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)

We have previously reported two common lipoprotein lipase (LPL) gene mutations underlying LPL deficiency in the majority of 37 French Canadians (Monsalve et al., 1990. J. Clin. Invest. 86: 728-734; Ma et al., 1991. N. Engl. J. Med. 324: 1761-1766). By examining the 10 coding exons of the LPL gene in another French Canadian patient, we have identified a third missense mutation that is found in two of the three remaining patients for whom mutations are undefined. This is a G to A transition in exon 6 that results in a substitution of asparagine for aspartic acid at residue 250. Using in vitro site-directed mutagenesis, we have confirmed that this mutation causes a catalytically defective LPL protein. In addition, the Asp250----Asn mutation was also found on the same haplotype in an LPL-deficient patient of Dutch ancestry, suggesting a common origin. This mutation alters a TaqI restriction site in exon 6 and will allow for rapid screening in patients with LPL deficiency.
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PMID:A missense mutation (Asp250----Asn) in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries. 163 92

We are studying naturally occurring mutations in the gene for lipoprotein lipase (LPL) to advance our knowledge about the structure/function relationships for this enzyme. We and others have previously described 11 mutations in human LPL gene and until now none of these directly involves any of the residues in the proposed Asp156-His241-Ser132 catalytic triad. Here we report two separate probands who are deficient in LPL activity and have three different LPL gene haplotypes, suggesting three distinct mutations. Using polymerase chain reaction cloning and DNA sequencing we have identified that proband 1 is a compound heterozygote for a G----A transition at nucleotide 721, resulting in a substitution of asparagine for aspartic acid at residue 156, and a T----A transversion, resulting in a substitution of serine for cysteine at residues 216. Proband 2 is homozygous for an A----G base change at nucleotide 722, leading to a substitution of glycine for aspartic acid at residue 156. The presence of these mutations in the patients and available family members was confirmed by restriction analysis of polymerase chain reaction-amplified DNA. In vitro site-directed mutagenesis and subsequent expression in COS cells have confirmed that all three mutations result in catalytically defective LPL. The two naturally occurring mutations, which both alter the same aspartic acid residue in the proposed Asp156-His241-Ser132 catalytic triad of human LPL, indicate that Asp156 plays a significant role in LPL catalysis. The Cys216----Ser mutation destroys a conserved disulfide bridge that is apparently critical for maintaining LPL structure and function.
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PMID:Two naturally occurring mutations at the first and second bases of codon aspartic acid 156 in the proposed catalytic triad of human lipoprotein lipase. In vivo evidence that aspartic acid 156 is essential for catalysis. 173 Jul 27

A gene (mdlA) encoding mono- and diacylglycerol lipase (MDGL) from Penicillium camembertii U-150 has been cloned using a 0.9-kb DNA fragment, generated by mixed oligodeoxyribonucleotide (oligo)-primed polymerase chain reaction (PCR), as a probe. Comparison of the nucleotide sequence of the gene and its cDNA clone, obtained by PCR, revealed the presence of two short introns (56 and 53 bp). Two transcription start points (tsp) were localized by primer extension analysis at 37 and 30 bp upstream from the ATG start codon and were preceded by the canonical TATAAA and CAAT sequences. The deduced amino acid (aa) sequence corresponds to 305 aa including a putative signal peptide of 26 aa. Despite significant differences in substrate specificity, the primary structure of the mature region shows homology (29% and 40%) to the triacylglycerol lipases from Mucor miehei and Humicola lanuginosa. Furthermore, the three residues presumed to form the catalytic site, serine, aspartic acid and histidine, are conserved. Primary structure comparisons of MDGL and triacylglycerol lipases are shown.
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PMID:Cloning and structure of the mono- and diacylglycerol lipase-encoding gene from Penicillium camembertii U-150. 187 99

Using polymerase chain reaction (PCR) based techniques, we have identified individuals in the ECTIM study of myocardial infarction survivors (cases) and healthy matched controls who are carriers for a mutation of the gene for lipoprotein lipase (LPL) which alters amino acid 9 from aspartic acid to asparagine (LPL-D9N). The frequency of carriers in the cases from Belfast and France (3 separate centres) was 2.5 and 3.7%, respectively (mean 3.3%, 95% CI 1.9-4.7) and in the controls 2.0 and 2.9%, respectively (mean 2.7%, 95% CI 1.6-3.8%), but this difference was not statistically significant. In the cases, carriers of the allele for LPL-N9 had higher levels of several plasma lipid traits including total triglycerides (TG) (30%), very low density lipoprotein (VLDL) cholesterol (19%), apo E (24%), apo C-III (17%), lipoprotein particles (Lp) containing both apo E and apo B (LpE:B) (32%), and particles containing both apo C-III and apo B (LpCIII:B) (39%), and this effect was consistent in cases both from Belfast and from the French centres combined. By contrast, in the controls there were no differences in any lipid trait between carriers and non-carriers of the mutation that was consistent between the French centres and Belfast. There were no significant differences in the levels of any measured factor between cases and controls that could explain the different effect on plasma lipid traits associated with the mutation. However, compared to the non-carriers, in both cases and controls who carried the mutation, plasma TG concentrations were higher in those whose body mass index (BMI) was above the mean of the sample (26.0 kg/m2), with statistically significant interaction seen between BMI and genotype and levels of apo C-III, and lipoprotein particles containing both apo C-III and apo B (P < 0.02). The data suggest that carriers for the LPL-N9 mutation have a mild genetic predisposition to developing hyperlipidaemia and an atherogenic lipid profile, but that this requires the presence of other genetic or environmental factors for full expression, one of which appears to be increasing obesity.
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PMID:Association between the LPL-D9N mutation in the lipoprotein lipase gene and plasma lipid traits in myocardial infarction survivors from the ECTIM Study. 872 8

