ENPP7 (Alkaline Sphingomyelin Phosphodiesterase) – Function, Localization, and Biological Role OpenAI o3-deep-research-2025-06-26 109 citations 2025-11-03T22:27:20.623726

ENPP7 (Alkaline Sphingomyelin Phosphodiesterase) – Function, Localization, and Biological Role

Gene and Protein Overview

ENPP7 (UniProt Q6UWV6), also known as alkaline sphingomyelin phosphodiesterase or alkaline sphingomyelinase (alk-SMase), is an enzyme predominantly expressed in the intestinal tract and, in humans, the liver (pmc.ncbi.nlm.nih.gov). It was first identified in 1969 as an intestinal enzyme that hydrolyzes sphingomyelin at high pH (pmc.ncbi.nlm.nih.gov). Unlike the acid and neutral sphingomyelinases, ENPP7 shares no homology with those lysosomal enzymes. Instead, cloning and sequence analysis showed it belongs to the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family (pmc.ncbi.nlm.nih.gov). In fact, ENPP7 is the only NPP family member specialized for sphingomyelin, earning it the alias NPP7 (pmc.ncbi.nlm.nih.gov). It is a glycoprotein that operates in the digestive tract to break down dietary sphingolipids and modulate bioactive lipid mediators. ENPP7’s activity has been linked to protective effects in the gut – including suppression of inflammation and tumorigenesis – based on both biochemical function and loss-of-function studies (pmc.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov).

Structure and Enzymatic Function

ENPP7 is a type I membrane enzyme composed of an N-terminal signal peptide and a C-terminal transmembrane helix (pmc.ncbi.nlm.nih.gov). The signal peptide directs it to the secretory pathway, while the C-terminal hydrophobic anchor tethers the protein at the cell surface (pmc.ncbi.nlm.nih.gov). The large extracellular domain contains the catalytic site and several conserved metal-binding residues characteristic of NPP family enzymes (pmc.ncbi.nlm.nih.gov). A 2017 structural study (J. Biol. Chem., 2017) resolved human ENPP7 in complex with a reaction product, revealing that the enzyme’s active site closely resembles other NPPs but with unique adaptations for lipid substrates (pubmed.ncbi.nlm.nih.gov). Specifically, ENPP7 has an aromatic “choline-binding box” of tyrosine residues that snugly recognize the choline headgroup of its substrates (pubmed.ncbi.nlm.nih.gov). It also features a positively charged surface patch and a hydrophobic loop that help recruit phospholipid substrates presented in bile salt micelles (pubmed.ncbi.nlm.nih.gov). These structural specializations explain why ENPP7 – unlike other ENPP paralogs – efficiently cleaves sphingomyelin and related lipids in the harsh, detergent-rich environment of the gut lumen (pubmed.ncbi.nlm.nih.gov).

Catalytic activity: ENPP7 functions as a phosphodiesterase with phospholipase C activity, meaning it cleaves the bond between the phosphate and the headgroup of its substrates. Its primary reaction is hydrolysis of sphingomyelin (SM) to yield ceramide and phosphocholine (pmc.ncbi.nlm.nih.gov). This reaction requires an alkaline pH optimum (hence the name “alkaline SMase”) and is strictly dependent on bile salts as co-factors (pmc.ncbi.nlm.nih.gov). In vitro, taurocholate and taurochenodeoxycholate (bile acids present in intestinal bile) strongly stimulate ENPP7 activity (pmc.ncbi.nlm.nih.gov). The bile salts not only emulsify lipid substrates but also directly interact with the enzyme to activate it (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Divalent metal ions are also required in the active site – the enzyme is inhibited by EDTA and loses activity if conserved zinc-binding residues are mutated (pmc.ncbi.nlm.nih.gov), consistent with the metallophosphoesterase mechanism of the ENPP family.

