Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bile-salt-activated lipase belongs to the cholinesterase alpha/beta-hydrolase-fold family of proteins. Here, we have investigated the structural organisation of the human isoform by mapping tryptic cleavage sites using limited proteolysis and by expression studies using a recombinant truncated variant. Two accessible regions in the tertiary structure were identified. The first is defined by a tryptic cleavage at Lys429 and lies within the alpha/beta-hydrolase fold in bile-salt-activated lipase between a central beta-sheet and an active-site histidine residue, as deduced from sequence similarity across the cholinesterases and known structural properties. This region exhibits a proteolytic and topological similarity to the lid region in pancreatic lipase. The other accessible region in the tertiary structure is defined by a tryptic cleavage at Arg520 and occurs within a catalytically non-essential segment Leu519-Gln535, as identified by expression of a truncated variant which lacks the C-terminus starting from Leu519. This region is consistent with an interdomain region between the cholinesterase-related part of the protein structure and the unique proline-rich C-terminal repeats. Both protease-sensitive regions appear to occur at domain borders, and, therefore, are consistent with a multi-domain structure. The truncated variant was fully functional as a lipase and as a bile-salt-stimulated esterase. However, compared to the full-length enzyme, the truncated variant showed an increased susceptibility to limited proteolysis, suggesting that the C-terminal repeats may regulate proteolytic degradation of the protein.
 ...
PMID:Structural organisation of human bile-salt-activated lipase probed by limited proteolysis and expression of a recombinant truncated variant. 760 35

The acidic amino acid residue required for the catalytic activity of rat pancreatic cholesterol esterase has been identified in this study by sequence comparison with other serine esterases and by site-directed mutagenesis experiments. The sequence comparison studies identified 3 acidic residues in homologous domains between cholesterol esterase, acetylcholinesterase, cholinesterase, and Geotrichum candida lipase that may potentially be the catalytic acidic residue in these proteins. The role of Glu78, Asp79, and Asp320 in the catalytic activity of rat cholesterol esterase was then addressed by mutagenesis and expression of the cDNA. Results showed that replacement of Glu78 or Asp79 with alanine has no effect on the ability of the cholesterol esterase to hydrolyze the artificial water-soluble substrate p-nitrophenyl butyrate. In contrast, the Asp320-->Ala320 substitution abolished the enzyme activity of the cholesterol esterase. The specific requirement of Asp320 for optimal enzyme activity was demonstrated by substitution of the aspartic acid with glutamic acid, thus retaining the charge unit at this position. The Asp320-->Glu320 substitution resulted in an enzyme that displayed normal interaction with bile salt. However, catalytic activity of this mutagenized protein was reduced by approximately 50%. These results strongly suggested that aspartic acid 320 is an important component of the catalytic triad of pancreatic cholesterol esterase. The specific requirement of aspartic acid, instead of glutamic acid, for optimal activity is different from that of other members of the serine esterase gene family.
 ...
PMID:Aspartic acid 320 is required for optimal activity of rat pancreatic cholesterol esterase. 841 37

The disulfide bonds and N-glycosylation sites in a glycoprotein from the Rathke's gland secretion of the Kemp's ridley turtle (Lepidochelys kempi) have been characterized with respect to peptide sequences and glycan structures. The glycoprotein constitutes about 70% of the total protein in the secretion, and based on partial sequence information, it shows more than 20% identity with both the catalytic (esterases) and the noncatalytic (thyroglobulin) members of the esterase/lipase family of proteins. For the determination of the disulfide locations, the glycoprotein was digested with chymotrypsin, and the three HPLC peptide peaks yielding fluorescent products after treatment with tributylphosphine (Bu3P) and 4-(aminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole (ABD-F) were collected. The three fractions were treated with the same reagents in separate experiments, the resulting pairs of ABD-Cys-containing peptides were separated by HPLC, and the sequence of each individual peptide was determined. The peptide identity established that three disulfide bonds existed in the glycoprotein: Cys 65-Cys 91, Cys 254-Cys 265, and Cys 130-Cys 404; the first two of these are conserved in all the members of the esterase family. For the study of the glycosylation sites, the glycoprotein was reduced with Bu3P and the SH groups covalently blocked with ABD-F, and the resulting product was digested with chymotrypsin. The glycopeptides were isolated by affinity chromatography, separated by reverse-phase HPLC, and subjected to sequence analysis and fast atom bombardment mass spectrometry before and after separation of the glycans and the peptides through the action of glycoamidase. Three separate glycosylation sites were identified, each containing multiple glycans. The sugar analyses of the hydrolysates of the glycoprotein indicated that only GlcNAc and Man were present as building blocks, and the mass spectrometric data showed that Man3GlcNAc2-, GlcNAc2-4Man3GlcNAc2-, and possibly GlcNAc2Man2GlcNAc2- were the major glycan structures, distributed differently at the three sites. The three glycosylation sites match three of the nine sites glycosylated in human serum choline esterase, and one of them, Asn 106, is also found as one of two glycosylation sites in the homologous segment of thyroglobulin.
 ...
PMID:Characterization of the disulfide bonds and the N-glycosylation sites in the glycoprotein from Rathke's gland secretions of Kemp's ridley sea turtle (Lepidochelys kempi). 878 16

