Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies indicated that there was an alkaline sphingomyelinase (SMase) activity in small intestine, but its properties have not been studied in detail. In the present work, we studied the distribution of this enzyme activity in rat gastrointestinal tract and characterized it in intestinal mucosal homogenates. Little alkaline SMase activity was detected in the stomach and the duodenum. The activity in both mucosa and intestinal content increased in the small intestine and reached the maximum at the distal jejunum, then declined in the ileum and slightly increased again in the colon. The activity distribution pattern differed markedly from those of acid SMase and alkaline phosphatase. Little alkaline SMase activity could be found in bile, liver and pancreas before or after treatment with trypsin. The optimum pH of the alkaline SMase was 9. It specifically hydrolyzed sphingomyelin (SM), not phosphatidylcholine, to ceramide and phosphocholine. The alkaline SMase was bile salt dependent and was optionally activated by 3 mM bile salts. Triton X-100 could not mimic the effect of bile salt, rather dose-dependently inhibited the enzyme activity. Ca2+, Mg2+ did not change the alkaline SMase activity in the presence of bile salts, and reduced the activity in the absence of bile salt. Trypsin inactivated acid SMase in pancreas, liver and duodenum but had no influence on intestinal alkaline SMase activity. In conclusion, the intestinal alkaline SMase has a specific distribution pattern and the characters of it differ in several respects from the known acid and neutral SMases.
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PMID:Alkaline sphingomyelinase activity in rat gastrointestinal tract: distribution and characteristics. 749 15

Previous studies showed that bile salts had a promoting effect on colon cancer development and this effect was inhibited by ursodeoxycholate (UDC). We recently found that both human colorectal adenomas and carcinomas were associated with a specific decrease in alkaline sphingomyelinase activity. In this work, we compared the effects of ursodeoxycholate and other bile salts on the levels of rat intestinal alkaline sphingomyelinase both in the intestinal loops and after oral administration. Bile salts at different concentrations were injected into intestinal loops and the dissociation of alkaline sphingomyelinase from the mucosa was assayed. We found that bile salts, including taurocholate, taurodeoxycholate, glycocholate, glycochenodeoxycholate, and 3-(3-cholamidopropyl dimethylammonio)-1-propanesulonate (CHAPS), dose dependently dissociated alkaline sphingomyelinase from the intestinal mucosa. UDC alone did not dissociate the enzyme but significantly inhibited the dissociation caused by other bile salts and CHAPS. Feeding rats with 0.3% (w/w) taurocholate for four days decreased peak activity of intestinal alkaline sphingomyelinase by 39% and total activity in the intestine by 20% and increased the output of the enzyme in the feces. In contrast, feeding 0.3% (w/w) UDC for four days increased the peak activity of alkaline sphingomyelinase in the small intestine by 87% and the activity in the colon by 187%. The total activity of alkaline sphingomyelinase was increased by 80% and the output of the enzyme in the feces was only slightly increased by UDC administration. The changes in alkaline phosphatase after feeding taurocholate and UDC were much smaller. Our results indicate that UDC and other bile salts have different effects on the levels of alkaline sphingomyelinase, which may be implicated in their different influences on cancer development reported previously.
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PMID:Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: a potential implication in tumorigenesis. 950 30

The hydrolysis of sphingomyelin generates key molecules regulating cell growth and inducing apoptosis. Data from animal cancer models support an inhibitory role for this pathway in the malignant transformation of the colonic mucosa. In the intestinal tract, a sphingomyelinase with an optimum alkaline pH has been identified. We recently found that the activity of alkaline sphingomyelinase is significantly decreased in colorectal adenocarcinomas, indicating a potential anticarcinogenic role of this enzyme. To further examine whether the reduction of sphingomyelinase is present already in the premalignant state of neoplastic transformation, we measured sphingomyelinase activities in patients with familial adenomatous polyposis (FAP) and in sporadic colorectal tubulovillous adenomas. Tissue samples were taken from adenomas and surrounding macroscopically normal mucosa from 11 FAP patients operated with ileorectal anastomosis, from three FAP patients with intact colon, from 13 patients with sporadic colorectal adenomas and from 12 controls. Activities of acid, neutral and alkaline sphingomyelinase were measured together with alkaline phosphatase. In FAP adenoma tissue, alkaline sphingomyelinase activity was reduced by 90% compared to controls (P < 0.0001), acid sphingomyelinase by 66% (P < 0.01) and neutral sphingomyelinase by 54% (P < 0.05). Similar reductions were found in the surrounding mucosa. In sporadic adenoma tissue, only alkaline sphingomyelinase was reduced significantly, by 57% (P < 0.05). Alkaline phosphatase was not changed in FAP adenomas, but decreased in the sporadic adenomas. We conclude that the markedly reduced levels of alkaline sphingomyelinase activities in FAP adenomas and in the surrounding mucosa may be a pathogenic factor that can lead to unrestrained cell proliferation and neoplastic transformation.
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PMID:Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation? 1049 47