Substrate specificity: ENPP7 specializes in phosphocholine-containing lipids. It was originally characterized for sphingomyelin, but subsequent work showed it also cleaves the phosphocholine headgroup from several other molecules:

Crucially, sphingomyelin is ENPP7’s primary natural substrate, and no other enzyme in the human gut duplicates this alkaline sphingomyelinase activity. Acidic and neutral sphingomyelinases operate inside cells or lysosomes, not in the intestinal lumen. Thus, ENPP7 is considered the main enzyme responsible for dietary sphingomyelin digestion (pmc.ncbi.nlm.nih.gov). This was conclusively shown by a knockout mouse model: mice lacking the ENPP7 gene (alk-SMase) were unable to digest the vast majority of sphingomyelin from food. In one study, ~90% of ingested sphingomyelin remained intact and accumulated in the colon of ENPP7-null mice, whereas wild-type mice digested most of it (pmc.ncbi.nlm.nih.gov). By comparison, humans are remarkably efficient at sphingomyelin digestion – roughly 81% of dietary sphingomyelin is absorbed – and this efficiency is attributed to robust ENPP7 activity in the human gut (both from intestinal and biliary sources) (pmc.ncbi.nlm.nih.gov).

Subcellular Localization and Expression Pattern

In intestinal tissues, ENPP7 is produced by epithelial cells and localizes to the apical (luminal) surface. Immunolocalization studies found ENPP7 concentrated on the microvillar membrane of small-intestine enterocytes (www.genecards.org). It is inserted as a single-pass membrane protein, with its catalytic domain exposed to the extracellular (luminal) side (www.genecards.org). This strategic positioning allows ENPP7 to directly encounter dietary sphingomyelin and luminal lipids as they pass through the gut.

ENPP7 can also be released from the membrane, producing a soluble form of the enzyme in the lumen. There is a trypsin-sensitive site just above the transmembrane anchor (pmc.ncbi.nlm.nih.gov). Pancreatic trypsin in the duodenum can cleave this site, shedding the catalytic domain into the intestinal fluid (www.genecards.org). Experimentally, treating intestinal cells with trypsin releases active ENPP7 into the medium (www.genecards.org). Bile salts have a similar releasing effect: the presence of bile in the duodenum can strip ENPP7 from the brush border membrane and into the intestinal contents (pmc.ncbi.nlm.nih.gov). This mechanism ensures that, during a meal, ENPP7 is abundantly available in soluble form (mixed into bile salt micelles) to digest sphingomyelin and other substrates in the gut lumen. Interestingly, the trypsin-released form of ENPP7 shows even higher catalytic activity than the membrane-bound form (pmc.ncbi.nlm.nih.gov), suggesting that proteolytic processing may activate the enzyme or improve its access to substrates.

Besides the small intestine, human ENPP7 is also expressed in the liver – a notable species difference. Humans (and some primates) have significant alk-SMase expression in the liver, whereas rodents and many other mammals do not (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The human liver enzyme is found on the apical surface of cholangiocytes and hepatocytes lining the bile canaliculi (pmc.ncbi.nlm.nih.gov). From there, it is secreted into bile. Human bile contains high ENPP7 activity, as first reported in the 1990s (pmc.ncbi.nlm.nih.gov). In contrast, bile from rats, mice, pigs, and other tested animals had little or no alk-SMase activity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The human enzyme in bile appears to mirror the intestinal form in properties – it requires bile salts for activity and is inhibited by excess phosphatidylcholine (which is abundant in bile) due to substrate competition at the choline-binding site (pmc.ncbi.nlm.nih.gov). The presence of ENPP7 in bile is believed to aid in digesting sphingomyelin that is secreted into the digestive tract via bile (sphingomyelin is a minor component of bile lipids) and possibly to protect the biliary epithelium. Supporting this, ENPP7 is enriched in bile during active secretion and can be further released from liver cell surfaces by bile salts in a similar fashion to the intestinal release (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The dual production sites — intestinal mucosa and liver — make ENPP7 somewhat unique among digestive enzymes and highlight an evolutionary adaptation in humans for efficient sphingolipid digestion.