We report the case of a 54-year-old male patient hospitalized for diarrhea and weight loss (8 kg over the previous three months). At admission, we observed pale oral and conjunctival mucosa and peripheral edema of the lower limbs. Stool frequency was 8-10 per day. Laboratory data were as follows: hemoglobin, 11 g/dL; total proteins, 4.3 g/dL; albumin, 2 g/dL; pseudocholinesterase, 1248 U/L; triglycerides, 54 mg/dL; serum cholesterol, 102 mg/dL; calcium, 7.9 mg/dL. Fecal fat was 8.2 g/24 hr. Fecal chymotrypsin (FCT) was 2.3 U/g. A duodenal probe was performed after administration of intravenous secretin and cerulein stimulation, and a contemporaneous mucosal biopsy was taken at the ligament of Treitz. Microscopic examination showed numerous Giardia lamblia in the fluid collected. Pancreatic enzyme activity in the duodenal fluid showed a severe reduction in lipase: 120 U/ml/min (normal value = 600 U/ml/min). Small bowel bacterial overgrowth was excluded by microbiologic examination of intestinal fluid. The patient was treated with metronidazole, leading to a complete remission of symptoms. Immediately after stopping treatment, the FCT was 15.2 U/g. Four months after hospitalization, the patient's weight had increased by 11 kg and he was asymptomatic; total proteins were 6.7 g/dL; albumin, 3.8 g/dL; triglycerides, 104 mg/dL; cholesterol, 152 mg/dL; pseudocholinesterase, 3,567 mg/dL; calcium, 10 mg/dL; steatorrhea was 3.6 g/24 hr and fecal chymotrypsin was 88 U/g. This case describes a severe, reversible impairment in pancreatic function leading to clinical malabsorption in the presence of Giardia infection.
 ...
PMID:Secondary impairment of pancreatic function as a cause of severe malabsorption in intestinal giardiasis: a case report. 923 Jul 86

Diarrhoea is a relatively frequent adverse event, accounting for about 7% of all drug adverse effects. More than 700 drugs have been implicated in causing diarrhoea; those most frequently involved are antimicrobials, laxatives, magnesium-containing antacids, lactose- or sorbitol-containing products, nonsteroidal anti-inflammatory drugs, prostaglandins, colchicine, antineoplastics, antiarrhythmic drugs and cholinergic agents. Certain new drugs are likely to induce diarrhoea because of their pharmacodynamic properties; examples include anthraquinone-related agents, alpha-glucosidase inhibitors, lipase inhibitors and cholinesterase inhibitors. Antimicrobials are responsible for 25% of drug-induced diarrhoea. The disease spectrum of antimicrobial-associated diarrhoea ranges from benign diarrhoea to pseudomembranous colitis. Several pathophysiological mechanisms are involved in drug-induced diarrhoea: osmotic diarrhoea, secretory diarrhoea, shortened transit time, exudative diarrhoea and protein-losing enteropathy, and malabsorption or maldigestion of fat and carbohydrates. Often 2 or more mechanisms are present simultaneously. In clinical practice, 2 major types of diarrhoea are seen: acute diarrhoea, which usually appears during the first few days of treatment, and chronic diarrhoea, lasting more than 3 or 4 weeks and which can appear a long time after the start of drug therapy. Both can be severe and poorly tolerated. In a patient presenting with diarrhoea, the medical history is very important, especially the drug history, as it can suggest a diagnosis of drug-induced diarrhoea and thereby avoid multiple diagnostic tests. The clinical examination should cover severity criteria such as fever, rectal emission of blood and mucus, dehydration and bodyweight loss. Establishing a relationship between drug consumption and diarrhoea or colitis can be difficult when the time elapsed between the start of the drug and the onset of symptoms is long, sometimes up to several months or years.
 ...
PMID:Drug-induced diarrhoea. 1064 76

