Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.34 (lipoprotein lipase)
7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fusarium heterosporum produces a solvent-tolerant lipase. A 1.3-kbp lipase cDNA was isolated from the cDNA library by colony hybridization with an oligonucleotide probe corresponding to the N-terminal amino acid sequence. Nucleotide sequence analysis showed an open reading frame of 999 bp, and the deduced amino acid sequence contained the N-terminal sequence determined by Edman degradation and the consensus pentapeptide (-Gly-X-Ser-X-Gly-), which is conserved in lipase, esterase, and serine protease. The mature lipase consisted of 301 amino acid residues with a molecular mass of 32.7 kDa, preceded by the putative signal peptide or preprosequence. The enzyme was homologous to lipases from Humicola lanuginosa (39% homology), Rhizomucor miehei (32%), Rhizopus delemar (32%), and Rhizopus niveus (32%), and to mono- and diacylglycerol lipase from Penicillium camembertii (38%). Comparison of this lipase with these homologous enzymes suggested that the catalytic triad was composed of Ser144, Asp198, and His256, and that the oxyanion hole was formed with Ser 82.
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PMID:Cloning and nucleotide sequence of cDNA encoding a lipase from Fusarium heterosporum. 785 71

Glycosyl-phosphatidylinositol-anchored membrane proteins (GPI-proteins) are normally identified either by cleavage of the lipid anchor using (glycosyl)phosphatidylinositol-specific phospholipases C or D (GPI-PLs) or by metabolic labeling of the lipid moiety with specific building blocks. Therefore, methods for discrimination between transmembrane proteins and GPI-proteins on the basis of their physicochemical properties are desirable. Here we are presenting a selective extraction method for typical well-characterized mammalian GPI-proteins, e.g., acetylcholine esterase, alkaline phosphatase, 5'-nucleotidase, and lipoprotein lipase, using a derivative of taurocholate. The results were compared to those obtained with well-characterized transmembrane proteins, e.g., insulin receptor and hydroxymethyl glutaryl coenzyme A-reductase, glucose transporters, or aminopeptidase M and several commercially available detergents. With regard to total membrane proteins, it was possible to selectively enrich GPI-proteins up to 8- to 14-fold by using concentrations between 0.1 and 0.3% of 4'-NH2-amino-7 beta-benzamido-taurocholic acid (BATC). In addition, the cleavage specificity and efficiency of (G)PI-PLs were increased in the presence of identical concentrations of BATC compared to commonly used detergents, e.g., Nonidet P-40. Therefore, the present study shows that the use of BATC facilitates the identification of glycosyl-phosphatidylinositol-anchored membrane proteins.
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PMID:4'-Amino-benzamido-taurocholic acid selectively solubilizes glycosyl-phosphatidylinositol-anchored membrane proteins and improves lipolytic cleavage of their membrane anchors by specific phospholipases. 813 45

Human lipoprotein lipase (LPL) monomer consists of two domains, a larger NH2-terminal domain that contains catalytic residues and a smaller COOH-terminal domain that modulates substrate specificity and is a major determinant of heparin binding. Analyses of NH2-terminal domain function were performed after site-directed mutagenesis of the putative active-site serine residue, while COOH-terminal domain function was assessed following reaction with a monoclonal antibody. The native enzyme and mutant LPL in which serine 132 was replaced with alanine, cysteine, or glycine were transiently expressed in COS-7 cells. Mutant proteins were synthesized and secreted at levels comparable to native LPL; however, none of the mutants retained enzymatic activity. The mutant with alanine replacing serine 132 was purified and shown to be inactive with both esterase and lipase substrates; however, binding to a 1,2-didodecanoyl-sn-glycero-3-phosphatidylcholine monolayer was comparable to native LPL. These results are consistent with a catalytic, and not a lipid binding, role for serine 132. To investigate the function of the smaller COOH-terminal domain, LPL lipolytic and esterolytic activities as well as heparin binding properties were determined after reaction with a monoclonal antibody specific for this domain. Lipolytic activity was inhibited by the monoclonal antibody, whereas esterolytic activity was only marginally affected, indicating that the LPL COOH-terminal domain is required for lipolysis, perhaps by promoting interaction with insoluble substrates. Also, the affinity of antibody-reacted LPL for heparin was not significantly different from that of LPL alone, suggesting that (i) the heparin-binding site is physically distinct from the COOH-terminal domain region required for lipolysis and (ii) binding of antibody did not cause dimer dissociation. A model is proposed for the two LPL domains fulfilling different roles in the lipolytic process.
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PMID:Lipoprotein lipase domain function. 814 12

