Solid-state CD and peptide helical screw sense.
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Circular Dichroism↗
Biomedical subjects
J Kamphuis
Publications and source records attributed to J Kamphuis.
Structural versatility of peptides from C alpha, alpha-disubstituted glycines: crystal-state conformational analysis of peptides from C alpha-methylhomophenylalanine, (alpha Me) Hph.
The molecular and crystal structures of the C alpha-tetrasubstituted, delta-branched alpha-amino acid C alpha-methylhomophenylalanine, H-D-(alpha Me)Hph-OH, and three peptides (to the pentamer level), including the homotripeptide, have been determined by X-ray diffraction. The peptides are Z-L-(alpha Me)Hph-(L-Ala)2-OMe pBrBz-[D-(alpha Me)Hph]3-OtBu and Ac-(Aib)2-L-(alpha Me)Hph-(Aib)2-OtBu. All the (alpha Me)Hph residues prefer phi, psi torsion angles in the helical region of the conformational map. The two terminally blocked tripeptides adopt a beta-bend conformation stabilized by a 1<--4 C = O... H-N intramolecular H-bond. The terminally blocked pentapeptide is folded in a regular 3(10)-helix. In general, the relationship between (alpha Me)Hph alpha-carbon chirality and helix handedness is the same as that exhibited by protein amino acids. A comparison is also made with the conclusions extracted from published work on peptides from other types of C alpha-alkylated aromatic alpha-amino acids.
Aminobutyrates↗
The preferred solid-state conformation of (alpha Me)Trp peptides.
The two Z-L-Ala-DL-(alpha Me)Trp-NH2 diastereomeric dipeptides were synthesized from (Z-L-Ala)2(O) and H-DL-(alpha Me)Trp-NH2. The latter racemate, prepared by phase-transfer catalyzed alkylation of the N alpha-benzylidene derivative of alanine amide followed by acidic hydrolysis of the resulting Schiff base, was characterized by X-ray diffraction. The molecular and crystal structure of Z-L-Ala-L-(alpha Me)Trp-NH2, separated from its diastereomer by silica-gel column chromatography, was determined by X-ray diffraction analysis. Both independent molecules in the asymmetric unit of the dipeptide adopt a type-II beta-bend conformation. However, only the more regularly folded conformation of molecule B is stabilized by a 1<--4 C = O...H--N intramolecular H bond. The present results indicate that: (i) the C alpha-methylated (alpha Me)Trp residue is a strong beta-bend and helix former, and (ii) the relationship between (alpha Me)Trp chirality and helix screw sense tends to be opposite to that of protein amino acids. The implications for the use of the (alpha Me)Trp residue in designing conformationally restricted analogs of bioactive peptides are briefly discussed.
Amino Acid Sequence↗
Pseudomonas fluorescens lipase adsorption and the kinetics of hydrolysis in a dynamic emulsion system.
To elucidate the adsorption characteristics of lipases and to study the influence of the reaction conditions on the catalytic properties of lipases, the hydrolysis of decylchloroacetate by Pseudomonas fluorescens lipase in an emulsion reactor was studied as a model system. During the reaction the droplet size distribution of the emulsion was measured on-line using a particle sizer based on light scattering. Desorption experiments revealed that, at low surface coverage, the initial rate of reaction was not influenced by either the stirring speed or the organic volume fraction. Dilution of the reaction mixture during hydrolysis did not result in a decrease in activity. Based on these results, it is assumed that under the specified conditions adsorption of Pseudomonas fluorescens lipase is quantitative and probably irreversible. Based on activity measurements and assuming that only a monolayer of lipase is active, it is calculated that at saturation the emulsion interface is covered with 3 mg lipase per m2. From these data the average interfacial area covered by one lipase molecule at saturation was calculated to be 1700-2100 A2 per molecule. The emulsion was shown to be dynamic, e.g., during hydrolysis a significant increase in interfacial area was observed as a result of a shift in droplet size distribution to smaller diameters. Experiments indicated that both the formation of decanol and the emulgating effect of the lipase account for these observations. The formation of decanol also resulted in a dramatic decrease in hydrolytic activity. Taking interfacial tension measurements into account, it is shown that decanol accumulates at the liquid-liquid interface.(ABSTRACT TRUNCATED AT 250 WORDS)
Adsorption↗
The potential of lyases for the industrial production of optically active compounds.
