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PubMed2003

Dietary n-3 fats as adjunctive therapy in a prototypic inflammatory disease: issues and obstacles for use in rheumatoid arthritis.

Eicosanoids derived from the n-6 fatty acid, arachidonic acid, and the cytokines interleukin-1beta and tumour necrosis factor-alpha are involved in the signs and symptoms of inflammatory joint disease, as well as the cartilage degradation seen in established rheumatoid arthritis (RA). Then n-3 fatty acids in fish and fish oil can inhibit production of both eicosanoid and cytokine inflammatory mediators and therefore, have the potential to modify RA pathology. Epidemiological studies suggest that fish intake may be preventive for RA and double-blind placebo-controlled studies demonstrate that dietary fish oil can alleviate the signs and symptoms of RA. The implementation of these findings will require among other things, a range of n-3 fat enriched foods, as well as physician awareness of the possibilities for dietary n-3 fat increases to be used as adjunctive therapy in RA.

Arthritis, Rheumatoid↗
PubMed2000

Analogues and derivatives of ciproxifan, a novel prototype for generating potent histamine H3-receptor antagonists.

Novel derivatives of the highly potent and selective histamine H3-receptor antagonist ciproxifan (3) with different chain lengths as well as with structural variants of the cyclopropyl ketone moiety have been prepared and screened for their antagonist H3-receptor potencies in vitro and in vivo. Some derivatives (2, 6-8, 12) containing other functionalities were effective in vitro in the same (sub)nanomolar concentration range and in vivo in a remarkably low oral dose.

Animals↗
PubMed2002

CDP840. A prototype of a novel class of orally active anti-inflammatory phosphodiesterase 4 inhibitors.

The discovery, synthesis and biological activity of a series of triarylethane phosphodiesterase 4 inhibitors is described. Structure-activity relationship studies are presented for CDP840 (29), a potent, chiral, selective inhibitor of PDE 4 (IC(50) 4nM). CDP840 is non-emetic in the ferret at 30mgkg(-1) (po), active in models of inflammation and reverses ozone-induced bronchial hyperreactivity in the guinea pig.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Crystal structure of Aeromonas proteolytica aminopeptidase: a prototypical member of the co-catalytic zinc enzyme family.

BACKGROUND: Aminopeptidases specifically cleave the amino-terminal residue from polypeptide chains and are involved in the metabolism of biologically active peptides. The family includes zinc-dependent enzymes possessing either one or two zinc ions per active site. Structural studies providing a detailed view of the metal environment may reveal whether the one-zinc and two-zinc enzymes constitute structurally and mechanistically distinct subclasses, and what role the metal ions play in the catalytic process. RESULTS: We have solved the crystal structure of the monomeric aminopeptidase from Aeromonas proteolytica at 1.8 A resolution. The protein is folded into a single alpha/beta globular domain. The active site contains two zinc ions (3.5 A apart) with shared ligands and symmetrical coordination spheres. We have compared it with the related bovine lens leucine aminopeptidase and the cobalt-containing Escherichia coli methionine aminopeptidase. CONCLUSIONS: The environment and coordination of the two zinc ions in A. proteolytica aminopeptidase strongly support the view that the two metal ions constitute a co-catalytic unit and play equivalent roles during catalysis. This conflicts with the conclusions drawn from the related bovine leucine aminopeptidase and early biochemical studies. In addition, the known specificity of the aminopeptidase for hydrophobic amino-terminal residues is reflected in the hydrophobicity of the active site cleft.

Aeromonas↗
PubMed2000

Solution structure of PCP, a prototype for the peptidyl carrier domains of modular peptide synthetases.

BACKGROUND: Nonribosomal peptide synthetases (NRPSs) are large modular enzymes responsible for the synthesis of a variety of microbial bioactive peptides. They consist of modules that each recognise and incorporate one specific amino acid into the peptide product. A module comprises several domains, which carry out the individual reaction steps. After activation by the adenylation domain, the amino acid substrate is covalently tethered to a 4'-phosphopantetheinyl cofactor of a peptidyl carrier domain (PCP) that passes the substrate to the reaction centres of the consecutive domains. RESULTS: The solution structure of PCP, a distinct peptidyl carrier protein derived from the equivalent domain of an NRPS, was solved using NMR techniques. PCP is a distorted four-helix bundle with an extended loop between the first two helices. Its overall fold resembles the topology of acyl carrier proteins (ACPs) from Escherichia coli fatty acid synthase and actinorhodin polyketide synthase from Streptomyces coelicolor; however, the surface polarity and the length and relative alignment of the helices are different. The conserved serine, which is the cofactor-binding site, has the same location as in the ACPs and is situated within a stretch of seven flexible residues. CONCLUSIONS: The structure of PCP reflects its character as a protein domain. The fold is well defined between residues 8 and 82 and the structural core of the PCP domain can now be defined as a region spanning 37 amino acids in both directions from the conserved serine. The flexibility of the post-translationally modified site might have implications for interactions with the cooperating proteins or NRPS domains.

