Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We examined the relationship between ornithine decarboxylase (ODC) and growth and differentiation in the developing rat exocrine pancreas. The ODC activity profile showed 2 distinct stages of increases with the first occurred at 14-16 days of age, and a second at 21-23 days of age. Growth parameters evaluated as gains in tissue mass, protein and DNA content in the pancreas indicated a low growth rate soon after birth with a transition to a much more rapid growth rate around the age of 20-21 days, a time corresponded to the second rise in ODC activity. Differentiation parameters evaluated as the accumulation of trypsinogen, amylase and lipase showed different temporal changes. While the rate of accumulation of all three enzymes was relatively low following birth, a rapid rate of accumulation of trypsinogen and amylase started around 15-16 days, a time corresponding to the first rise in ODC activity. Lipase, however, did not show an increase in its accumulation until around age 20 days. These results indicate that a rise in ODC activity is closely associated with growth and differentiation in the developing rat pancreas. To further examine this issue, the steady state levels of ODC mRNA in developing rats were evaluated by Northern blots probed with an ODC cDNA. The developmental profile of ODC mRNA showed a broad peak with a pronounced shoulder occurring at 10 days of age. A higher peak was reached around 20 days of age, then dropped precipitously to a very low level at the age of 24 days. This temporal changes in the level of ODC mRNA show good relationship to the changes in ODC activity suggesting that the control of ODC expression occurs at least in part at the pre-translational level.
Mol Cell Biochem 1995 Oct 04
PMID:Expression of ornithine decarboxylase in pancreatic development. 858 18

The crystal structure of a lipase from the bacterium Chromobacterium viscosum ATCC 6918 (CVL) has been determined by isomorphous replacement and refined at 1.6 angstroms resolution to an R-factor of 17.8%. The lipase has the overall topology of an alpha/beta type protein, which was also found for previously determined lipase structures. The catalytic triad of the active center consists of the residues Ser87, Asp263 and His285. These residues are not exposed to the solvent, but a narrow channel connects them with the molecular surface. This conformation is very similar to the previously reported closed conformation of Pseudomonas glumae lipase (PGL), but superposition of the two lipase structures reveals several conformational differences. r.m.s. deviations greater than 2 angstroms are found for the C alpha-atoms of the polypeptide chains from His15 to Asp28, from Leu49 to Ser54 and from Lys128 to Gln158. Compared to the PGL structure in the CVL structure, three alpha-helical fragments are shorter, one beta-strand is longer and an additional antiparallel beta-sheet is found. In contrast to PGL, CVL displays an oxyanion hole, which is stabilized by the amide nitrogen atoms of Leu17 and Gln88, and a cis-peptide bond between Gln291 and Leu292. CVL contains a Ca2+, like the PGL, which is coordinated by four oxygen atoms from the protein and two water molecules.
J Mol Biol 1996 Jun 21
PMID:Crystal structure of a bacterial lipase from Chromobacterium viscosum ATCC 6918 refined at 1.6 angstroms resolution. 868 77

The isolated digestive juice of Aeshna cyanea larvae hydrolysed trioleoylglycerol preferentially at the terminal 1 and 3 positions, yielding 1, 2-dioleoylglycerol as first intermediate. Hydrolysis continued to 1- and 2-monooleoylglycerol as second intermediate. Separate incubation of monooleoylglycerol revealed that hydrolysis could proceed to completion. Inadequate inhibition of mono[1-14C]oleoylglycerol hydrolysis in the cold and in the presence of the lipase inhibitor tetrahydrolipstatin provided no information on whether monooleoylglycerol was absorbed in addition to free oleic acid. On the other hand, the analogue oleylglyceryl ethers were resistant towards hydrolysis by the digestive juice. Both monoethers and both diethers were esterified with [1-14C]palmitic acid by the homogenate of the midgut wall, whereas esterification in vivo occurred only with the monoethers. These were recovered from the haemolymph after saponification of the joint diacylglycerol and acyl-0-alkylglycerol fraction, indicating that the monoethers had been absorbed and transported into the haemolymph. Ingestion of mono-1-0-[3H]octadecylglycerol showed that the ether was absorbed unchanged by the midgut epithelium, where the major part of the alkyl moiety was oxidized to free fatty acid and incorporated into phospholipids, acylglycerols and acyl-0-alkylglycerols. It is concluded from the absorption of the analogous monoalkylglyceryl ethers that monoacylglyceryl esters are also absorbed by Aeshna larvae.
Comp Biochem Physiol B Biochem Mol Biol 1996 Jul
PMID:Is monoacylglycerol as an intermediate of triacylglycerol digestion absorbed by Aeshna cyanea larvae? 876 Nov 72