Lyases catalyse the cleavage of C-C, C-N, C-O and other bonds by elimination to produce double bonds or, conversely, catalyse the addition of groups to double bonds. These enzymes do not require cofactor recycling, show an absolute stereospecificity and can give a theoretical yield of 100%, compared with only 50% for enantiomeric resolutions. Lyases are therefore attracting considerable interest as biocatalysts for the production of optically active compounds, and have already found application in several large commercial processes.
Catalysis↗
Vascular effects of pentoxifylline in humans.
In this study, we investigated the vasoactive effects of the alkylxanthine pentoxifylline and its interaction with the nucleoside adenosine in the forearm skeletal muscle vascular bed of 18 normotensive healthy volunteers. Pentoxifylline infusion into the brachial artery in dosages of 100, 300, and 1,000 micrograms/100 ml forearm volume (FAV)/min, induced increments of forearm blood flow (FBF) of 41 +/- 6, 125 +/- 22, and 295 +/- 57%, respectively (n = 12). Calculated forearm vascular resistance (FVR) showed a dose-dependent decrease during pentoxifylline infusion. Concomitant administration of caffeine (100 micrograms/100 ml/min), an adenosine antagonist, did not attenuate the vasodilator response to pentoxifylline (n = 6). Intraarterial (i.a.) infusion of adenosine alone (0.75, 1.5, 3.0, and 4.5 micrograms/100 ml/min) induced a dose-dependent forearm vasodilator response. Concomitant infusion of pentoxifylline (100 micrograms/100 ml/min) did not cause a convincing potentiation of the forearm vasodilator effect of adenosine. This study demonstrates that pentoxifylline induces vasodilation in human forearm skeletal muscle vascular bed of healthy young volunteers. This vasodilator response occurred at concentrations that are probably much higher than those achieved with oral treatment with pentoxifylline. Our data further suggest that pentoxifylline-induced vasodilation is not mediated by adenosine receptor stimulation, but may result from inhibition of the enzyme phosphodiesterase (PDE).
Adenosine↗
Structures of peptides from alpha-amino acids methylated at the alpha-carbon.
The structural preferences of peptides (and depsipeptides) from the achiral MeAib and Hib residues, and the chiral Iva, (alpha Me) Val, (alpha Me) Leu, and (alpha Me) Phe residues, as determined by conformational energy computations, x-ray diffraction analyses, and 1H-nmr and spectroscopic studies, are reviewed and compared with literature data on Aib-containing peptides. The results obtained indicate that helical structures are preferentially adopted by peptides rich in these alpha-amino acids methylated at the alpha-carbon. Intriguing experimental findings on the impact of the chirality of Iva, (alpha Me) Val, and (alpha Me) Phe residues on helix screw sense are illustrated.
Amino Acid Sequence↗
Reverse relationship between alpha-carbon chirality and helix handedness in (alpha Me)Phe peptides.
The crystal-state preferred conformations of two tripeptides, one tetrapeptide, and one pentapeptide, each containing a single residue of the chiral, C alpha, alpha-disubstituted glycine C alpha-methyl, C alpha-benzylglycine [(alpha Me)Phe], have been determined by X-ray diffraction. The tripeptides are Z-L-(alpha Me)Phe-(Aib)2-OH dihydrate and Z-Aib-D-(alpha Me)Phe-Aib-OtBu, the tetrapeptide is Z-(Aib)2-D-(alpha Me)Phe-Aib-OtBu, and the pentapeptide is pBrBz-(Aib)2-DL-(alpha Me)Phe-(Aib)2-OtBu. While the two tripeptides are folded in a beta-bend conformation, two such conformations are consecutively formed by the tetrapeptide. The pentapeptide adopts a regular 3(10)-helix promoted by three consecutive beta-bends. This study confirms the strong propensity of short peptides containing C alpha-methylated alpha-aminoacids to fold into beta-bends and 3(10)-helical structures. Since Aib is achiral, the handedness of the observed bends and helices is dictated by the presence of the (alpha Me)Phe residue. In general, we have found that the relationship between (alpha Me)Phe chirality and helix handedness is opposite to that exhibited by protein aminoacids. A comparison with the preferred conformation of other extensively investigated C alpha-methylated aminoacids is made.
Models, Molecular↗
Response to innovation: behavioral patterns.
An innovation model describes behavior patterns and the specific responses these groups display when introduced to change. These six categories, which are not inclusive, extend along a continuum ranging from eager participation to outright rejection of change. Using this knowledge, the nurse manager can team up with certain group types to smoothly implement innovation into the system.