Amino Acid Sequence↗
PubMed2000

Structure and mechanism of homoserine kinase: prototype for the GHMP kinase superfamily.

BACKGROUND: Homoserine kinase (HSK) catalyzes an important step in the threonine biosynthesis pathway. It belongs to a large yet unique class of small metabolite kinases, the GHMP kinase superfamily. Members in the GHMP superfamily participate in several essential metabolic pathways, such as amino acid biosynthesis, galactose metabolism, and the mevalonate pathway. RESULTS: The crystal structure of HSK and its complex with ADP reveal a novel nucleotide binding fold. The N-terminal domain contains an unusual left-handed betaalphabeta unit, while the C-terminal domain has a central alpha-beta plait fold with an insertion of four helices. The phosphate binding loop in HSK is distinct from the classical P loops found in many ATP/GTP binding proteins. The bound ADP molecule adopts a rare syn conformation and is in the opposite orientation from those bound to the P loop-containing proteins. Inspection of the substrate binding cavity indicates several amino acid residues that are likely to be involved in substrate binding and catalysis. CONCLUSIONS: The crystal structure of HSK is the first representative in the GHMP superfamily to have determined structure. It provides insight into the structure and nucleotide binding mechanism of not only the HSK family but also a variety of enzymes in the GHMP superfamily. Such enzymes include galactokinases, mevalonate kinases, phosphomevalonate kinases, mevalonate pyrophosphate decarboxylases, and several proteins of yet unknown functions.

Adenosine Diphosphate↗
PubMed1998

The crystal structure of the novel snake venom plasminogen activator TSV-PA: a prototype structure for snake venom serine proteinases.

BACKGROUND: Trimeresurus stejnejeri venom plasminogen activator (TSV-PA) is a snake venom serine proteinase that specifically activates plasminogen. Snake venom serine proteinases form a subfamily of trypsin-like proteinases that are characterised by a high substrate specificity and resistance to inhibition. Many of these venom enzymes specifically interfere with haemostatic mechanisms and display a long circulating half-life. For these reasons several of them have commercial applications and are potentially attractive pharmacological tools. RESULTS: The crystal structure of TSV-PA has been determined to 2.5 A resolution and refined to an R factor of 17.8 (R free, 24.4). The enzyme, showing the overall polypeptide fold of trypsin-like serine proteinases, displays unique structural elements such as the presence of a phenylalanine at position 193, a C-terminal tail clamped via a disulphide bridge to the 99-loop, and a structurally conserved Asp97 residue. The presence of a cis proline at position 218 is in agreement with evolutionary relationships to glandular kallikrein. CONCLUSIONS: We postulate that Phe 193 accounts for the high substrate specificity of TSV-PA and renders it incapable of forming a stable complex with bovine pancreatic trypsin inhibitor and other extended substrates and inhibitors. Mutational studies previously showed that Asp97 is crucial for the plasminogenolytic activity of TSV-PA, here we identify the conservation of Asp97 in both types of mammalian plasminogen activator - tissue-type (tPA) and urokinase-type (uPA). It seems likely that Asp97 of tPA and uPA will have a similar role in plasminogen recognition. The C-terminal extension of TSV-PA is conserved among snake venom serine proteinases, although its function is unknown. The three-dimensional structure presented here is the first of a snake venom serine proteinase and provides an excellent template for modelling other homologous family members.

Amino Acid Chloromethyl Ketones↗
PubMed1998

The three-dimensional structure of a type I module from titin: a prototype of intracellular fibronectin type III domains.