The effect of nickel (Ni) on the enzymatic activities in the pancreas of mice was studied. Administration of Ni at the dose of 5 mg Ni/kg increased the trypsin activity and decreased carboxypeptidase A activity, but did not affect the activities of chymotrypsin, carboxypeptidase B, amylase, and lipase. Increases in Ca concentrations in the pancreas after Ni administration were observed. In the pancreatic slice experiments, Ni treatment showed a slight decrease in trypsin activity and remarkable decreases in chymotrypsin and carboxypeptidase A activities, and Ca treatment induced increases in the activities of trypsin and carboxypeptidase A. These results suggest that the increase in trypsin activity in the pancreas after Ni administration results from the activation of trypsinogen by the Ca ion and that the decrease in carboxypeptidase A activity is based on the inhibitory effect of Ni on carboxypeptidase A activity.
Res Commun Mol Pathol Pharmacol 1996 May
PMID:Effect of nickel on enzymatic activities in the mouse pancreas. 877 77

Chronic pancreatitis is characterized by inflammation and fibrosis leading to tissue destruction; in industrialized nations, alcohol abuse is the cause of 70-80% of cases of pancreatitis in adults. The purpose of the current work was to determine whether free radical adducts are produced by the pancreas during the early phases of chronic exposure to ethanol. Accordingly, rats were chronically fed ethanol using the model of continuous enteral infusion developed by Tsukamoto et al.[Am. J. Physiol. 247: R595-R599 (1984)]. Histological evaluation revealed only mild acinar steatosis and spotty necrosis after 4 weeks of alcohol treatment; the pancreatic enzymes lipase and amylase were not elevated. Furthermore, no fibrosis was detected, nor were there differences in pancreatic collagen alpha 1(l) mRNA levels between the dietary control and ethanol-treated groups. After 4 weeks, rats were injected with the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (1 g/kg intravenously), and pancreatic secretions were collected over a 4-hr period. A six-line free radical adduct spectrum indicative of a carboncentered free radical was detected in pancreatic secretions and in Folch extracts of pancreatic tissue by electron spin resonance spectroscopy. Control experiments ruled out ex vivo radical formation. This study represents the first detection of radical adducts in pancreatic secretions. When [13C]ethanol (3 g/kg intragastrically) was administered, a definitive 12-line spectrum was detected in pancreatic secretions, demonstrating that the alpha-hydroxyethyl radical adduct was formed in the pancreas from [13C]ethanol. Interestingly, only a six-line signal was detected in tissue extracts under these conditions. Free radicals, therefore, are formed in the pancreas during the early phases of chronic alcohol intake in rats before the development of overt pathology.
Mol Pharmacol 1996 Sep
PMID:Detection of alpha-hydroxyethyl free radical adducts in the pancreas after chronic exposure to alcohol in the rat. 879 7

A complete understanding of host-parasite interactions must necessarily include the identification and characterization of gene products expressed by both parties during the infectious process. We have developed a new screen to identify bacterial genes that are transcriptionally induced during infection of a host animal. The method is based on pre-selection of strains carrying tnpR operon fusions (encoding resolvase, a site-specific DNA recombinase) which are not expressed in vitro, followed by screening for a subset of these strains that subsequently express resolvase within the host environment. The latter subset was recognized as recombinants that had deleted a resolvase-specific reporter construct. Thirteen transcription units of Vibrio cholerae were identified that were induced during infection in an infant mouse model of cholera. Five of these were predicted to encode polypeptides with diverse functions in metabolism, biosynthesis and motility; one encoded a secreted lipase; two appear to be antisense to genes involved in motility; and five are predicted to encode polypeptides of unknown function. Three of the transcripts were shown to be required for full virulence in infant mice, as assessed by competition experiments.
Mol Microbiol 1995 Nov
PMID:Use of recombinase gene fusions to identify Vibrio cholerae genes induced during infection. 881 90

Many surface proteins of Gram-positive bacteria are covalently anchored to the cell wall by a ubiquitous mechanism, involving a specific, C-terminal sorting signal. To achieve cell-wall immobilization of a normally secreted enzyme in vivo, we constructed a hybrid protein consisting of Staphylococcus hyicus lipase and the C-terminal region of Staphylococcus aureus fibronectin binding protein B (FnBPB). This region comprised the authentic cell-wall-spanning region and cell-wall sorting signal of FnBPB. Expression of the hybrid protein in Staphylococcus carnosus resulted in efficient cell-wall anchoring of enzymatically active lipase. The cell-wall-immobilized lipase (approximately 10,000 molecules per cell) retained more than 80% of the specific activity, compared to the C-terminally unmodified S. hyicus lipase secreted by S.carnosus cells. After releasing the hybrid protein from the cell wall by lysostaphin treatment. Its specific activity was indistinguishable from that of the unmodified lipase. Thus, the C-terminal region of FnBPB per se was fully compatible with folding of the lipase to an active conformation. To study the Influence of the distance between the cell-wall sorting signal and the C-terminus of the lipase on the activity of the immobilized lipase, the length of this spacer region was varied. Reduction of the spacer length gradually reduced the activity of the surface-immobilized lipase. On the other hand, elongation of this spacer did not stimulate the activity of the immobilized lipase, indicating that the spacer must exceed a critical length of approx. 90 amino acids to allow efficient folding of the enzyme, which probably can only be achieved outside the peptidoglycan web of the cell wall. When the lipase was replaced by another enzyme, the Escherichia coli beta-lactamase, the resulting hybrid was also efficiently anchored in an active conformation to the cell wall of S. carnosus. These results demonstrate that it is possible to immobilize normality soluble enzymes on the cell wall of S. carnosus-without radically altering their catalytic activity-by fusing them to a cell-wall-immobilization unit, consisting of a suitable cell-wall-spanning region and a standard cell-wall sorting signal.
Mol Microbiol 1996 Aug
PMID:In vivo immobilization of enzymatically active polypeptides on the cell surface of Staphylococcus carnosus. 886 73