Adaptation, Psychological↗
New developments in the synthesis of natural and unnatural amino acids.
Amino acids play an important role in biochemistry and chemistry. They are the building blocks of proteins and play an essential role in the regulation of the metabolism of living organisms. In general, it can be stated that microbial processes (fermentation) are the industrial production methods of choice for large-scale production of naturally occurring proteinogenic L-alpha-H-amino acids, while for the production of synthetic D- and/or L-alpha-H-amino acids, several other methods are highly competitive. At DSM, several routes, i.e., (chemoenzymatic) synthesis, towards L-alpha-H and D-alpha-H-amino acids have been elaborated since the midseventies. A general process for the synthesis of natural as well as synthetic optically pure amino acids has been developed, using an enzymatic kinetic resolution step on racemic amino acid amides as the key step. In this case, both enantiomers of the alpha-H-amino acids are prepared in one single step. This process has been commercialized since 1988. More recent developments using L- or D-amino peptidases in combination with amino acid amide racemases and an asymmetric transformation concept are discussed.
Amino Acid Sequence↗
Determination of biocatalyst consumption in an aminopeptidase process using automated sample preparation and high-performance liquid chromatography.
A rapid and sensitive method has been developed for the determination of the biocatalyst consumption in the chemo-enzymic production of optically pure natural and synthetic alpha-H-amino acids. It is based on automated sample preparation from an enzymic reaction mixture, reversed-phase high-performance liquid chromatographic separation, post-column reaction and fluorimetric detection. The assay procedure has been applied to the enzymic conversion of racemic norvaline amide into L-norvaline, catalysed by an L-specific aminopeptidase from Pseudomonas putida. Both norvaline amide and norvaline can be analysed in a single assay in the low nanogram range. The method yields reproducible results and requires 30 min from the time of sampling the enzymic reaction mixture to quantitation. The reaction mixture is automatically sampled and analysed several times during the course of the reaction. With the results obtained a conversion curve can be constructed from which the exact biocatalyst consumption can be calculated. By adaptation of the mobile phase, the method can also be applied to other amino acid amides used as substrates in the aminopeptidase reaction.
Aminopeptidases↗
Peptides from chiral C alpha,alpha-disubstituted glycines. Crystallographic characterization of conformation of C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] in simple derivatives and model peptides.
The molecular and crystal structures of one derivative and three model peptides (to the pentapeptide level) of the chiral C alpha,alpha-disubstituted glycine C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] have been determined by X-ray diffraction. The derivative is mClAc-L-(alpha Me)Val-OH, and the peptides are Z-L-(alpha Me)Val-(L-Ala)2-OMe monohydrate, Z-Aib-L-(alpha Me)Val-(Aib)2-OtBu, and Ac-(Aib)2-L-(alpha Me)Val-(Aib)2OtBu acetonitrile solvate. The tripeptide adopts a type-I beta-turn conformation stabilized by a 1----4N--H...O = C intramolecular H-bond. The tetra- and pentapeptides are folded in regular right-handed 3(10)-helices. All four L-(alpha Me)Val residues prefer phi, psi angles in the right-handed helical region of the conformational map. The results indicate that: (i) the (alpha Me)Val residue is a strong type-I/III beta-turn and helix former, and (ii) the relationship between (alpha Me)Val chirality and helix screw sense is the same as that of C alpha-monosubstituted protein amino-acids. The implications for the use of the (alpha Me)Val residue in designing conformationally constrained analogues of bioactive peptides are briefly discussed.
Amino Acid Sequence↗
New developments in the chemo-enzymatic production of amino acids.
Recent progress in the chemo-enzymatic production of amino acids is reviewed. Both recently developed commercial processes and potentially important new developments are discussed. Emphasis is placed on the use of acylases, aminopeptidases and hydantoinases. The discovery of D-specific enzymes in combination with racemases is an exciting and promising new area. Also, a goal-orientated approach towards the selective generation of these novel enzyme activities using in vivo protein engineering techniques is highlighted. The interest in dipeptide sweeteners has triggered a major research effort towards the production of L-phenylalanine and D-alanine. A number of methods for the production of these amino acids is briefly discussed. Finally, chemo-enzymatic methods for the synthesis of enantiomerically pure alpha-alkyl-alpha-amino acids are reviewed.
Amino Acids↗
Rogers' adoption model in the implementation of change.