Biological Roles and Pathways

Sphingomyelin Digestion and Lipid Signaling

The primary biological role of ENPP7 is the digestion of dietary sphingomyelin, which in turn influences multiple bioactive lipid pathways. By cleaving sphingomyelin in the gut, ENPP7 generates ceramide, a sphingolipid second messenger known to regulate cell growth, differentiation, and apoptosis (pmc.ncbi.nlm.nih.gov). Ceramide produced in the intestinal lumen can be absorbed or further metabolized to sphingosine (by ceramidases) and then to sphingosine-1-phosphate (S1P). These metabolites have potent but opposing effects: ceramide and sphingosine tend to be growth-inhibitory or pro-apoptotic, whereas S1P is pro-proliferative and promotes cell survival (pmc.ncbi.nlm.nih.gov). In a healthy gut, ENPP7-derived ceramide is thought to contribute to maintaining normal turnover of epithelial cells and suppressing uncontrolled proliferation (pmc.ncbi.nlm.nih.gov). For example, ceramide can trigger apoptosis in damaged or pre-cancerous colon cells by down-regulating pro-survival signaling pathways (ceramide is known to inactivate Akt/PKB, PKC, Bcl-2, and other oncogenic signals) (pmc.ncbi.nlm.nih.gov).

Consistent with this, the absence of ENPP7 leads to an imbalance in sphingolipid signals. ENPP7-knockout mice have significantly lower intestinal ceramide levels and elevated S1P levels compared to wild-type (pubmed.ncbi.nlm.nih.gov). This shift toward the pro-proliferative S1P has tangible consequences: in ENPP7-null mice, the intestinal epithelium exhibits hyperproliferative traits, and the animals are more susceptible to tumor formation (discussed below) (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Thus, by regulating the ceramide/S1P balance, ENPP7 links sphingolipid metabolism to cell fate decisions in the gut.

Beyond local effects, sphingolipid breakdown products can also act as signaling molecules in immune and metabolic pathways. S1P, for instance, is a key regulator of lymphocyte trafficking and immune responses in mucosal tissues. The higher S1P levels observed in ENPP7-deficient mice have been correlated with changes in gut immunity (pubmed.ncbi.nlm.nih.gov). In a recent 2023 study (Frontiers in Immunology), Alyamani et al. examined ENPP7 knockout mice and found marked immunological changes: the KO mice had significantly increased T-lymphocyte numbers in the small and large intestine (CD3⁺ T cells, including CD4⁺ and CD8⁺ subsets, were higher than in wild-type), while certain dendritic cell populations were reduced (pmc.ncbi.nlm.nih.gov). Interestingly, the distribution of T cells in gut-associated lymphoid tissues was altered – knockout mice showed fewer T cells in mesenteric lymph nodes, suggesting that excess S1P or other lipid signals in the ENPP7-null gut might be retaining T cells in the intestinal tissue (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The study concluded that ENPP7 plays a role in maintaining intestinal immune homeostasis, likely through its regulation of sphingomyelin-derived mediators like ceramide and S1P (pmc.ncbi.nlm.nih.gov). While the precise signaling mechanisms remain to be clarified, this finding underscores that ENPP7’s enzymatic activity can have downstream effects on the mucosal immune system. It provides a novel link between dietary lipid metabolism and immune cell behavior in the intestine.

Inactivation of Pro-inflammatory Lipid Mediators

Another critical role of ENPP7 is to detoxify or inactivate certain inflammatory lipid molecules in the gut. Chief among these is platelet-activating factor (PAF). PAF is a powerful phospholipid mediator that can induce inflammation, increase intestinal permeability, and contribute to pathologies like inflammatory bowel disease. ENPP7, by cleaving PAF’s phosphocholine headgroup, renders PAF inactive (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This is essentially a defensive mechanism: high PAF activity in the intestine can trigger neutrophil infiltration, cytokine release, and mucosal damage, but ENPP7 can locally dampen PAF signaling. The importance of this function is illustrated by experiments showing that ENPP7 treatment negates PAF’s biological effects in vitro. For example, when human colon cancer cells (HT-29) were stimulated with PAF, they normally responded with activation of MAPK (ERK1/2) and secretion of the chemokine IL-8 – responses associated with inflammation. However, if PAF was first incubated with recombinant ENPP7, these responses were completely abolished, as the enzyme had hydrolyzed PAF into an inert glyceride form (pmc.ncbi.nlm.nih.gov). Likewise, PAF-driven chemotaxis of leukocytes was stopped by ENPP7 (pmc.ncbi.nlm.nih.gov). These results, reported by Wu et al. in 2006 (Biochem. J. 394:299), revealed PAF as a physiological substrate of ENPP7 and established that ENPP7 acts as an anti-inflammatory enzyme in the gut mucosa (pmc.ncbi.nlm.nih.gov). In diseases like ulcerative colitis (UC), where PAF levels and activity are elevated, one might expect ENPP7 to be protective. In line with this, clinical biopsies have shown that ulcerative colitis patients often have reduced ENPP7 levels in the intestinal mucosa compared to healthy individuals (pmc.ncbi.nlm.nih.gov). The enzyme’s deficiency may permit higher PAF activity, exacerbating inflammation. This correlation has been noted in the literature and suggests ENPP7 loss could contribute to chronic colitis severity (pmc.ncbi.nlm.nih.gov).