The hydrolysis of triacylglycerols of chylomicrons and very low density lipoproteins by lipoprotein lipase (LPL) requires the presence of apolipoprotein (apo) CII as a cofactor. To obtain further information on the interaction of apo CII and LPL, we generated two fusion proteins consisting of the complete LPL molecule and the mature form of apo CII. The cDNAs of both proteins were either connected directly or by a segment encoding a 16-amino-acid linker peptide. The fused cDNAs were stably expressed in human embryonic kidney (HEK) 293 cells and the enzymic properties of the recombinant proteins were examined. The fusion proteins hydrolysed both emulsified long-chain (lipase) triacyglycerol substrate and a water-soluble short-chain (esterase) fatty acid ester substrate (p-nitrophenylbutyrate), regardless of whether or not they contained the linker peptide. In the absence of exogenous apo CII, the fusion proteins had up to 3.5-times higher basal activity than wild-type LPL. Similar to wild-type LPL, the fusion proteins were inhibited by 1 M NaCl, however less than wild-type LPL. A polyclonal antibody specific for apo CII impaired their ability to hydrolyse triacylglycerol emulsions. A similar effect was seen when the tetrapeptide KGEE was used as inhibitor, which corresponds to the carboxy-terminal four amino acids of apo CII.
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PMID:Construction and functional characterization of recombinant fusion proteins of human lipoprotein lipase and apolipoprotein CII. 864 97

The role of sialic acid linked with lipoprotein lipase (LPL) in its catalytic activity was studied. When LPL was treated with sialidase, the molecular weight decreased by 2000. The sialidase-treated LPL showed unchanged hydrolyzing activity for tributyrin, a water-soluble substrate of esterase, compared with the untreated LPL. The sialidase-treated LPL also showed similar hydrolyzing activity for triolein emulsified with Triton X-100, phosphatidylcholine and phosphatidylethanolamine, whereas it showed significantly increased hydrolyzing activity for triolein emulsified with phosphatidylserine and cardiolipin (152% and 183%, compared with untreated LPL, respectively). In addition, the sialidase-treated LPL showed significantly increased hydrolyzing activity against triolein incorporated into very low-density lipoproteins and chylomicrons (151% and 186%, compared with the untreated LPL, respectively). These results suggest that the loss of sialic acids does not modify the function of the catalytic site of LPL, but facilitates the interaction of the enzyme with the interface of the surface of substrate lipoproteins.
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PMID:Modification of lipoprotein lipase catalytic activity by sialic acids. 1035 18

NO-1886 ([4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester) increases lipoprotein lipase activity, resulting in a reduction in plasma triglycerides and an increase in high-density lipoprotein cholesterol. The metabolism of NO-1886 in human liver was investigated in the present study. Ester cleavage of NO-1886 from diethyl phosphonate to monoethyl phosphonate was the major metabolic pathway catalyzed by cytochrome P450. In addition, the minor metabolic pathway in human liver was the hydrolysis of the amide bond of NO-1886 by a specific cytosolic esterase. Eadie-Hofstee plots of phosphonate O-deethylation of NO-1886 in human liver microsomes showed a biphasic curve, indicating low- and high-K(m) components. Inhibition experiments with chemical inhibitors and antibodies against various cytochrome P450 isoforms suggested the involvement of CYP2C8 and CYP3A in the phosphonate O-deethylation. Recombinant CYP3A4 and CYP2C8 expressed in baculovirus-infected insect cells and human lymphoblastoid cells exhibited a high activity for phosphonate O-deethylation of NO-1886. The recombinant cytochrome P450 enzymes indicated that CYP2C8 and CYP3A4 were responsible for the low- and high-K(m) components in human liver microsomes, respectively. The selectivity of CYP2C8 in catalyzing phosphonate O-deethylation indicates that coadministration of drugs that are metabolized by the same enzyme requires careful consideration.
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PMID:Phosphonate O-deethylation of [4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester, a lipoprotein lipase-promoting agent, catalyzed by cytochrome P450 2C8 and 3A4 in human liver microsomes. 1185 49