BACKGROUND: Titin is a huge protein ( approximately 3 MDa) that is present in the contractile unit (sarcomere) of striated muscle and has a key role in muscle assembly and elasticity. Titin is mainly composed of two types of module (type I and II). Type I modules are found exclusively in the region of titin localised in the A band, where they are arranged in a super-repeat pattern that correlates with the ultrastructure of the thick filament. No structure of a titin type I module has been reported so far. RESULTS: We have determined the structure of a representative type I module, A71, using nuclear magnetic resonance (NMR) spectroscopy. The structure has the predicted fibronectin type III fold. Titin-specific conserved residues are either located at the putative module-module interfaces or along one side of the protein surface. Several proline residues that contribute to two stretches in a polyproline II helix conformation are solvent-exposed and line up as a continuous ribbon extending over more than two-thirds of the module surface. Homology models of the type I module N-terminal to A71 (A70) and the double module A70-A71 were used to discuss possible intermodule interactions and their role in module-module orientation. CONCLUSIONS: As residues at the module-module interfaces are highly conserved, we speculate that similar interactions govern all of the interfaces between type I modules in titin. This conservation would lead to a regular multiple array of similar surface structures. Such an arrangement would allow arrays of contiguous type I modules to expose multiple proline stretches in a highly regular way and these may act as binding sites for other thick filament proteins.

Amino Acid Sequence↗
PubMed1999

A prototypical cytidylyltransferase: CTP:glycerol-3-phosphate cytidylyltransferase from bacillus subtilis.

BACKGROUND: The formation of critical intermediates in the biosynthesis of lipids and complex carbohydrates is carried out by cytidylyltransferases, which utilize CTP to form activated CDP-alcohols or CMP-acid sugars plus inorganic pyrophosphate. Several cytidylyltransferases are related and constitute a conserved family of enzymes. The eukaryotic members of the family are complex enzymes with multiple regulatory regions or repeated catalytic domains, whereas the bacterial enzyme, CTP:glycerol-3-phosphate cytidylyltransferase (GCT), contains only the catalytic domain. Thus, GCT provides an excellent model for the study of catalysis by the eukaryotic cytidylyltransferases. RESULTS: The crystal structure of GCT from Bacillus subtilis has been determined by multiwavelength anomalous diffraction using a mercury derivative and refined to 2.0 A resolution (R(factor) 0.196; R(free) 0.255). GCT is a homodimer; each monomer comprises an alpha/beta fold with a central 3-2-1-4-5 parallel beta sheet. Additional helices and loops extending from the alpha/beta core form a bowl that binds substrates. CTP, bound at each active site of the homodimer, interacts with the conserved (14)HXGH and (113)RTXGISTT motifs. The dimer interface incorporates part of a third motif, (63)RYVDEVI, and includes hydrophobic residues adjoining the HXGH sequence. CONCLUSIONS: Structure superpositions relate GCT to the catalytic domains from class I aminoacyl-tRNA synthetases, and thus expand the tRNA synthetase family of folds to include the catalytic domains of the family of cytidylyltransferases. GCT and aminoacyl-tRNA synthetases catalyze analogous reactions, bind nucleotides in similar U-shaped conformations, and depend on histidines from analogous HXGH motifs for activity. The structural and other similarities support proposals that GCT, like the synthetases, catalyzes nucleotidyl transfer by stabilizing a pentavalent transition state at the alpha-phosphate of CTP.

Amino Acid Sequence↗
PubMedDate not supplied

Prototype miniature endoluminal MR imaging catheter.

PURPOSE: The feasibility of a miniature endoluminal magnetic resonance (MR) detection coil was investigated for imaging mural and perimural anatomy of small, tubular structures. MATERIALS AND METHODS: To this end, remotely tunable, single-loop, multiturn, receive-only radio-frequency coils, housed in 6-9-F arterial sheaths, were built. A 1.9-T imager was used. Phantom excitation was accomplished with a 62-mm-diameter bird-cage quadrature coil, and ex vivo specimen excitation was accomplished with a single-turn, untuned wire loop. Phantom images obtained with use of a 9-F catheter coil showed a signal-to-noise improvement on the border of 20 dB compared with images obtained with the quadrature coil. An 8-F catheter coil was used to obtain high-resolution (100 microns in-plane pixel size, 500 microns section thickness) spin-echo images (repetition time = 2,400 msec, echo time = 53 msec) of the wall of a fresh ex vivo human popliteal artery. RESULTS: Prospectively, these images were suggestive of the presence of diffuse intimal hyperplasia, medial calcification, and focal atherosclerotic plaque. These findings were confirmed histologically. Three-dimensional restacking of the axial images simplified examination of the normal layers and pathologic changes within the wall. The improved signal-to-noise characteristics of these miniature coils permit fast high-resolution imaging, allowing visualization of microscopic anatomic details. CONCLUSIONS: With further development, this technology may be useful for studying atherosclerosis and for providing imaging guidance during endoluminal MR interventions.

Arteries↗
PubMedDate not supplied

Prototype stent: in vivo swine studies in the biliary system.

