinifosfaatiksi ja rasvahappoaldehydiksi (trans-2-hexanaali).
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Löysin joukon entsyymeitä, joita nyt katson.ASAH1 (aCDase, pH 4-5) ), ASAH2 (nCDase, pH 7-9)
https://www.ncbi.nlm.nih.gov/gene/427
Niiden tehtävä on tuottaa sfingosiinia (SO) . Esim ASAH2 on ruoansulatuksellinen entsyymi ja hajoitata sfingomyeliinejä, joita ravinnosta tulee.
- ASAH1 (8p22) asidinen keramidaasi , aCDase , lysosomaalinen
- Also known as
- AC; PHP; ASAH; PHP32; ACDase; SMAPME
- Summary This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide (Cer) into sphingosine (So) and free fatty acid (FFA) . This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015] Expression Broad expression in thyroid (RPKM 225.8), heart (RPKM 191.4) and 24 other tissues See more Orthologs mouse all
- Preferred Names
- acid ceramidase
- Names
- N-acylethanolamine hydrolase ASAH1
- N-acylsphingosine amidohydrolase (acid ceramidase) 1
- acid CDase
- acylsphingosine deacylase
- putative 32 kDa heart protein
- Conserved Domains (2) summary
-
- cd01903
Location:128 → 373 - Ntn_AC_NAAA; AC_NAAA This conserved domain includes two closely related proteins, acid ceramidase (AC, also known as N-acylsphingosine amidohydrolase), and N-acylethanolamine-hydrolyzing acid amidase (NAAA). AC catalyzes the hydrolysis of ceramide to sphingosine and fatty acid. Ceramide is required for the biosynthesis of most sphingolipids and plays an important role in many signal transduction pathways by inducing apoptosis and/or arresting cell growth. An inherited deficiency of AC activity leads to the lysosomal storage disorder known as Farber disease. AC is considered a "rheostat" important for maintaining the proper intracellular levels of these lipids since hydrolysis of ceramide is the only source of sphingosine in cells. NAAA is a eukaryotic glycoprotein that hydrolyzes bioactive N-acylethanolamines, including anandamide (an endocannabinoid) and N-palmitoylethanolamine (an anti-inflammatory and neuroprotective substance), to fatty acids and ethanolamine at acidic pH. NAAA shows structural and functional similarity to acid ceramidase, but lacks the ceramide-hydrolyzing activity of AC.
- pfam15508
Location:68 → 133 - NAAA-beta; beta subunit of N-acylethanolamine-hydrolyzing acid amidase
- cd01903
- Structural basis for the activation of acid ceramidase. Gebai A, et al. Nat Commun, 2018 Apr 24. PMID 29692406, Free PMC Article
- ASAH1-Related Disorders Dyment DA, et al. , 1993. PMID 29595935
- The value of detection of S100A8 and ASAH1 in predicting the chemotherapy response for breast cancer patients. Li YH, et al. Hum Pathol, 2018 Apr. PMID 29320752
- Endogenous acid ceramidase protects epithelial cells from Porphyromonas gingivalis-induced inflammation in vitro. Azuma MM, et al. Biochem Biophys Res Commun, 2018 Jan 22. PMID 29278706, Free PMC Article
- Identification of ASAH1 as a susceptibility gene for familial keloids. Santos-Cortez RLP, et al. Eur J Hum Genet, 2017 Oct. PMID 28905881, Free PMC Article
GeneRIFs: Gene References Into Functions
- The expression of ASAH1 was associated significantly with lymph nodes metastasis, indicating that ASAH1 may serve as a biomarker to predict patients' lymph nodes status in breast cancers.
- We also identified ASAH1 as a new target of MITF, thereby involving MITF in the regulation of sphingolipid metabolism. Together, our findings provide new cues to the mechanisms underlying the phenotypic plasticity of melanoma cells and identify new anti-metastatic targets.
