Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (E-NPP 7) also known as alkaline sphingomyelin phosphodiesterase (Alk-SMase) or intestinal alkaline sphingomyelinase is an enzyme that in humans is encoded by the ENPP7 gene.
ENPP7 is a new name for an old enzyme whose activity was originally identified in 1969 by Nilsson as a type of sphingomyelinase that hydrolyses sphingomyelin to ceramide in the intestinal tract. The enzyme was then purified and characterized by Duan et al. and named alkaline sphingomyelinase (alk-SMase), as the optimal pH of the enzyme was 9.0 and its main substrate is sphingomyelin. Most previous studies used the name of alk-SMase for this protein. The name of ENPP7 was created based on the results of cloning studies which show that alk-SMase shares no structural similarities with either acid or neutral SMase but belongs to the family of ecto nucleotide pyrophosphatase/phosphodiesterase (ENPP). As a new addition to the family it is therefore called ENPP7 or NPP7. A 3D homology model of ENPP7 was recently constructed using the crystal structural of an NPP member in bacteria as a template.[unreliable source?]
Differing from other ENPP members, ENPP7 seems only expressed in the intestinal mucosa in many species and additionally in human liver. In the intestinal tract, ENPP7 activity is low in the duodenum and colon but high in the middle of the jejunum. As an ecto enzyme, ENPP7 is located on the surface of the intestinal mucosa and is released in the lumen by bile salt and pancreatic trypsin. The enzyme expressed in human liver is released in the bile and delivered to the intestine.
The activity of ENPP7 depends specifically on two types of primary bile salts, taurocholate (TC) and taurochenodeoxycholate (TCDC) at critical micelle concentrations. Other detergents, such as CHAPS and Triton X-100 have no stimulatory effects rather inhibitory effects, indicating a biologic interaction between bile salts and the enzyme. Unlike acid and neutral SMases in the intestinal tract that are rapidly inactivated by pancreatic trypsin, alk-SMase is resistant to trypsin digestion. Thus ENPP7 is active in the intestinal lumen and is transported along the intestinal tract. Significant activity can be detected in the faeces.
The substrates of ENPP family vary greatly. Some have activity against nucleotides, some have activity against phospholipid and lysophospholipids. ENPP7 is the only enzyme that has a type of phospholipase C activity against sphingomyelin.
Physiological functions and clinical implications
ENPP7 is the key enzyme in the gut that digests sphingomyelin. Sphingomyelin is a lipid constituent of cell membrane, and a dietary component being particularly abundant in milk, cheese, egg, and meat. Digestion of sphingomyelin mainly occurs in the middle part of the small intestine, where ENPP7 is abundant, indicating a role of the enzyme in sphingomyelin digestion. Recent studies on ENPP7 knockout mice clearly showed that digestion of sphingomyelin and generation of ceramide is severely affected in ENPP7 deficiency mice. ENPP7 is fully developed in the intestine before birth, which gives the infant ability to digest sphingomyelin in the milk.
The daily intake of sphingomyelin for human with Western diet is about 300 mg. Under physiological conditions, only part of the sphingomyelin can be digested and absorbed. The limitation is thought to be caused by several factors that are present in the intestine such as cholesterol, phospholipids, fat and high concentrations of bile salts. It is thus understandable why SM digestion occurs most effectively in the low part of the small intestine, where most fat, phospholipids, and bile salt have been absorbed or up taken. It is also understandable that considerable amount of dietary sphingomyelin is delivered into the colon and excreted in the feces.
ENPP7 may have important roles in preventing tumorigenesis in the intestinal tract, as ceramide, the product of sphingomyelin hydrolysis, can inhibit cell proliferation and stimulate cell differentiation and apoptosis. Animal studies showed that supplement of SM or ceramide in the diet may inhibit the development of colon cancer. Of particular interest is that the activity of ENPP7 is significantly decreased in human colorectal adenoma and carcinoma as well as in the feces of the cancer patients. The decrease is caused by expression of a few mutant forms of ENPP7, which lack exon 4, resulting in total inactivation of the enzyme, as found in human colon and liver cancer cells.
Besides sphingomyelin, ENPP7 can also degrade and inactivate platelet-activating factor (PAF), which is proinflammatory, indicating that ENPP7 may also have antiinflammatory effects. Rectal administration of recombinant ENPP7 has been shown to improve ulcerative colitis in an animal study, and patients with chronic ulcerative colitis are associated with a reduced ENPP7 activity.