PURPOSE: To evaluate the safety of implantation and the biocompatibility of a new balloon-expandable stent in the biliary system of the swine model. MATERIALS AND METHODS: Thirty stents, varying in diameter from 4 mm to 12 mm and in length from 2 cm to 6 cm, were placed in the bile ducts of 10 microswine. After implantation, one-third of the animal subjects were killed at 2 months and the rest, at 6 months. All animals underwent premorbid cholangiography. Stents were pressure fixed, harvested, and encased in methacrylate. Specimens were then sectioned with a diamond saw, prior to staining. Individual specimens were photographed for visualization of the histologic reaction. RESULTS: Technical success (implantation) was 100%. All stents were widely patent at 2-month and 6-month follow-up. Histopathologic study demonstrated a very thin epithelial hyperplasia that formed between stent wires. This did not cover the stent wires. CONCLUSION: This new stent is safely implantable and demonstrates minimal tissue reaction in the biliary system of the swine, when compared with other metallic biliary stents.

Animals↗
PubMedDate not supplied

Vascular stent prototype: in vivo swine studies.

PURPOSE: Evaluation of implantation technique and biocompatibility of a new balloon-expandable peripheral vascular stent. MATERIALS AND METHODS: Twenty-four stents, varying in diameter from 4 mm to 14 mm and length from 2 cm to 6 cm, were placed in eight microswine. After implantation, two of the animals were killed at 2 months and the remaining animals were killed at 6 months. All animals underwent premorbid angiography. The stents were then pressure fixed, harvested, and encased in methacrylate. The specimens were then sectioned by a diamond saw prior to staining. Individual specimens were then photographed, projected against a screen, and the neointimal thickness quantified by calibration with the diameter of the stent wire retained in the specimen. RESULTS: Technical success (implantation) was 96% (one embolization). All stents were widely patent at 2- and 6-month follow-up. Histopathologic examination demonstrated a very thin neointima covering the stent wires, with a maximum thickness measuring 254 microns. CONCLUSION: This new stent is safely implantable and biocompatible as tested in the arterial system of this animal model. Human clinical trials are indicated.

Angiography↗
PubMed2004

Area beam equalization: optimization and performance of an automated prototype system for chest radiography.

RATIONALE AND OBJECTIVES: To evaluate the feasibility and performance of an x-ray beam equalization system for chest radiography using anthropomorphic phantoms. MATERIALS AND METHODS: Area beam equalization involves the process of the initial unequalized image acquisition, attenuator thickness calculation, mask generation using a 16 x 16 piston array, and final equalized image acquisition. Chest radiographs of three different anthropomorphic phantoms were acquired with no beam equalization and equalization levels of 4.8, 11.3, and 21. Six radiologists evaluated the images by scoring them from 1-5 using 13 different criteria. The dose was calculated using the known attenuator material thickness and the mAs of the x-ray tube. RESULTS: The visibility of anatomic structures in the under-penetrated regions of the chest radiographs was shown to be significantly (P < .01) improved after beam equalization. An equalization level of 4.8 provided most of the improvements with moderate increases in patient dose and tube loading. Higher levels of beam equalization did not show much improvement in the visibility of anatomic structures in the under-penetrated regions. CONCLUSION: A moderate level of x-ray beam equalization in chest radiography is superior to both conventional radiographs and radiographs with high levels of beam equalization. X-ray beam equalization can significantly improve the visibility of anatomic structures in the under-penetrated regions while maintaining good image quality in the lung region.

Feasibility Studies↗
PubMed1995

Two prototype blood-pool agents for contrast-enhanced magnetic resonance angiography of the portal vein in pigs.

RATIONALE AND OBJECTIVES: Macromolecular "blood-pool" agents such as polylysine-gadopentetate dimeglumine or albumin-gadopentetate dimeglumine, which provide prolonged intravascular enhancement, were tested as magnetic resonance (MR) angiography contrast agents for the portal vein in pigs. METHODS: Phase-contrast MR angiography of the portal veins was performed on six pigs before and after intravenous administration of polylysine-gadopentetate dimeglumine (n = 3) or albumin-gadopentetate dimeglumine (n = 3). RESULTS: The contrast-to-noise ratio of the portal veins was improved by 74% and 52%, respectively, using polylysine-gadopentetate dimeglumine or albumin-gadopentetate dimeglumine. More branches of the intrahepatic portal veins were visualized on postcontrast images. CONCLUSION: Blood-pool paramagnetic contrast agents improved the visualization of hepatic vasculature using phase-contrast MR angiography in our experimental model.

Albumins↗