Oil-induced mononuclear phagocytes (MN) were quantitatively assayed for various hydrolases as unfractionated suspensions of frozen and thawed cells. They apparently contain two proteases. The first, measured with urea- or acid-denatured hemoglobin, was similar to purified Proteinase I of lung with respect to pH optimum (pH 4), stability, hydrolytic and polymerizing activities, and reactions to various inhibitors. The second protease resembled chymotrypsin in its hydrolysis of glycyl-L-phenylalanine amide, acetyl-L-tyrosine ethyl ester and N-benzoyl-DL-phenylalanine-beta-naphthol ester (BPN). With the latter, its pH optimum was between 5.0 and 5.8, and its action was inhibited by diisopropylphosphorofluoridate (DFP) and p-chloromercuribenzoate. When assayed under the above conditions, polymorphonuclear exudate cells (PMN) and red blood corpuscles (RBC) manifested little or no hydrolysis of either hemoglobin or BPN. MN also contained esterases that split methyl butyrate and beta-naphthyl acetate. The pH optimum with the latter was 7.4, and its hydrolysis was partially inhibited by DFP, fluoride, taurocholate, and eserine. PMN had low esterase activity; RBC had little or none. MN, but not PMN or RBC, contained a stable lipase with a pH optimum of 6.1 in maleate buffer. Protamine, NaCl, heat, p-chloromercuribenzoate, ethylenediamine tetraacetate, taurocholate, and DFP were inhibitory, but no appreciable activation occurred in the presence of heparin or serum. Thus it possessed some of the characteristics of Korn's lipoprotein lipase, but not others.
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PMID:HYDROLYTIC ENZYMES OF RABBIT MONONUCLEAR EXUDATE CELLS. I. QUANTITATIVE ASSAY AND PROPERTIES OF CERTAIN PROTEASES, NON-SPECIFIC ESTERASES, AND LIPASES OF MONONUCLEAR AND POLYMORPHONUCLEAR CELLS AND ERYTHROCYTES. 1415 92

The central role of the intracellular enzyme hormone-sensitive lipase (HSL) in regulating fatty acid metabolism makes it an interesting pharmacological target for the treatment of insulin resistant and dyslipidemic disorders where a decrease in delivery of fatty acids to the circulation is desirable, e.g., in individuals with type 2 diabetes, metabolic syndrome, or impaired glucose tolerance. On the basis of a lead structure from high throughput screening, we have identified a very potent type of carbamoyl-triazole inhibitors of HSL. As part of the lead optimization program, four new classes of carbamoyl-triazoles were synthesized and tested with respect to potency, efficacy and selectivity. Methyl-phenyl-carbamoyl-triazoles were identified as potent and efficacious HSL inhibitors. These compounds do not inhibit other hydrolases such as hepatic lipase, lipoprotein lipase, pancreatic lipase, and butyrylcholine esterase. However, the inhibitors 4b and 4g with IC(50) values for HSL of 0.17 and 0.25 microM, respectively, were the only inhibitors selective against acetylcholine esterase. A reversible pseudosubstrate inhibition mechanism is proposed for this class of inhibitors.
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PMID:Synthesis and structure-activity relationship for a novel class of potent and selective carbamoyl-triazole based inhibitors of hormone sensitive lipase. 1471 11

Elevated serum hydrocortisone (HC) levels are associated with larger fat cells and elevated levels of lipogenic and associated enzymes in late term pig fetuses from genetically obese dams. We have investigated the influence of HC status per se on these and other adipose tissue traits by chronically treating pig fetuses hypophysectomized (hypox) on day 70 with HC between either day 70 and 90 or 90 and 105 of gestation. Treatment with HC during both periods increased serum HC levels (P<.05) and increased fat cell size (P<.05) in the perirenal (PERI) and subcutaneous (SQ) depots, but failed to influence body weights, insulin-like growth factor-1 and insulin levels. Quantitative analysis of sections of PERI and SQ adipose tissue indicated that HC increased lipoprotein lipase (LPL), esterase and glucose-6-phosphate dehydrogenase (G6PDH) activities. The degree of esterase and G6PDH, but not LPL response to HC, was greater during the 90- to 105-day period than during the earlier period. HC significantly increased lipid accretion only in the SQ depot between 90 and 105 days. Overall, HC significantly augmented hypox-induced alterations in cellular and metabolic traits of developing adipose tissue. The general increase in fat cell size (21%) with moderate (SQ-105d) or no (PERI-90, 105d; SQ-90d) increase in lipid accretion indicates that HC either did not influence or decreased apparent fat cell number. Regardless, these data indicate that changes in serum HC per se may account for adipose tissue traits that characterize fetuses from genetically obese dams.
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PMID:The influence of hydrocortisone (HC) on differentiation of adipose tissue is dependent on fetal age. 1635 93

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.
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PMID:Each lipase has a unique sensitivity profile for organophosphorus inhibitors. 1644 51


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