Equally important is ENPP7’s role in controlling lysophosphatidic acid (LPA) generation. LPA is not normally abundant in the lumen, but its precursor LPC is generated during fat digestion. If not degraded, some LPC can be converted by autotaxin (ENPP2) into LPA, which then might interact with LPA receptors on intestinal and immune cells. LPA is a potent mitogen and pro-motility factor, and in the colon it can promote polyp growth and angiogenesis. ENPP7 curbs this threat by premptively degrading LPC before autotaxin can act (pmc.ncbi.nlm.nih.gov). By doing so, ENPP7 is thought to reduce LPA formation and thereby reduce pro-tumoral signaling in the local environment (pmc.ncbi.nlm.nih.gov). This biochemical interplay between ENPP7 and ENPP2 highlights how different members of the NPP family can have counter-balancing effects on lipid mediators. It also provides a mechanistic explanation for some of ENPP7’s observed protective effects: diminishing LPA would conceivably slow epithelial cell migration and angiogenesis that fuel tumor growth.

Impact on Colon Cancer and Disease – Experimental Evidence

Given ENPP7’s functions (ceramide generation, PAF inactivation, LPA limitation), researchers have long hypothesized that it serves as a tumor suppressor and anti-inflammatory factor in the colon (pmc.ncbi.nlm.nih.gov). A body of evidence accumulated in the 2000s supports this hypothesis:

Clinical Significance and Current Perspectives

ENPP7 as a biomarker: The changes in ENPP7 activity in disease have spurred interest in using it as a diagnostic or prognostic biomarker. Italian researchers proposed measuring alkaline sphingomyelinase activity in stool as a non-invasive marker for colorectal cancer screening (pmc.ncbi.nlm.nih.gov). In an initial study, fecal ENPP7 levels were significantly lower in patients with colorectal cancer compared to healthy controls, suggesting that a loss of this enzyme accompanies tumor development (pmc.ncbi.nlm.nih.gov). Fecal enzyme measurement could potentially augment existing screening methods, although more validation is needed before clinical use. In the context of liver diseases, ENPP7 is being explored as well. Because humans uniquely have ENPP7 in bile, researchers have examined bile samples from patients with hepatobiliary conditions. A recent study (Duan, World J Hepatol, 2018) found that biliary ENPP7 activity is markedly reduced in cholangiocarcinoma (bile duct cancer) and in primary sclerosing cholangitis, a chronic inflammatory disease of the bile ducts (pmc.ncbi.nlm.nih.gov). The 1.2 kb ENPP7 mRNA splice variant (a truncated form) was found to be elevated in cholangiocarcinoma patient bile, whereas the normal 1.4 kb transcript was diminished (pmc.ncbi.nlm.nih.gov). This mirrors the findings in colon cancer cell lines and hints that similar mechanisms of ENPP7 downregulation occur in biliary malignancies. If these aberrant splice forms or low enzyme levels can be detected in bile or blood, they might serve as early warning signals for bile duct or liver cancers (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). However, such applications are still in research stages.