Lysosomal acid lipase (LAL) gene mutations were identified in three patients with cholesteryl ester storage disease (CESD). Direct sequencing of genomic DNA revealed that: patient 1 was a compound heterozygote for a P181L mutation and an A to G3' splice site substitution that causes skipping of exon 7, with a loss of 49 amino acids from LAL (delta 205-253); patient 2 was a compound heterozygote for a G66V mutation and a 5' splice site mutation (G to A) that leads to skipping of exon 8 (delta 254-277); and patient 3 was a compound heterozygote for a L273S mutation and an unidentified null allele. Furthermore, patients 2 and 3 showed a novel G-2A polymorphism that could be detected by an Xbal restriction fragment length polymorphism. All these mutants and a previously reported H274Y allele were expressed in vitro in HeLa cells using the vaccinia T7 expression system. The resulting recombinant proteins were inactive towards cholesteryl oleate and trioleylglycerol, demonstrating the direct involvement of these mutations in the pathogenesis of CESD. Immunoblotting of normal LAL expressed in HeLa cells revealed four major molecular forms, at least two of high molecular mass (54 and 50-51 kDa) and two of low molecular mass (42 and 43 kDa). L273S and P181L substitutions and delta 254-277 were shown to result in altered LAL molecular forms, some of which suggest that post-translational processing may interfere with the catalytic activity of LAL.
Hum Mol Genet 1996 Oct
PMID:Expression of lysosomal acid lipase mutants detected in three patients with cholesteryl ester storage disease. 889 96

A number of experimental paradigms have been used to demonstrate that NCAM, N-cadherin, and L1 stimulate axonal growth. The molecular basis of this response has been extensively studied and a range of agents that inhibit neurite outgrowth stimulated by the above CAMs, but not integrins, have now been identified. These studies pointed to the activation of a tyrosine kinase-PLCgamma cascade as being important for the neurite outgrowth responses stimulated by all three CAMs, and this was substantiated by the identification of agents that could activate the cascade and mimic the growth response. In this review we will suggest that the neurite growth response stimulated by these CAMs is mediated by activation of the fibroblast growth factor receptor (FGFR) in neurons and that this results in the recruitment and activation of PLCgamma via interactions of its SH2 domain with the activated receptor. In this context the key events downstream from activation of PLCgamma required for neurite growth appear to be the conversion of diacylglycerol (DAG) to arachidonic acid (AA) via DAG lipase activity, followed by an increased influx of calcium into the neurons. The evolutionary conservation of putative binding motifs between the above CAMs and the FGFR suggests that activation of the FGFR-PLCgamma cascade by the CAMs might involve a direct CAM-FGFR interaction. The identification of the binding motifs also allows for predictions to be made concerning whether other CAMs might directly interact with the FGFR.
Mol Cell Neurosci 1996
PMID:CAM-FGF receptor interactions: a model for axonal growth. 891 27

A number of experimental paradigms have been used to demonstrate that NCAM, N-cadherin, and L1 stimulate axonal growth. The molecular basis of this response has been extensively studied and a range of agents that inhibit neurite outgrowth stimulated by the above CAMs, but not integrins, have now been identified. These studies pointed to the activation of a tyrosine kinase-PLCgamma cascade as being important for the neurite outgrowth responses stimulated by all three CAMs, and this was substantiated by the identification of agents that could activate the cascade and mimic the growth response. In this review we will suggest that the neurite growth response stimulated by these CAMs is mediated by activation of the fibroblast growth factor receptor (FGFR) in neurons and that this results in the recruitment and activation of PLCgamma via interactions of its SH2 domain with the activated receptor. In this context the key events downstream from activation of PLCgamma required for neurite growth appear to be the conversion of diacylglycerol (DAG) to arachidonic acid (AA) via DAG lipase activity, followed by an increased influx of calcium into the neurons. The evolutionary conservation of putative binding motifs between the above CAMs and the FGFR suggests that activation of the FGFR-PLCgamma cascade by the CAMs might involve a direct CAM-FGFR interaction. The identification of the binding motifs also allows for predictions to be made concerning whether other CAMs might directly interact with the FGFR.
Mol Cell Neurosci 1996 Aug
PMID:CAM-FGF Receptor Interactions: A Model for Axonal Growth 895 25


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