Various proteins/enzymes obtained commercially were tested for the presence of endogenously nitrated tyrosine by Western blot analysis omitting reducing agent in the step of SDS-PAGE. Histones II-S and VIII-S, IgG, cAMP-dependent protein kinase (PKA), phosphorylase b, and phosphorylase kinase exhibited strong immunoreactive bands. Histone VI-S, glycogen synthase, lactate dehydrogenase, actin, thyroglobulin, and macroglobulin exhibited moderate immunoreactivity. Histone III-S, casein, acetyl cholinesterase, DNase I, and lipase had only traceable immunoreactivity. Whereas histone VII-S, pyruvate kinase, trypsin, pepsin, chymotrypsin, protease IV, and protease XIII, and glutathione S-transferase lacked immunoreactivity. A variation of immunoreactivity between hypertensive and normaltensive rat hearts was found in the histone-agarose fractions of crude extracts. Additionally, nitrotyrosine immunoreactivity was observed in non-mammalian organisms including Eschericia coli, Saccharomyces cerevisiae and Triticum vulgaris. Upon the treatment of 15 microM peroxynitrite (PN), strong oxidant derived from nitric oxide (NO), the apparent Km of PKA for cAMP increased from approximately 10(-8) to 10(-6) M. The results imply that the varied nitration of tyrosine residues in proteins/enzymes may occur as a post-translational modification in vivo, and such discriminative nitration may be vital in PN/NO-regulated signal transduction cascade.
 ...
PMID:Protein nitration. 1119 83

Diphenylmethyleneaminooxycarboxylic acids were found to represent novel type inhibitors of the enzyme aldose reductase. Ester derivatives of the most active compound (3c) (IC(50)=33 microM) were prepared as potential prodrugs and the rate of degradation was studied by treatment with buffers, plasma, and various hydrolytic enzymes. Whereas all compounds were not hydrolysed at physiological pH, incubation in the presence of enzyme led to hydrolysis. The rate of enzymatic degradation, however, depended on the nature of the ester function. Whereas the isopropyl ester (4) turned out to be the most stable compound, the ethyl ester (2c) could be cleaved in the presence of esterase and lipase, respectively. The benzylic and aromatic esters were found to be hydrolysed rapidly in the presence of lipase (benzyl ester, 7), or in plasma, by cholinesterase and esterase (phenyl ester, 6), respectively.
 ...
PMID:On the prodrug potential of novel aldose reductase inhibitors with diphenylmethyleneaminooxycarboxylic acid structure. 1180 27

Quantitative determination of newly reported enzymes activity in the crude skin toxin (CST) of catfish revealed highest activities of hyaluronidase and lipase, lesser activities of phospholipase A2, lactate dehydrogenase (LDH), cholinesterase (CE), alkaline phosphatase (ALP), and aspartate transaminase (AST), and least activities of proteinase and 5-nucleotidase (5'-NT). The CST has a hemolytic activity of 54% and no ichthyotoxicity up to 500 ug/ml. The chosen dose of CST (LD12.5) showed a potential cytotoxic activity against solid Ehrlich carcinoma-bearing mice demonstrated by an increase in the mean survival time (238.8%) and tumor growth inhibition ratio (T/C) of 73%. The CST ameliorated the relative weights of heart and liver after three weeks, while modulating the elevation in the relative spleen weight throughout the treatment periods (three, six, and nine weeks). The levels of serum triglyceride, total cholesterol, and liver total lipids were normalized after three weeks, whereas the serum albumin and hepatic glycogen concentrations, as well as ALT, AST, 5'-NT, and G-6-Pase activities were ameliorated after 6 weeks. Serum levels of glucose, LDH, and creatine kinase (CK) activities were significantly modulated throughout the treatment periods. Histological examinations of the tumor and liver tissues of treated tumor-bearing animals were carried out. Tumor tissues showed many cytolytic and cytopathic changes after treatment, while liver tissues showed moderate dysplastic changes after six weeks of treatment, which became more marked after nine weeks.
 ...
PMID:Biological activities of the crude skin toxin of the Suez Gulf oriental catfish (Plotosus lineatus) and its antitumor effect in vivo (mice). 1250 71