Therapeutic considerations: The protective roles of ENPP7 raise the question of whether boosting its activity could be beneficial. While no enzyme replacement therapy exists for ENPP7, a few experimental strategies have been noted. Oral supplementation with sphingomyelin-rich diets has been tested in animal models of colon cancer; intriguingly, giving extra sphingomyelin can be protective against colon carcinogenesis, presumably because microbial or residual alkaline SMase activity generates more ceramide locally (pmc.ncbi.nlm.nih.gov). This seems counter to the idea that ENPP7 helps absorb sphingomyelin (which would reduce ceramide in colon), but in practice, if enough sphingomyelin reaches the colon, bacterial sphingomyelinases or residual alk-SMase might produce tumor-suppressive ceramides. Another angle is the use of PAF antagonists or LPA pathway inhibitors to mimic the enzyme’s effects when it is missing. Since ENPP7-null mice have high PAF and LPA activity contributing to cancer, drugs targeting PAF receptors or LPA receptors might compensate. Indeed, blocking LPA signaling is being explored in oncology generally, though not specifically tied to ENPP7 yet. Meanwhile, maintaining gut health through diet (e.g. consuming sphingolipid-rich foods like dairy, which might enhance luminal ceramide) or through managing inflammation (thus not overwhelming the limited alk-SMase in colitis) are practical considerations derived from ENPP7 research.

Expert outlook: Researchers in the field, such as Rui-Dong Duan who has extensively studied ENPP7, emphasize that this enzyme is a uniquely human factor in lipid metabolism that deserves more attention (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The findings that ENPP7 protects against colon cancer and inflammation are compelling, and current efforts aim to translate this knowledge into clinical tools. There is growing interest in the ENPP family as drug targets, given ENPP2 (autotaxin) already has inhibitors in trials (for fibrosis and cancer). Conceivably, ENPP7 enhancers or stabilization approaches could be beneficial in colonic inflammatory diseases or cancer prevention. On the flip side, because ENPP7 enhances cholesterol absorption, any therapy would need to consider systemic metabolic effects. As of 2024, no drugs directly targeting ENPP7 are available, but its role in diseases is under active investigation. The recent insights into ENPP7’s structure and substrate binding (pubmed.ncbi.nlm.nih.gov) may facilitate the design of specific modulators or improved assays for the enzyme. In summary, ENPP7 is a distinctive enzyme linking diet to gut health: it digests dietary sphingomyelin and concurrently regulates important lipid signaling pathways, with effects on cell proliferation, inflammation, and possibly metabolic homeostasis. Ongoing research – from structural biology to mouse knockouts to human clinical studies – continues to shed light on this enzyme’s functions, confirming its significance in gastrointestinal biology and its potential as a biomarker or therapeutic target (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

References: ENPP7 (alkaline sphingomyelinase) has been characterized in numerous studies and reviews, including Frontiers in Immunology (2023) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), Journal of Lipid Research (2011) (pmc.ncbi.nlm.nih.gov), Biochemical Journal (2006) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), World Journal of Hepatology (2018) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), and others as cited above. These sources provide detailed experimental evidence for the enzyme’s localization, substrate specificity, and role in health and disease. The consensus from recent research is that ENPP7 is crucial for sphingomyelin processing and gut homeostasis, performing a protective, regulatory function at the interface of diet, lipid signaling, and mucosal immunity. Each major claim in this report is supported by the cited literature, reflecting the current scientific understanding of ENPP7 as of 2024.