- Acid ceramidase ablation blocks cell cycle progression and accelerates senescence. Importantly, ASAH1-null cells also lose the ability to form cancer-initiating cells and to undergo self-renewal, which is suggestive of a key role for acid ceramidase in maintaining malignancy and self-renewal of invasive melanoma cells. ...Since increases in ceramide and consequent decreases of S1P reduce proliferation of various cancers, AC might offer a new target for anti-tumor therapy
- http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24903&path[]=78082
- Autocleavage of ASAH1 triggers a conformational change exposing a hydrophobic channel leading to the active site.
- results demonstrate a tissue-specific role for AC in regulating neutrophilic inflammation and cytokine production.
- Acid ceramidase plays a critical role in acute myeloid leukemia cell survival via regulation of both sphingolipid levels and Mcl-1.
- Collectively, our data show the novel discovery of anti-inflammatory and anti-apoptotic effects of acid ceramidase in host cells exposed to periodontal bacteria, and the attenuation of the expression of host-protective acid ceramidase in periodontal lesions.
- we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation .Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p<10 a="">
- ASAH1 variant Leu401Pro co-segregates with keloid phenotype in a large Yoruba family.
- We report an atypical presentation of Farber disease with her pathology and associated genetic defect. This case expands the phenotypic spectrum of Farber disease to include novel mutations of ASAH1, which pose a diagnostic challenge.
ASAH2 (10q11.23) neutraali keramidaasi (nCDase)
ASAH2 N-acylsphingosine amidohydrolase 2 [ Homo sapiens (human) ]
- Also known as
- HNAC1; BCDase; LCDase; NCDase; N-CDase
- Summary
- Ceramidases (EC 3.5.1.23), such as ASAH2, catalyze hydrolysis of the N-acyl linkage of ceramide, a second messenger in a variety of cellular events, to produce sphingosine. Sphingosine exerts both mitogenic and apoptosis-inducing activities, and its phosphorylated form functions as an intra- and intercellular second messenger (see MIM 603730) (Mitsutake et al., 2001 [PubMed 11328816]).[supplied by OMIM, Mar 2008]
- Expression
- Biased expression in duodenum (RPKM 35.9), small intestine (RPKM 31.0) and 1 other tissue See more
- Orthologs
- mouse all
- Preferred Names
- neutral ceramidase
- Names
- N-acylsphingosine amidohydrolase (non-lysosomal ceramidase) 2
- acylsphingosine deacylase 2
- mitochondrial ceramidase
- neutral/alkaline ceramidase
- non-lysosomal ceramidase
- Conserved Domains (3) summary
-
- PTZ00487
Location:100 → 743 - PTZ00487; ceramidase; Provisional
- pfam04734
Location:102 → 573 - Ceramidase_alk;
Neutral/alkaline non-lysosomal ceramidase, N-terminalThis family represents N-terminal domain of a group of neutral/alkaline ceramidases found in both bacteria and eukaryotes. The EC classification is EC:3.5.1.23. The enzyme hydrolyzes ceramide to generate sphingosine and fatty acid. The enzyme plays a regulatory role in a variety of physiological events in eukaryotes and also functions as an exotoxin in particular bacteria. This N-terminal domain carries two metal-binding sites, the first for Zn2+ residing within the domain, and the second, for Mg2+/Ca2+ lying at the interface between the two domains.
- pfam17048
Location:575 → 742 - Ceramidse_alk_C; Neutral/alkaline non-lysosomal ceramidase, C-terminalThis family represents C-terminal domain of a group of neutral/alkaline ceramidases found in both bacteria and eukaryotes. The EC classification is EC:3.5.1.23. The enzyme hydrolyzes ceramide to generate sphingosine and fatty acid. The enzyme plays a regulatory role in a variety of physiological events in eukaryotes and also functions as an exotoxin in particular bacteria. This C-terminal tail of the enzyme is highly conserved across all species and may play a role in the interaction of the enzyme with the plasma membranes. The tail is also vital for the stabilization of the enzyme as a whole.