Phenyl carbamates are used to treat Alzheimer's disease. These compounds inhibit acetylcholinesterase and butyrylcholinesterase. The goal of this work was to determine the chemical characteristics of ortho substituents that make some carbamates better inhibitors of butyrylcholinesterase than of acetylcholinesterase, cholesterol esterase, and lipase. The inhibition constants, Ki, Ki', kc, and ki were measured for nine different carbamates. The values were plotted according to Hammett, Taft-Kutter-Hansch, and Swan-Lupton to obtain constants that correlated the chemical nature of the substituents with inhibition potency. It was found that the negative charges of tetrahedral intermediates were more stabilized by ortho electron-withdrawing substituents of the inhibitors in butyrylcholinesterase than in acetylcholinesterase. This result confirmed formation of 3-pronged hydrogen bonds for the oxyanion hole of butyrylcholinesterase and 2-pronged hydrogen bonds for the oxyanion hole of acetylcholinesterase. Furthermore, it was found that ortho electron-donating substituents of the inhibitors accelerated inhibition of butyrylcholinesterase by ortho polar effects. Conformations of enzyme-inhibitor tetrahedral intermediates for butyrylcholinesterase were different from those for acetylcholinesterase and cholesterol esterase; ortho substituents in the tetrahedral intermediates were located far from the negatively charged carbonyl oxygens in butyrylcholinesterase, but close to the negatively charged carbonyl oxygens in acetylcholinesterase and cholesterol esterase. In conclusion, electron-donating substituents in the ortho position were better inhibitors of butyrylcholinesterase than acetylcholinesterase, while electron-withdrawing substituents were better inhibitors of acetylcholinesterase.
 ...
PMID:Ortho effects for inhibition mechanisms of butyrylcholinesterase by o-substituted phenyl N-butyl carbamates and comparison with acetylcholinesterase, cholesterol esterase, and lipase. 1602 4

Lipases sensitive to organophosphorus (OP) inhibitors play critical roles in cell regulation, nutrition, and disease, but little is known on the toxicological aspects in mammals. To help fill this gap, six lipases or lipase-like proteins are assayed for OP sensitivity in vitro under standard conditions (25 degrees C, 15 min incubation). Postheparin serum lipase, lipoprotein lipase (LPL) (two sources), pancreatic lipase, monoacylglycerol (MAG) lipase, cholesterol esterase, and KIAA1363 are considered with 32 OP pesticides and related compounds. Postheparin lipolytic activity in rat serum is inhibited by 14 OPs, including chlorpyrifos oxon (IC50 50-97 nM). LPL (bovine milk and Pseudomonas) generally is less inhibited by the insecticides or activated oxons, but the milk enzyme is very sensitive to six fluorophosphonates and benzodioxaphosphorin oxides (IC50 7-20 nM). Porcine pancreatic lipase is very sensitive to dioctyl 4-nitrophenyl phosphate (IC50 8 nM), MAG lipase of mouse brain to O-4-nitrophenyl methyldodecylphosphinate (IC50 0.6 nM), and cholesterol esterase (bovine pancreas) to all of the classes of OPs tested (IC50 < 10 nM for 17 compounds). KIAA1363 is sensitive to numerous OPs, including two O-4-nitrophenyl compounds (IC50 3-4 nM). In an overview, inhibition of 28 serine hydrolases (including lipases) by eight OPs (chlorpyrifos oxon, diazoxon, paraoxon, dichlorvos, and four nonpesticides) showed that brain acetylcholinesterase is usually less sensitive than butyrylcholinesterase, liver esterase, cholesterol esterase, and KIAA1363. In general, each lipase (like each serine hydrolase) has a different spectrum of OP sensitivity, and individual OPs have unique ranking of potency for inhibition of serine hydrolases.
 ...
PMID:Each lipase has a unique sensitivity profile for organophosphorus inhibitors. 1644 51


<< Previous 1 2 3 4 5 6 Next >>