Citations

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  27. AnnotationURLCitation(end_index=9114, start_index=9007, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2002%20%29,17%2C%201999')
  28. AnnotationURLCitation(end_index=9451, start_index=9344, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2002%20%29,17%2C%201999')
  29. AnnotationURLCitation(end_index=9804, start_index=9603, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=Alkaline%20sphingomyelinase%20cleaves%20phosphocholine%20from,inhibits%20colonic%20tumorigenesis%20and%20inflammation')
  30. AnnotationURLCitation(end_index=10111, start_index=9910, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=Alkaline%20sphingomyelinase%20cleaves%20phosphocholine%20from,inhibits%20colonic%20tumorigenesis%20and%20inflammation')
  31. AnnotationURLCitation(end_index=10874, start_index=10710, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=additionally%20in%20human%20liver,human%20enzyme%20in%20hepatobiliary%20diseases')
  32. AnnotationURLCitation(end_index=11307, start_index=11192, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=Presence%20of%20alk,41%5D.%20In')
  33. AnnotationURLCitation(end_index=11670, start_index=11555, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=Presence%20of%20alk,41%5D.%20In')
  34. AnnotationURLCitation(end_index=12060, start_index=11954, title='ENPP7 Gene - GeneCards | ENPP7 Protein | ENPP7 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ENPP7#:~:text=,PubMed%3A12671034')
  35. AnnotationURLCitation(end_index=12321, start_index=12182, title='ENPP7 Gene - GeneCards | ENPP7 Protein | ENPP7 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ENPP7#:~:text=%2A%20Cell%20membrane%3B%20Single,PubMed%3A12671034')
  36. AnnotationURLCitation(end_index=12752, start_index=12634, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=can%20be%20released%20by%20bile,29')
  37. AnnotationURLCitation(end_index=13033, start_index=12871, title='ENPP7 Gene - GeneCards | ENPP7 Protein | ENPP7 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ENPP7#:~:text=%7BECO%3A0000269%20PubMed%3A12671034%2C%2015205117%7D%20,PubMed%3A12671034')
  38. AnnotationURLCitation(end_index=13290, start_index=13128, title='ENPP7 Gene - GeneCards | ENPP7 Protein | ENPP7 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ENPP7#:~:text=%7BECO%3A0000269%20PubMed%3A12671034%2C%2015205117%7D%20,PubMed%3A12671034')
  39. AnnotationURLCitation(end_index=13571, start_index=13453, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=can%20be%20released%20by%20bile,29')
  40. AnnotationURLCitation(end_index=14019, start_index=13874, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=intestinal%20mucosa%20can%20also%20be,Wu%20et%20al%2C%202004b')
  41. AnnotationURLCitation(end_index=14487, start_index=14355, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=et%20al%2C%202004b%20%29,The%20enzyme%20in%20the')
  42. AnnotationURLCitation(end_index=14623, start_index=14488, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=pancreas,functioning%20as%20a%20proliferative%20and')
  43. AnnotationURLCitation(end_index=14866, start_index=14740, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=mucosa%2C%20confirming%20that%20it%20is,30')
  44. AnnotationURLCitation(end_index=15114, start_index=14982, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=et%20al%2C%202004b%20%29,The%20enzyme%20in%20the')
  45. AnnotationURLCitation(end_index=15350, start_index=15218, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=et%20al%2C%202004b%20%29,The%20enzyme%20in%20the')
  46. AnnotationURLCitation(end_index=15486, start_index=15351, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=pancreas,functioning%20as%20a%20proliferative%20and')
  47. AnnotationURLCitation(end_index=15890, start_index=15735, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=Similar%20also%20to%20intestinal%20alk,SMase%20is%20inhibited%20by%20PC')
  48. AnnotationURLCitation(end_index=16453, start_index=16304, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=match%20at%20L123%20surface%20of,bile%20salt%20into%20the%20lumen')
  49. AnnotationURLCitation(end_index=16571, start_index=16454, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=effects,SMase%20from%20intestinal')
  50. AnnotationURLCitation(end_index=17294, start_index=17164, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=First%2C%20it%20hydrolyses%20SM%20to,13%20Duan')
  51. AnnotationURLCitation(end_index=17815, start_index=17644, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=Sphingomyelin%20metabolism%20generates%20both%20antiproliferative,15%20Pettus%20et%20al')
  52. AnnotationURLCitation(end_index=18107, start_index=17977, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=First%2C%20it%20hydrolyses%20SM%20to,13%20Duan')
  53. AnnotationURLCitation(end_index=18457, start_index=18327, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=First%2C%20it%20hydrolyses%20SM%20to,13%20Duan')