Familial lipoprotein lipase (LPL) deficiency is an inherited disorder of lipoprotein metabolism characterized by hypertriglyceridemia and recurrent episodes of abdominal pain and pancreatitis. We have studied the genetic basis of LPL deficiency in a 62-year-old black male with undetectable pre- and post-heparin plasma LPL mass and activity, DNA sequence analysis of the patient's LPL cDNA and gene as well as digestion with Bcl I and Asu I revealed that the proband is a homozygote for two separate gene defects. One mutation changed a G to an A, resulting in the conversion of amino acid 9 of the mature protein, aspartic acid (GAC), to asparagine (AAC). The second substitution, a C for a T, replaced tyrosine (TAC) at residue 262 with histidine (CAC). Northern blot analysis of monocyte-derived macrophage RNA demonstrated the presence of LPL mRNA of approximately normal size and quantity when compared to control. Expression of both mutations separately (pCMV-9 and pCMV-262) or in combination (pCMV-9+262) in human embryonal kidney-293 cells demonstrated that LPL-9 had approximately 80% the specific activity of wild type LPL, but LPL-262 and LPL-9+262 had no enzymic activity, thus establishing the functional significance of the LPL-262 defect. Despite an absolute deficiency of LPL mass and activity demonstrated by analysis of patient post-heparin plasma, in vitro expression of both LPL mutants was normal, suggesting that the absence of LPL in patient post-heparin plasma was a result of altered in vivo processing. Analysis of the heparin binding properties of the mutant enzymes by heparin-Sepharose affinity chromatography indicated that most of the LPL-262 mass was present in an inactive peak, which like the normal LPL monomer, eluted at 0.8 M NaCl. Thus, the Tyr262 --> His mutation may alter the stability of the LPL dimer, leading to the formation of inactive LPL-262 monomer which exhibits reduced heparin affinity. Based on these results, we propose that, in vivo, enhanced formation of LPL-9+262 monomer leads to abnormal binding of the mutant lipase to endothelial glycosaminoglycans ultimately resulting in enhanced catabolism of the mutant enzyme and lower enzyme mass in post-heparin plasma.
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PMID:Homozygosity for two point mutations in the lipoprotein lipase (LPL) gene in a patient with familial LPL deficiency: LPL(Asp9-->Asn, Tyr262-->His). 872 26

Aspergillus oryzae IFO4202 produces at least two extracellular lipolytic enzymes L1 and L2 (cutinase, and mono- and diacylglycerol lipase, respectively). Southern hybridization of restriction enzyme-digested genomic DNA fragments with 23-mer oligonucleotides synthesized according to the amino acid sequence of the L2 as probe suggested the presence of the L2 gene (tentatively designated as mdlB) and an additional weakly hybridizing region. A fragment containing the genomic mdlB gene was cloned in Escherichia coli. Nucleotide sequencing of the fragment revealed an open reading frame, comprising 1021 nucleotides, which contains two introns (51 and 52 nucleotides). Putative polyadenylation signals were found 182 and 287 bp downstream of the stop codon. The deduced amino acid sequence of the mdlB gene corresponds to 306 amino acid residues including a leader sequence of 28 amino acids and is highly similar to that of the mdlA gene of Penicillium camembertii. Three residues presumed to form the catalytic triad (serine, aspartic acid and histidine) of lipases were also conserved.
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PMID:Cloning and nucleotide sequence of the mono- and diacylglycerol lipase gene (mdlB) of Aspergillus oryzae. 880 3

Rat platelets secrete two types of phospholipases upon stimulation; one is type II phospholipase A2 and the other is serine-phospholipid-selective phospholipase A. In the current study we purified serine-phospholipid-selective phospholipase A and cloned its cDNA. The final preparation, purified from extracellular medium of activated rat platelets, gave a 55-kDa protein band on SDS-polyacrylamide gel electrophoresis. [3H]Diisopropyl fluorophosphate, an inhibitor of the enzyme, labeled the 55-kDa protein, suggesting that this polypeptide possesses active serine residues. The cDNA for the enzyme was cloned from a rat megakaryocyte cDNA library. The predicted 456-amino acid sequence contains a putative short N-terminal signal sequence and a GXSXG sequence, which is a motif of an active serine residue of serine esterase. Amino acid sequence homology analysis revealed that the enzyme shares about 30% homology with mammalian lipases (lipoprotein lipase, hepatic lipase, and pancreatic lipase). Regions surrounding the putative active serine, histidine, and aspartic acid, which may form a "lipase triad," were highly conserved among these enzymes. The recombinant protein, which we expressed in Sf9 insect cells using the baculovirus system, hydrolyzed a fatty acyl residue at the sn-1 position of lysophosphatidylserine and phosphatidylserine, but did not appreciably hydrolyze phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, and triglyceride. The present enzyme, named phosphatidylserine-phospholipase A1, is the first phospholipase that exclusively hydrolyses the sn-1 position and has a strict head group specificity for the substrate.
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PMID:Serine phospholipid-specific phospholipase A that is secreted from activated platelets. A new member of the lipase family. 899 22