In this era of marketplace competition and cost containment, the most efficient methods of implementing change must be utilized. Rogers' adoption of innovation theory (1972; 1983) provides a framework to identify human responses to innovation/change. The model's six categories exemplify varying degrees of acceptance or rejection behaviors. In the current paper employee responses to the implementation of a new computer system in a larger hospital in the upper midwest with implications for clinical nurse specialists will be discussed.
Adaptation, Psychological↗
Conformational characterization of the 1-aminocyclobutane-1-carboxylic acid residue in model peptides.
A series of N- and C-protected, monodispersed homo-oligopeptides (to the dodecamer level) from the small-ring alicyclic C alpha, alpha-dialkylated glycine 1-aminocyclobutane-1-carboxylic acid (Ac4c) and two Ala/Ac4c tripeptides were synthesized by solution methods and fully characterized. The conformational preferences of all the model peptides were determined in deuterochloroform solution by FT-IR absorption and 1H-NMR. The molecular structures of the amino acid derivatives Z-Ac4c-OH and Z2-Ac4c-OH, the tripeptides Z-(Ac4c)3-OtBu, Z-Ac4c-(L-Ala)2-OMe and Z-L-Ala-Ac4c-L-Ala-OMe, and the tetrapeptide Z-(Ac4c)4-OtBu were determined in the crystal state by X-ray diffraction. The average geometry of the cyclobutyl moiety of the Ac4c residue was assessed and the tau(N-C alpha-C') bond angle was found to be significantly expanded from the regular tetrahedral value. The conformational data are strongly in favour of the conclusion that the Ac4c residue is an effective beta-turn and helix former. A comparison with the structural propensities of alpha-aminoisobutyric acid, the prototype of C alpha, alpha-dialkylated glycines, and the other extensively investigated members of the family of 1-aminocycloalkane-1-carboxylic acids (Acnc, with n = 3, 5-8) is made and the implications for the use of the Ac4c residue in conformationally constrained peptide analogues are briefly examined.
Amino Acids↗
Inversion of 3(10)-helix screw sense in a (D-alpha Me)Leu homo-tetrapeptide induced by a guest D-(alpha Me)Val residue.
The terminally blocked tetrapeptide pBrBz-[D-(alpha Me)Leu]2-D-(alpha Me)Val-D-(alpha Me)Leu-OfBu is folded in the crystal state in a left-handed 3(10)-helical structure stabilized by two consecutive 1<--4 C = O...H-N intramolecular H-bonds, as determined by X-ray diffraction analysis. A CD study strongly supports the view that this conformation is also that largely prevailing in MeOH solution. A comparison with the published conformation of pBrBz-[D-(alpha Me)Leu]4-OfBu indicates that incorporation of a single internal beta-branched (alpha Me)Val guest residue into the host homo-tetrapeptide from the gamma-branched (alpha Me)Leu residue is responsible for a dramatic structural perturbation, i.e. an inversion of the 3(10) screw sense from right to left-handed.
Amino Acid Sequence↗
Candida tropicalis arthritis in a patient with acute myeloid leukemia successfully treated with fluconazole: case report and review of the literature.
The case of a 77-year-old woman with acute myeloid leukemia who developed Candida tropicalis septic arthritis of the knee after remission-inducing chemotherapy is reported. A literature review of C. tropicalis non-prosthetic arthritis is included. The isolate was susceptible to fluconazole (MIC 0.25 mg/l). She was treated with fluconazole (400 mg orally) and frequent relieving synovial aspirations. After 1 month of antifungal therapy the synovial fluid became culture negative. Fluconazole concentration in the synovial fluid and serum were 20 mg/l and 19.4 mg/l, respectively. The patient was treated for a total of 7 months and made a full recovery. This is the first report of the successful use of fluconazole in the treatment of septic arthritis due to C. tropicalis.
Aged↗
Synthesis, characterization, and solution conformational analysis of C alpha-methyl-, C alpha-benzylglycine [(alpha Me)Phe] model peptides.
We have synthesized, by solution methods, and fully characterized a variety of (alpha Me)Phe derivatives and model peptides (to the pentapeptide level). The results of the solution conformational analysis, performed by using infrared absorption and 1H nuclear magnetic resonance, support the view that the (alpha Me)Phe residue is a stronger beta-turn and helix promoter than the unmethylated Phe analog. A comparison is also made with the conclusions extracted from published work on peptides rich in other C alpha-alkylglycyl residues.
Amino Acid Sequence↗