  54. AnnotationURLCitation(end_index=18812, start_index=18677, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=32,induced%20colonic%20tumorigenesis%20associated%20with')
  55. AnnotationURLCitation(end_index=19172, start_index=19041, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=injection,in%20feces%20were%20significantly%20higher')
  56. AnnotationURLCitation(end_index=19340, start_index=19173, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=more%20pronounced%20in%20KO%20mice,induced%20colonic%20tumorigenesis%20associated%20with')
  57. AnnotationURLCitation(end_index=19967, start_index=19800, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=more%20pronounced%20in%20KO%20mice,induced%20colonic%20tumorigenesis%20associated%20with')
  58. AnnotationURLCitation(end_index=20510, start_index=20342, title='Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9894718/#:~:text=The%20numbers%20of%20both%20small,neutrophils%20were%20similar%20between%20genotypes')
  59. AnnotationURLCitation(end_index=20958, start_index=20790, title='Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9894718/#:~:text=The%20numbers%20of%20both%20small,neutrophils%20were%20similar%20between%20genotypes')
  60. AnnotationURLCitation(end_index=21124, start_index=20959, title='Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9894718/#:~:text=NPP7%20contributes%20to%20the%20regulation,be%20addressed%20in%20future%20studies')
  61. AnnotationURLCitation(end_index=21468, start_index=21303, title='Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9894718/#:~:text=NPP7%20contributes%20to%20the%20regulation,be%20addressed%20in%20future%20studies')
  62. AnnotationURLCitation(end_index=22376, start_index=22220, title='Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1386028/#:~:text=products%20were%20assayed%20with%20TLC,could%20be%20inhibited%20by%20the')
  63. AnnotationURLCitation(end_index=22525, start_index=22377, title='Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1386028/#:~:text=of%20protein%29,intestinal%20inflammation%20and%20colon%20cancer')
  64. AnnotationURLCitation(end_index=23387, start_index=23239, title='Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1386028/#:~:text=of%20protein%29,intestinal%20inflammation%20and%20colon%20cancer')
  65. AnnotationURLCitation(end_index=23604, start_index=23456, title='Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1386028/#:~:text=of%20protein%29,intestinal%20inflammation%20and%20colon%20cancer')
  66. AnnotationURLCitation(end_index=23964, start_index=23816, title='Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1386028/#:~:text=of%20protein%29,intestinal%20inflammation%20and%20colon%20cancer')
  67. AnnotationURLCitation(end_index=24382, start_index=24267, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2006%20%3B%20Wu%20et%20al%2C,21')
  68. AnnotationURLCitation(end_index=24701, start_index=24586, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2006%20%3B%20Wu%20et%20al%2C,21')
  69. AnnotationURLCitation(end_index=25351, start_index=25244, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2002%20%29,17%2C%201999')
  70. AnnotationURLCitation(end_index=25584, start_index=25477, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2002%20%29,17%2C%201999')
  71. AnnotationURLCitation(end_index=26353, start_index=26206, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=of%20tumour%20,it%20degrades%20lysophosphatidylcholine%20by%20a')
  72. AnnotationURLCitation(end_index=26817, start_index=26686, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=injection,in%20feces%20were%20significantly%20higher')
  73. AnnotationURLCitation(end_index=27214, start_index=27083, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=injection,in%20feces%20were%20significantly%20higher')
  74. AnnotationURLCitation(end_index=27515, start_index=27356, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=colonic%20tumorigenesis%20in%20alk,treatments%20induced%20colonic%20tumors%20and')
  75. AnnotationURLCitation(end_index=27877, start_index=27711, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=AOM%2FDSS%20method%2C%20tumor%20number%20per,in%20feces%20were%20significantly%20higher')
  76. AnnotationURLCitation(end_index=28225, start_index=28090, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=32,induced%20colonic%20tumorigenesis%20associated%20with')
  77. AnnotationURLCitation(end_index=28518, start_index=28351, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=more%20pronounced%20in%20KO%20mice,induced%20colonic%20tumorigenesis%20associated%20with')
  78. AnnotationURLCitation(end_index=28973, start_index=28806, title='Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25381265/#:~:text=more%20pronounced%20in%20KO%20mice,induced%20colonic%20tumorigenesis%20associated%20with')
  79. AnnotationURLCitation(end_index=29104, start_index=28974, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=First%2C%20it%20hydrolyses%20SM%20to,13%20Duan')