- PTZ00487
- Transcriptional regulation of the human neutral ceramidase gene. O'Neill SM, et al. Arch Biochem Biophys, 2011 Jul. PMID 21531200, Free PMC Article
- Mechanisms of sphingosine and sphingosine 1-phosphate generation in human platelets. Tani M, et al. J Lipid Res, 2005 Nov. PMID 16061940
- Subcellular localization of human neutral ceramidase expressed in HEK293 cells. Hwang YH, et al. Biochem Biophys Res Commun, 2005 May 27. PMID 15845354
- Functions of neutral ceramidase in the Golgi apparatus. Sakamoto W, et al. J Lipid Res, 2018 Nov. PMID 30154232,
- Structural Basis for Ceramide Recognition and Hydrolysis by Human Neutral Ceramidase. Airola MV, et al. Structure, 2015 Aug 4. PMID 26190575, Free PMC Article
GeneRIFs: Gene References Into Functions
- The structural basis for ceramide recognition and hydrolysis by human neutral ceramidase has been uncovered.
- These results demonstrate for the first time that adiponectin inhibits TNFalpha-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion.
- cloned a 3000 bp region upstream of the translational start site of the nCDase gene
- c-Jun/AP-1 signaling may, in part, regulate serum-induced nCDase gene transcription
- Both acidic ceramidase (aCDase) and neutral ceramidase (nCDase) activities declined after low- and high-UVB, but returned to normal only in low-UVB cells
- Observational study of gene-disease association. (HuGE Navigator)
- serine palmitoyltransferase and ceramidase are two major ceramide metabolizing enzymes that may have roles in psoriatic epidermis
-
the
purification and characterization of neutral ceramidase from human
ileostomy content, using octanoyl-[(14)C]sphingosine as substrateAbstractSphingolipids are degraded by sphingomyelinase and ceramidase in the gut to ceramide and sphingosine, which may inhibit cell proliferation and induce apoptosis, and thus have anti-tumour effects in the gut. Although previous rodent studies including experiments on knockout mice indicate a role of neutral ceramidase in ceramide digestion, the human enzyme has never been purified and characterized in its purified form. We here report the purification and characterization of neutral ceramidase from human ileostomy content, using octanoyl-[(14)C]sphingosine as substrate. After four chromatographic steps, a homogeneous protein band with 116kDa was obtained. MALDI mass spectrometry identified 16 peptide masses similar to human ceramidase previously cloned by El Bawab et al. [Molecular cloning and characterization of a human mitochondrial ceramidase, J. Biol. Chem. 275 (2000) 21508-21513] and Hwang et al. [Subcellular localization of human neutral ceramidase expressed in HEK293 cells, Biochem. Biophys. Res. Commun. 331 (2005) 37-42]. By RT-PCR and 5'-RACE methods, a predicted partial nucleotide sequence of neutral ceramidase was obtained from a human duodenum biopsy sample, which was homologous to that of known neutral/alkaline ceramidases. The enzyme has neutral pH optimum and catalyses both hydrolysis and formation of ceramide without distinct bile salt dependence. It is inhibited by Cu(2+) and Zn(2+) ions and by low concentrations of cholesterol. The enzyme is a glycoprotein but deglycosylation does not affect its activity. Our study indicates that neutral ceramidase is expressed in human intestine, released in the intestinal lumen and plays a major role in ceramide metabolism in the human gut.
- Important for the generation of sphgosine 1 phosphqte (S1P) and S1P-mediated cell proliferation and survival.
- Blocking acid ceramidase but not sphingosine kinase activity in alveolar macrophages led to decreased ERK and Akt activity and induction of cell death.
Suoliston neutraalin keramidaasin merkitys terveydessä 19 hakulöytöä sanoilla "intestinal ceramidase". Pidän tätä tärkeänä entsyyminä ja otan kaikki löydöt tähän netistä:
https://www.ncbi.nlm.nih.gov/pubmed/?term=intestinal+neutral+ceramidase%2C
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- 15217782
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Br J Nutr. 2004 May;91(5):715-23.
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Yang L, Mutanen M, Cheng Y, Duan R.
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- 12165363
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- 12138298
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Duan RD, Cheng Y, Yang L, Ohlsson L, Nilsson A.
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- 11592731
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Lundgren P, Nilsson A, Duan RD.
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- 11330410
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Hertervig E, Nilsson A, Nyberg L, Duan RD.
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