A new lipoprotein lipase-like gene has been cloned from endothelial cells through a subtraction methodology aimed at characterizing genes that are expressed with in vitro differentiation of this cell type. The conceptual endothelial cell-derived lipase protein contains 500 amino acids, including an 18-amino acid hydrophobic signal sequence, and is 44% identical to lipoprotein lipase and 41% identical to hepatic lipase. Comparison of primary sequence to that of lipoprotein and hepatic lipase reveals conservation of the serine, aspartic acid, and histidine catalytic residues as well as the 10 cysteine residues involved in disulfide bond formation. Expression was identified in cultured human umbilical vein endothelial cells, human coronary artery endothelial cells, and murine endothelial-like yolk sac cells by Northern blot. In addition, Northern blot and in situ hybridization analysis revealed expression of the endothelial-derived lipase in placenta, liver, lung, ovary, thyroid gland, and testis. A c-Myc-tagged protein secreted from transfected COS7 cells had phospholipase A1 activity but no triglyceride lipase activity. Its tissue-restricted pattern of expression and its ability to be expressed by endothelial cells, suggests that endothelial cell-derived lipase may have unique functions in lipoprotein metabolism and in vascular disease.
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PMID:Cloning of a unique lipase from endothelial cells extends the lipase gene family. 1031 35

Genetic variants of lipoprotein lipase (LPL), a key enzyme in the hydrolysis of triglyceride (TG)-rich particles, may contribute to ischaemic heart disease (IHD) risk. We have examined the risk of IHD in carriers of two common LPL variants, asparagine substitution for aspartic acid at residue 9 (D9N) and serine for asparagine at residue 291 (N291S) in 2708 middle-aged healthy European men, followed for over 6 years. The carrier frequencies were 2.6% for N9, and 3.9% for S291. Both variants were associated with higher plasma TG at baseline of 9% and 14%, respectively. At baseline, 28% of men were current smokers and smoking was unrelated to genotype. Associations between LPL variants and disease outcome, according to smoking status, were assessed by Cox's proportional hazards analysis. S291 carriers showed no increased risk of IHD compared to non-carriers, while there was strong evidence of interaction between D9N genotype and smoking status (P = 0.0003) in determining the risk of IHD. In 2248 non-carriers of N9, smoking increased the risk of an IHD event by 1.6 (95% CI: 1.1-2.4%) times. Among 58 N9 carriers, no IHD events occurred in 42 who were non-smokers, whereas five events were reported in 16 who smoked. The combined effect of smoking and N9 allele was to increase the risk of an IHD event by 10.4 (95% CI: 4.7-22.8%) times compared with D9 non-smokers. These findings could not be explained by confounding effects of baseline TG. Carriers of N9 appear to be especially vulnerable to the adverse effects of cigarette smoking on IHD risk, but this susceptibility is unrelated to the influence of this variant on plasma TG levels.
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PMID:Substitution of asparagine for aspartic acid at residue 9 (D9N) of lipoprotein lipase markedly augments risk of ischaemic heart disease in male smokers. 1070 17

Although long-term depression (LTD) is a well-studied form of synaptic plasticity, it is clear that multiple cellular mechanisms are involved in its induction. In the leech, LTD is observed in a polysynaptic connection between touch mechanosensory neurons (T cells) and the S interneuron following low frequency stimulation. LTD elicited by 450 s low frequency stimulation was blocked by N-methyl-D-aspartic acid (NMDA) receptor antagonists. However, LTD elicited by 900 s low frequency stimulation was insensitive to NMDA receptor antagonists and was instead dependent on cannabinoid signaling. This LTD was blocked by both a cannabinoid receptor antagonist and by inhibition of diacylglycerol lipase, which is necessary for the synthesis of the cannabinoid transmitter 2-arachidonyl glycerol (2-AG). Bath application of 2-AG or the cannabinoid receptor agonist CP55 940 also induced LTD at this synapse. These results indicate that two forms of LTD coexist at the leech T-to-S polysynaptic pathway: one that is NMDA receptor-dependent and another that is cannabinoid-dependent and that activation of either form of LTD is dependent on the level of activity in this circuit.
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PMID:Two forms of long-term depression in a polysynaptic pathway in the leech CNS: one NMDA receptor-dependent and the other cannabinoid-dependent. 1965 62


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