ENPP7 may also affect cholesterol absorption. In the intestinal tract cholesterol and sphingomyelin are co-exiting in plasma membrane and in lipid vesicles, liposomes and micelles. The two molecules form a stable complex via van der Waals forces. Cholesterol absorption can be inhibited by supplementation of sphingomyelin in the diet. Milk sphingomyelin seems more potent than egg sphingomyelin, indicating that the inhibition is related to the degree of the saturation and the length of sphingomyelin. Recent studies further showed that formation of ceramide by ENPP7 in the gut enhanced sphingomyelin-induced inhibition of cholesterol, indicating regulatory roles of ENPP7 in cholesterol absorption.
The expression of ENPP7 can be modified by dietary factors. High fat diet (53% energy) greatly reduces ENPP7 activities and enzyme protein in the intestinal mucosa by 50%. On the other hand, water-soluble fiber psyllium was shown to increase both the activities and protein of ENPP7 in the colon of mice. Sphingomyelin can also increase the levels of ENPP7 after a long term of administration. Besides, ursodeoxycholic acid and probiotic VSL#3 may stimulate the expression of ENPP7 in the intestine.
- Duan RD, Bergman T, Xu N, Wu J, Cheng Y, Duan J, Nelander S, Palmberg C, Nilsson A (Sep 2003). "Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family". J Biol Chem. 278 (40): 38528–36. doi:10.1074/jbc.M305437200. PMID 12885774.
- "Entrez Gene: ENPP7 ectonucleotide pyrophosphatase/phosphodiesterase 7".
- Nilsson A (March 1969). "The presence of spingomyelin- and ceramide-cleaving enzymes in the small intestinal tract". Biochim. Biophys. Acta. 176 (2): 339–47. doi:10.1016/0005-2760(69)90192-1. PMID 5775951.
- Cheng Y, Nilsson A, Tömquist E, Duan RD (February 2002). "Purification, characterization, and expression of rat intestinal alkaline sphingomyelinase". J. Lipid Res. 43 (2): 316–24. PMID 11861674.
- Duan RD, Cheng Y, Hansen G, Hertervig E, Liu JJ, Syk I, Sjostrom H, Nilsson A (June 2003). "Purification, localization, and expression of human intestinal alkaline sphingomyelinase". J. Lipid Res. 44 (6): 1241–50. doi:10.1194/jlr.M300037-JLR200. PMID 12671034.
- Wu J, Cheng Y, Palmberg C, Bergman T, Nilsson A, Duan RD (February 2005). "Cloning of alkaline sphingomyelinase from rat intestinal mucosa and adjusting of the hypothetical protein XP_221184 in GenBank". Biochim. Biophys. Acta. 1687 (1–3): 94–102. doi:10.1016/j.bbalip.2004.11.006. PMID 15708357.
- Duan J, Wu J, Cheng Y, Duan RD (October 2010). "Understanding the molecular activity of alkaline sphingomyelinase (NPP7) by computer modeling". Biochemistry. 49 (42): 9096–105. doi:10.1021/bi101069u. PMID 20839774.
- Suresh PS, Olubiyi O, Thirunavukkarasu C, Strodel B, Kumar MS (March 2011). "Molecular modeling of human alkaline sphingomyelinase". Bioinformation. 6 (2): 9096–105. PMC 3082857. PMID 21544170.
- Duan RD, Nyberg L, Nilsson A (October 1995). "Alkaline sphingomyelinase activity in rat gastrointestinal tract: distribution and characteristics". Biochim. Biophys. Acta. 1259 (1): 49–55. doi:10.1016/0005-2760(95)00137-2. PMID 7492615.
- Duan RD, Cheng Y, Tauschel HD, Nilsson A (January 1998). "Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: a potential implication in tumorigenesis". Dig. Dis. Sci. 43 (1): 26–32. doi:10.1023/A:1018807600683. PMID 9508530.
- Wu J, Liu F, Nilsson A, Duan RD (November 2004). "Pancreatic trypsin cleaves intestinal alkaline sphingomyelinase from mucosa and enhances the sphingomyelinase activity". Am. J. Physiol. Gastrointest. Liver Physiol. 287 (5): G967–73. doi:10.1152/ajpgi.00190.2004. PMID 15205117.
- Duan RD (March 2006). "Alkaline sphingomyelinase: an old enzyme with novel implications". Biochim. Biophys. Acta. 1761 (3): 281–91. doi:10.1016/j.bbalip.2006.03.007. PMID 16631405.