  80. AnnotationURLCitation(end_index=29551, start_index=29405, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=and%20induces%20apoptosis%20mainly%20by,SMase%20activity%20was')
  81. AnnotationURLCitation(end_index=29903, start_index=29773, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=First%2C%20it%20hydrolyses%20SM%20to,13%20Duan')
  82. AnnotationURLCitation(end_index=30410, start_index=30295, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2006%20%3B%20Wu%20et%20al%2C,21')
  83. AnnotationURLCitation(end_index=30636, start_index=30521, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2006%20%3B%20Wu%20et%20al%2C,21')
  84. AnnotationURLCitation(end_index=30926, start_index=30831, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=of%20alk,21')
  85. AnnotationURLCitation(end_index=31427, start_index=31312, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2006%20%3B%20Wu%20et%20al%2C,21')
  86. AnnotationURLCitation(end_index=32130, start_index=31983, title='Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3284167/#:~:text=match%20at%20L884%20sphingomyelin%20suppresses,Google%20Scholar')
  87. AnnotationURLCitation(end_index=32432, start_index=32327, title='Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3284167/#:~:text=Scholar%5D%20,Dietary')
  88. AnnotationURLCitation(end_index=32775, start_index=32649, title='Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3284167/#:~:text=match%20at%20L894%20sphingomyelin,cleaving')
  89. AnnotationURLCitation(end_index=33071, start_index=32922, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=additionally%20in%20human%20liver,for%20close%20study%20on%20this')
  90. AnnotationURLCitation(end_index=33243, start_index=33072, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=Core%20tip%3A%20Alkaline%20sphingomyelinase%20is,the%20implications%20of%20the%20enzyme')
  91. AnnotationURLCitation(end_index=34402, start_index=34228, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=and%20in%20longstanding%20ulcerative%20colitis,genetic%20perturbations%2C%20as%20an%20exon')
  92. AnnotationURLCitation(end_index=34717, start_index=34602, title='Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2360232/#:~:text=2006%20%3B%20Wu%20et%20al%2C,21')
  93. AnnotationURLCitation(end_index=35391, start_index=35283, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=steatosis%20and%20PSC,69')
  94. AnnotationURLCitation(end_index=35707, start_index=35566, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=match%20at%20L281%20the%20bile,In%20the%20bile%20of%20one')
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  96. AnnotationURLCitation(end_index=36317, start_index=36152, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=match%20at%20L300%20aberrant%20isoform,known%20that%20cholangiocarcinoma%20is%20a')
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  100. AnnotationURLCitation(end_index=39428, start_index=39263, title='Crystal structure of the human alkaline sphingomyelinase provides insights into substrate recognition - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/28292932/#:~:text=of%20substrate%20recognition%2C%20we%20determined,within%20the%20NPP%20enzyme%20family')
  101. AnnotationURLCitation(end_index=40199, start_index=40034, title='Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9894718/#:~:text=NPP7%20contributes%20to%20the%20regulation,be%20addressed%20in%20future%20studies')
  102. AnnotationURLCitation(end_index=40349, start_index=40200, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=additionally%20in%20human%20liver,for%20close%20study%20on%20this')
  103. AnnotationURLCitation(end_index=40653, start_index=40499, title='Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9894718/#:~:text=Alkaline%20sphingomyelinase%20,of%20the%20intestinal%20immune%20system')
  104. AnnotationURLCitation(end_index=40819, start_index=40654, title='Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9894718/#:~:text=NPP7%20contributes%20to%20the%20regulation,be%20addressed%20in%20future%20studies')
  105. AnnotationURLCitation(end_index=40995, start_index=40856, title='Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3284167/#:~:text=More%20than%2040%20years%20ago%2C,SMase%20activity%20in')
  106. AnnotationURLCitation(end_index=41187, start_index=41026, title='Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC1386028/#:~:text=%5B%5E%7B3%7DH%5DOctadecyl,bile%20salt%2C%20particularly%20taurocholate%20and')
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  108. AnnotationURLCitation(end_index=41576, start_index=41375, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=Alkaline%20sphingomyelinase%20cleaves%20phosphocholine%20from,inhibits%20colonic%20tumorigenesis%20and%20inflammation')
  109. AnnotationURLCitation(end_index=41741, start_index=41577, title='Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5838443/#:~:text=additionally%20in%20human%20liver,human%20enzyme%20in%20hepatobiliary%20diseases')