Sphingomyelin (SM) metabolism in the gut has been implicated in colonic tumorigenesis. Intestinal alkaline sphingomyelinase (alk-SMase) hydrolyses SM in the intestinal content and at the brush border. The enzyme activity is decreased in the tissues of human colorectal tumours. This study examines whether site or chain-mutation of alk-SMase occurs in colon cancer HT-29 cells and Caco-2 cells. Total RNA was isolated and the cDNA of alk-SMase was amplified by RT-PCR. The size of the cDNA from HT-29 cells was smaller than that of the wild-type cDNA. DNA sequencing identified a deletion of exon 4 in alk-SMase cDNA in HT-29 cells. No mutation in genomic alk-SMase DNA from exon 3 to 5 was identified. The exon 4 deletion was caused by a shift of RNA splice site in chromosome 17q25. In Caco-2 cells, no mutation of alk-SMase cDNA was identified. Transient expression in COS-7 cells showed that the enzyme from the cDNA in HT-29 cells had little alk-SMase activity whereas that in Caco-2 cells was as active as the wild-type alk-SMase. The deleted region included residue His353, which is predicted to form a substrate-binding site of alk-SMase. H353A substitution resulted in a protein with no alk-SMase activity. In monolayer cultured Caco-2 cells and HT-29 cells the alk-SMase activities were low. However, to culture the cells under polarizing conditions increased alk-SMase activity and reduced SM level in Caco-2 cells. The alk-SMase activity varied in parallel with alkaline phosphatase activity. In conclusion, we identified an inactive deletion in alk-SMase in HT-29 cells, and a differentiation-related expression of the enzyme in Caco-2 cells. The results provide a molecular mechanism related to previous findings of reduced alk-SMase activity in human colon cancers.
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PMID: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. 1501 55

Dietary fibre and fat affect colonic tumourigenesis and inflammation. Sphingomyelin metabolism may have implications for the pathogenesis of colonic tumours and ulcerative colitis. The present study examined the effects of psyllium and fat on the enzymes responsible for sphingomyelin metabolism and apoptosis in the colon. Mice were fed control, psyllium-containing (100 g/kg), high-fat (313 g/kg, 53 % energy as fat) or high-fat plus psyllium diets for 4 weeks. The activities of acid, neutral and alkaline sphingomyelinase (SMase), neutral ceramidase, and caspase 3, 8 and 9 in colonic mucosa were determined. The expressions of alkaline SMase and caspase 3 were examined. The psyllium-containing diet was found to increase significantly the activities of alkaline SMase and caspase 3 and decreased those of acid SMase and neutral ceramidase. The high-fat diet had opposite effects on these enzymes and attenuated the effects of psyllium. Western blotting showed that psyllium increased and high-fat decreased the levels of alkaline SMase and caspase 3 in colonic mucosa. The change in caspase 3 activity was positively correlated with that of alkaline SMase and negatively with acid SMase. No similar changes of acid and alkaline phosphatase activities in the colon or acid and neutral SMase activity in the liver were identified. In conclusion, colonic sphingomyelin metabolism and apoptosis were affected by psyllium and fat in an opposite manner. The results may have implications for colorectal tumourigenesis and inflammation.
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PMID:Psyllium and fat in diets differentially affect the activities and expressions of colonic sphingomyelinases and caspase in mice. 1513 23