- Stefan C, Jansen S, Bollen M (October 2005). "NPP-type ectophosphodiesterases: unity in diversity". Trends Biochem. Sci. 30 (10): 542–50. doi:10.1016/j.tibs.2005.08.005. PMID 16125936.
- Duan RD (July 1998). "Sphingomyelin hydrolysis in the gut and clinical implications in colorectal tumorigenesis and other gastrointestinal diseases". Scand. J. Gastroenterol. 33 (7): 673–83. doi:10.1080/00365529850171594. PMID 9712229.
- Nyberg L, Nilsson Å, Lundgren P, Duan RD (1997). "Localization and capacity of sphingomyelin digestion in the rat intestinal tract". The Journal of Nutritional Biochemistry. 8 (3): 112–118. doi:10.1016/S0955-2863(97)00010-7.
- Duan RD, Cheng Y, Jönsson BA, Ohlsson L, Herbst A, Hellström-Westas L, Nilsson A (January 2007). "Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites". Pediatr. Res. 61 (1): 61–6. doi:10.1203/01.pdr.0000250534.92934.c2. PMID 17211142.
- Lillienau J, Cheng Y, Nilsson A, Duan RD (May 2003). "Development of intestinal alkaline sphingomyelinase in rat fetus and newborn rat". Lipids. 38 (5): 545–9. doi:10.1007/s11745-003-1340-1. PMID 12880111.
- Nilsson A, Hertervig E, Duan RD (2003). "Digestion and absorption of sphingolipids in food". In Willem van Nieuwenhuyzen, Bernard F. Szuchaj. Nutrition and Biochemistry of Phospholipids. AOCS Publishing. ISBN 1-893997-42-1.
- Liu JJ, Nilsson A, Duan RD (April 2000). "Effects of phospholipids on sphingomyelin hydrolysis induced by intestinal alkaline sphingomyelinase: an in vitro study". J. Nutr. Biochem. 11 (4): 192–7. doi:10.1016/S0955-2863(00)00064-4. PMID 10827341.
- Nilsson A (December 1968). "Metabolism of sphingomyelin in the intestinal tract of the rat". Biochim. Biophys. Acta. 164 (3): 575–84. doi:10.1016/0005-2760(68)90187-2. PMID 5701698.
- Ohlsson L, Hertervig E, Jönsson BA, Duan RD, Nyberg L, Svernlöv R, Nilsson A (March 2010). "Sphingolipids in human ileostomy content after meals containing milk sphingomyelin". Am. J. Clin. Nutr. 91 (3): 672–8. doi:10.3945/ajcn.2009.28311. PMID 20071649.
- Dillehay DL, Webb SK, Schmelz EM, Merrill AH (May 1994). "Dietary sphingomyelin inhibits 1,2-dimethylhydrazine-induced colon cancer in CF1 mice". J. Nutr. 124 (5): 615–20. PMID 8169652.
- Hertervig E, Nilsson A, Nilbert M, Duan RD (July 2003). "Reduction in alkaline sphingomyelinase in colorectal tumorigenesis is not related to the APC gene mutation". Int J Colorectal Dis. 18 (4): 309–13. doi:10.1007/s00384-002-0471-y. PMID 12774245.
- Hertervig E, Nilsson A, Nyberg L, Duan RD (February 1997). "Alkaline sphingomyelinase activity is decreased in human colorectal carcinoma". Cancer. 79 (3): 448–53. doi:10.1002/(SICI)1097-0142(19970201)79:3<448::AID-CNCR4>3.0.CO;2-E. PMID 9028353.
- Di Marzio L, Di Leo A, Cinque B, Fanini D, Agnifili A, Berloco P, Linsalata M, Lorusso D, Barone M, De Simone C, Cifone MG (April 2005). "Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer". Cancer Epidemiol. Biomarkers Prev. 14 (4): 856–62. doi:10.1158/1055-9965.EPI-04-0434. PMID 15824156.
- Cheng Y, Wu J, Hertervig E, Lindgren S, Duan D, Nilsson A, Duan RD (November 2007). "Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis". Br. J. Cancer. 97 (10): 1441–8. doi:10.1038/sj.bjc.6604013. PMC 2360232. PMID 17923876.
- Wu J, Cheng Y, Nilsson A, Duan RD (August 2004). "Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells". Carcinogenesis. 25 (8): 1327–33. doi:10.1093/carcin/bgh140. PMID 15016655.
- Wu J, Nilsson A, Jönsson BA, Stenstad H, Agace W, Cheng Y, Duan RD (February 2006). "Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity". Biochem. J. 394 (Pt 1): 299–308. doi:10.1042/BJ20051121. PMC 1386028. PMID 16255717.
- Andersson D, Kotarsky K, Wu J, Agace W, Duan RD (July 2009). "Expression of alkaline sphingomyelinase in yeast cells and anti-inflammatory effects of the expressed enzyme in a rat colitis model". Dig. Dis. Sci. 54 (7): 1440–8. doi:10.1007/s10620-008-0509-2. PMID 18989780.
- Sjöqvist U, Hertervig E, Nilsson A, Duan RD, Ost A, Tribukait B, Löfberg R (July 2002). "Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity". Inflamm. Bowel Dis. 8 (4): 258–63. doi:10.1097/00054725-200207000-00004. PMID 12131609.
- Nyberg L, Duan RD, Nilsson A (May 2000). "A mutual inhibitory effect on absorption of sphingomyelin and cholesterol". J. Nutr. Biochem. 11 (5): 244–9. doi:10.1016/S0955-2863(00)00069-3. PMID 10876096.
- Noh SK, Koo SI (October 2004). "Milk sphingomyelin is more effective than egg sphingomyelin in inhibiting intestinal absorption of cholesterol and fat in rats". J. Nutr. 134 (10): 2611–6. PMID 15465755.
- Feng D, Ohlsson L, Ling W, Nilsson A, Duan RD (April 2010). "Generating Ceramide from Sphingomyelin by Alkaline Sphingomyelinase in the Gut Enhances Sphingomyelin-Induced Inhibition of Cholesterol Uptake in Caco-2 Cells". Dig. Dis. Sci. 55 (12): 3377–83. doi:10.1007/s10620-010-1202-9. PMID 20393874.
- Cheng Y, Ohlsson L, Duan RD (May 2004). "Psyllium and fat in diets differentially affect the activities and expressions of colonic sphingomyelinases and caspase in mice". Br. J. Nutr. 91 (5): 715–23. doi:10.1079/BJN20041107. PMID 15137923.
- Zhang P, Li B, Gao S, Duan RD (2008). "Dietary sphingomyelin inhibits colonic tumorigenesis with an up-regulation of alkaline sphingomyelinase expression in ICR mice". Anticancer Res. 28 (6A): 3631–5. PMID 19189644.
- Liu F, Cheng Y, Wu J, Tauschel HD, Duan RD (April 2006). "Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Caco 2 cells" (PDF). Cancer Lett. 235 (1): 141–6. doi:10.1016/j.canlet.2005.04.016. PMID 16290921.
- Soo I, Madsen KL, Tejpar Q, Sydora BC, Sherbaniuk R, Cinque B, Di Marzio L, Cifone MG, Desimone C, Fedorak RN (March 2008). "VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation". Can. J. Gastroenterol. 22 (3): 237–42. PMC 2662197. PMID 18354751.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Duan RD, Cheng Y, Hansen G, et al. (2004). "Purification, localization, and expression of human intestinal alkaline sphingomyelinase". J. Lipid Res. 44 (6): 1241–50. doi:10.1194/jlr.M300037-JLR200. PMID 12671034.
- Clark HF, Gurney AL, Abaya E, et al. (2003). "The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Wu J, Cheng Y, Nilsson A, Duan RD (2004). "Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells". Carcinogenesis. 25 (8): 1327–33. doi:10.1093/carcin/bgh140. PMID 15016655.
- Zhang Z, Henzel WJ (2005). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Sci. 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
- Wu J, Hansen GH, Nilsson A, Duan RD (2005). "Functional studies of human intestinal alkaline sphingomyelinase by deglycosylation and mutagenesis". Biochem. J. 386 (Pt 1): 153–60. doi:10.1042/BJ20041455. PMC 1134777. PMID 15458386.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Wu J, Cheng Y, Palmberg C, et al. (2005). "Cloning of alkaline sphingomyelinase from rat intestinal mucosa and adjusting of the hypothetical protein XP_221184 in GenBank". Biochim. Biophys. Acta. 1687 (1–3): 94–102. doi:10.1016/j.bbalip.2004.11.006. PMID 15708357.
- Wu J, Nilsson A, Jönsson BA, et al. (2006). "Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity". Biochem. J. 394 (Pt 1): 299–308. doi:10.1042/BJ20051121. PMC 1386028. PMID 16255717.